Clinical trial NCT03567291
Conditions: Tourette Syndrome
Keywords: adolescents children
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2018-05-25; Completion date: 2020-05-15
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an otherwise open-label, single-arm study that includes a 2-week, double-blind, placebo controlled, randomized drug withdrawal period followed by a 3 week blinded maintenance or re-titration, and then a maintenance period. This study aims to evaluate the safety and efficacy of TEV-50717 tablets in patients with tics associated with TS who have previously completed participation in any of the parent studies.

Detailed description:
This is an otherwise open-label, single-arm study (Part A) that includes a 2-week, double-blind, placebo controlled, randomized drug withdrawal period (Part B) followed by a 3 week blinded maintenance or re-titration (Part A resumed), and then a maintenance period. This study aims to evaluate the safety and efficacy of TEV-50717 tablets in patients with tics associated with TS who have previously completed participation in any of the parent studies (SD-809-C-17 \[Phase 1b\], TV50717-CNS 30046 \[Phase 2/3\], or TV50717-CNS 30060 \[Phase 3\]).

Arms: arm 1: All patients will undergo TEV-50717 dose titration in this study. Patients will receive 6 mg of TEV-50717 with food on the evening of day 1. The titration scheme and maximum dose will be determined by body weight and cytochrome P450 2D6 (CYP2D6) impairment status from the parent study. arm 2: TEV-50717 is administered during Part B Randomized Drug Withdrawal (RW) 2-week period. arm 3: Placebo is administered during Part B Randomized Drug Withdrawal (RW) 2-week period only.
Interventions: intervention 1: TEV-50717 intervention 2: Placebo
Intervention descriptions: intervention 1: 6, 9, and 12 mg oral tablets intervention 2: Placebo comparator

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-
Controlled, Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for 
the Treatment of Tourette Syndrome in Children and Adolescents 
 
 
Study Number TV50717-CNS-30047 
 
 
NCT03567291 
 
 
Protocol Approval Date: 22 May 2019 


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
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Clinical Study Protocol with Amendment 04
Study Number TV50717-CNS-30047
An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-Controlled,
Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for the Treatment of 
Tourette Syndrome in Children and Adolescents
Phase 3
IND number: 127692;
NDA number: NA;
EudraCT number: 2016-000630-22
Original Protocol Approval Date: 26 February 2016
Protocol Amendment 04 Approval Date: 22 May 2019
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road
Frazer, Pennsylvania 19355
United States of America
Teva’s Development Partner
Nuvelution TS Pharma, Inc.
101 Main Street, 12th Floor
Cambridge, Massachusetts 02142
United States of America
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Conference for Harmonisation (ICH); United States (US) Code of Federal 
Regulations (CFR), and European Union (EU) Directives (as applicable in the region of the study); national country 
regulations; and the sponsor’s Standard Operating Procedures (SOPs).
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, 
and Nuvelution TS Pharma, Inc., and/or its affiliates. The recipient agrees that no information contained herein may 
be published or disclosed without written approval from the sponsor.
© 2019 Teva Branded Pharmaceutical Products R&D, Inc. and Nuvelution TS Pharma, Inc. All rights reserved.


Uncontrolled Study–Tourette Syndrome
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AMENDMENT HISTORY
The protocol for Study TV50717-CNS-30047 (original protocol dated 26 February 2016) has 
been amended and reissued as follows:
Amendment 04
22 May 2019
100 patients randomized/enrolled to date
Amendment 03
01 February 2018
No patients randomized/enrolled to date
Amendment 02
15 November 2017
No patients randomized/enrolled to date
Amendment 01
22 June 2017
No patients randomized/enrolled to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 17.


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INVESTIGATOR AGREEMENT
Original Protocol Dated 26 February 2016
Amendment 04 Dated 22 May 2019
IND number: 127692;
EudraCT number: 2016-000630-22
Article 45 or 46 of 1901/2006 does not apply
An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-Controlled,
Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for the Treatment of 
Tourette Syndrome in Children and Adolescents
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations.
Principal Investigator
Signature
Date


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SPONSOR PROTOCOL APPROVAL


Uncontrolled Study–Tourette Syndrome
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COORDINATING INVESTIGATOR AGREEMENT


Uncontrolled Study–Tourette Syndrome
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COORDINATING INVESTIGATOR AGREEMENT


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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Central Institutional Review Board
Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Central Clinical Laboratory
Q2 Solutions (Quest) LLC
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Electronic Data Capture
Medidata RAVE (through Syneos Health, LLC)
Contract Research Organization; Safety and Efficacy Data Analysis
Syneos Health, LLC
1030 Sync Street
Morrisville, NC 27560
USA
Central Electrocardiogram Evaluation
ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Integrated Response Technology
Endpoint
55 Francisco Street, Suite 200
San Francisco, CA 94133
USA
ePRO, eCOA, and Scales Training 
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
Sponsor’s Authorized Representative:
 Teva Branded Pharmaceutical Products R&D, Inc.
Email: 
Legal Representative of the Sponsor in the EU
Syneos Health Netherlands B.V.
For medical issues, contact the physician listed below:
USA
Office: 
Mobile: 
Email: 
Mobile: 
Email: 
Syneos Health, LLC
Av. del Libertador 7270 9th Floor
Ciudad de Buenos Aires, Argentina
Office: 
Mobile: 


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Fax: 
Email: 
Office: 
Mobile: 
E-mail: 
For protocol issues, contact the study leader listed below:
.
Tel: 
Email: 
Tel: 
Email: 
For operational issues, contact the Head of Operations listed below:
Tel: 
Email: 
For serious adverse events:
Send by e-mail to the local safety officer (LSO)/Syneos Health. The email address will be 
provided in the serious adverse event report form. In the event of difficulty transmitting the form, 
contact the sponsor’s study personnel identified above for further instruction.


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CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV50717-CNS-30047
Title of Study: An Open-Label, Long-Term Safety Study Including a Double-Blind, 
Placebo-Controlled, Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for the 
Treatment of Tourette Syndrome in Children and Adolescents
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc., 41 Moores Road, Frazer, 
Pennsylvania 19355 United States of America
Sponsor’s Development Partner: Nuvelution TS Pharma, Inc., 601 Gateway Boulevard, Suite 
1270, South San Francisco, California 94080, United States of America
Investigational New Drug (IND) Number: 127692
New Drug Application (NDA)
Number: Not available
EudraCT Number: 2016-000630-22
Name of Active Ingredient: Deutetrabenazine
Name of Investigational Medicinal Product (IMP): TEV-50717 (previously SD-809)
Type of the Study: Safety (Phase 3)
Number of Investigational Centers Planned: Approximately 120
Countries Planned: Global (per Study SD-809-C-17, Study TV50717-CNS-30046, and 
Study TV50717-CNS-30060)
Planned Study Period: May 2018 to January 2021 with a duration of approximately 32 months
Number of Patients Planned: Up to approximately 227 patients are planned to be enrolled
(approximately 1 patient is estimated to enroll from the Phase 1b Study SD-809-C-17, up to 
approximately 99 patients are estimated to enroll from the Phase 2/3 Study TV50717-
CNS-30046, and up to approximately 127 patients are estimated to enroll from the Phase 3 
Study TV50717-CNS-30060). 
Study Population: Male and female patients with tics associated with Tourette syndrome (TS) 
who have previously completed participation in Study SD-809-C-17, Study TV50717-
CNS-30046, or Study TV50717-CNS-30060.
Primary Objective: The primary objective of this study is to evaluate the safety and tolerability 
of long-term therapy with TEV-50717.
Secondary Objectives: The secondary objectives of this study are as follows:

to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the 
severity of TS tics

to confirm long-term maintenance of effect by means of a double-blind, 
placebo-controlled, randomized drug withdrawal period after 28 weeks of open-label 
treatment 


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Study Endpoints:
Safety Endpoints:
The following safety endpoints will be assessed in Part A (Day 1, Titration, and 
Maintenance):

incidence of adverse events 

observed values and changes from day 1 in vital signs

observed values and changes from day 1 in the Children’s Depression Inventory, 
Second Edition, Parent and Self-Report Profiles (CDI-2)

observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS)

observed values in electrocardiogram (ECG) parameters and shifts from parent study 
baseline (for patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060) or from day 1 (for patient[s] rolling over from 
Study SD-809-C-17) for clinically significant abnormal findings

observed values and changes from day 1 in clinical laboratory parameters 
(hematology, serum chemistry, and urinalysis)
The following safety endpoints will be assessed in Part B (Blinded, Randomized Drug 
Withdrawal Period and Titration Post-Drug Withdrawal):

incidence of adverse events
In addition to routine monitoring of adverse events, clinical laboratory parameters, 12-lead 
ECGs, and safety scales, an Independent Data Monitoring Committee will monitor safety 
during the conduct of the study.
Efficacy Endpoints:
The following efficacy endpoints will be assessed in Part A (Day 1, Titration, and 
Maintenance): 

change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) 
from day 1 to each visit in which the scale is administered

change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from 
day 1 to each visit in which the scale is administered

change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) 
score from day 1 to each visit in which the scale is administered

change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life
(C&A-GTS-QOL) activities of daily living (ADL) subscale score from day 1 to each 
visit in which the scale is administered
The following efficacy endpoint will be assessed in Part B (Blinded, Randomized Drug 
Withdrawal Period and Titration Post-Drug Withdrawal): 

change in the TTS of the YGTSS from week 28 to week 30, with the primary 
analyses and sensitivity testing done as described in Section 9.5.3.1


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Exploratory Endpoints:
The following exploratory endpoints will be assessed in Part A (Day 1, Titration, and 
Maintenance):
 
 
 
 
 
 
 
 
 
General Design and Methodology:
This is an open-label, single-arm study that includes a 2-week, double-blind, placebo-controlled, 
randomized drug withdrawal period followed by a 3-week blinded re-titration period in which 
patients with tics associated with TS may be eligible to participate after successful completion of 
any of the parent studies (SD-809-C-17 [Phase 1b], TV50717-CNS-30046 [Phase 2/3], or 
TV50717-CNS-30060 [Phase 3]). Patients rolling over from Study SD-809-C-17 will need to 
undergo all day 1 assessments. For patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, the week 13 visit (Study TV50717-CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) will be the day 1 visit for Study TV50717-CNS-30047. If the 
patient does not wish to enroll in Study TV50717-CNS-30047 at that visit, they can enroll up to 
1 week following the week 13 or week 9 visits, respectively. The end of study is defined as the 
date of the week 56 visit of the last participant.
Patients who have successfully completed a parent study may be eligible to enroll in this study 
after they complete a 1-week washout period and the final evaluation at week 13 (TV50717-
CNS-30046) or week 9 (TV50717-CNS-30060) in the parent study. 
Site-administered scales include the YGTSS, 
, Mini International Neuropsychiatric 
Interview For Children and Adolescents (MINI Kid, version 6.0), and the C-SSRS; and 
self-administered scales include the TS-PGII, 
, 
, CDI-2, and 
C&A-GTS-QOL. For the YGTSS, input from the caregiver/adult is required. For 
 
TS-PGII 
, input from the caregiver/adult is permitted. For all other scales, for 


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children 13 years of age and under, interviews may be performed separately or jointly with the 
caregiver/adult as appropriate or as defined by the scale. For children over 13 years of age, 
caregiver/adult involvement is strongly encouraged. Questions should be directed to the child, 
but the caregiver/adult should be encouraged to add relevant information. It should be noted that 
the CDI-2 has individual parent and child questionnaires.
Informed consent/assent, depending on the child’s age, as appropriate, will be obtained before 
any study procedures are performed. For patients rolling over from Study TV50717-CNS-30046 
or Study TV50717-CNS-30060, informed consent/assent, as appropriate, may be obtained prior 
to the day 1 visit, up to 4 weeks in advance of open-label study participation. Any patient that 
turns 18 years of age during the course of Study TV50717-CNS-30047 will need to be 
re-consented as an adult.
In the study period descriptions below, “week X” refers to the end of that week, which coincides 
with the study visit, unless stated otherwise. Some dose changes will occur at the start of a week 
rather than at the end of a week and will be indicated as such.
Screening 
For patients from Study SD-809-C-17:
During the screening period (up to 31 days), all screening procedures will be performed for 
patients rolling over from Study SD-809-C-17 as they will have been off IMP for several months 
at the time of enrollment into this study. 
After informed consent/assent, depending on the child’s age, as appropriate, is obtained, patients 
who are stable from a medical and psychiatric standpoint will undergo a screening evaluation, 
including medical history, physical and neurological examination, assessment of vital signs, 
laboratory testing, and 12-lead ECG, along with rating scales to assess comorbid TS symptoms 
and behavioral status.
At the discretion of the investigator, the screening visit may be divided into 2 visits if the visit 
length is deemed to be too burdensome for the patient. Patients may be rescreened 1 time if there 
is a change in the patient’s medical background, a modification of study entry criteria, or other 
relevant change. (Note: Details of rescreening must be approved and documented by the medical 
monitor and/or Clinical Surveillance and Training team.) For patients from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060:
The screening evaluation for this open label study occurs at the end of the treatment period in the 
double-blind study. To reduce patient burden and not collect duplicate information, after 
obtaining informed consent/assent, depending on the child’s age, as appropriate, relevant data 
collected in Study TV50717-CNS-30046 or Study TV50717-CNS-30060 will be used to provide 
corresponding data in this open-label study (see Table 1).
YGTSS Rater Certification: All investigators and subinvestigators who will be administering the 
YGTSS from screening through the end of study visit must undergo and pass a Rater 
Certification Program which will be provided separately from this protocol. Every effort must be 
made to ensure that the same certified rater administers the YGTSS to a specific patient at all 
visits where this scale is administered, especially at day 1 and at weeks 28, 30, and 54/early 
termination visits. However, if due to unforeseen circumstances the same rater is absolutely 
unavailable to complete a visit rating, the YGTSS can be administered only by another certified 
individual from that study site.


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Part A: 
Day 1 visit (all patients): For patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, the week 13 visit (Study TV50717-CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) will be the day 1 visit for Study TV50717-CNS-30047. Patients 
rolling over from Study SD-809-C-17 will need to undergo all day 1 assessments. Day 1
assessments for Study TV50717-CNS-30047 that are identical to Study TV50717-CNS-30046 
week 13 or Study TV50717-CNS-30060 week 9 visit assessments do not need to be repeated.
Additionally, Study TV50717-CNS-30047 required evaluations will be completed at 
Study TV50717-CNS-30046 week 13 visit or Study TV50717-CNS-30060 week 9 visit (see
Table 1). For all patients, the day 1 visit should occur on or as close as possible to the week 13 or 
week 9 visit from Study TV50717-CNS-30046 and Study TV50717-CNS-30060, respectively, 
but not >7 days beyond those respective visits.
For patients with clinically significant laboratory abnormalities at week 12 in Study TV50717-
CNS-30046 or at week 8 in Study TV50717-CNS-30060, week 13 values (Study TV50717-
CNS-30046) or week 9 values (Study TV50717-CNS-30060) will serve as day 1 laboratory 
values in this study. 
Titration period (7 weeks): As patients from Study SD-809-C-17 will have been off IMP for 
several months at the time of enrollment, and since patients from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 will have discontinued IMP (TEV-50717 or placebo) for at least 
1 week at completion of the parent study, all patients will undergo TEV-50717 dose titration in 
this study. Patients will receive 6 mg of TEV-50717 with food on the evening of day 1. Tablets 
should be taken with food (eg, a snack) and should not be taken on an empty stomach. The 
titration scheme and maximum dose will be determined by body weight and cytochrome P450 
2D6 (CYP2D6) impairment status from the parent study. Patients will be classified as CYP2D6 
impaired if they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 poor metabolizer 
based on blinded assessment of CYP2D6 genotype at baseline of the parent study. Patients who 
are CYP2D6 impaired will have a dose cap in the open-label trial, as shown in the table below. 
Patients and their caregiver/adult will interact weekly with the clinical research staff, either by 
telephone contact or in-clinic visits from week 1 through week 7 of the titration period, in order 
to evaluate safety and establish a dose of TEV-50717 that optimally reduces tics and is well 
tolerated (optimal dose). Safety evaluations during the titration period include assessment of vital 
signs, monitoring for adverse events and concomitant medications, 12-lead ECGs, and rating 
scales for depression and suicidality. 
In-person (in-clinic) study visits will be scheduled at weeks 2, 4, and 6, and telephone contacts 
will be scheduled for weeks 1, 3, 5, and 7 in order to assess tic severity and adverse events. 
The dose of the IMP should be increased on a weekly basis until one of the following occurs:

The investigator determines there has been a clinically meaningful reduction in tics.

The patient experiences a protocol-defined “clinically significant” adverse event 
(defined as an adverse event that is related to the IMP and is either moderate or severe 
in intensity or meets the criteria for a serious adverse event).

The maximum allowable dose is reached based on the patient’s weight and CYP2D6 
impairment status.


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If a stable dose is reached before the week 7 telephone call, the patient should continue on that 
dose (ie, the dose should not be increased further) for the remainder of the titration period. If a 
patient experiences depression, suicidal ideation or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes with daily activity, or adverse event that is 
related to IMP, the investigator will determine if a dose reduction or suspension is necessary. If 
the patient requires a dose reduction or suspension during a telephone contact, an unscheduled
in-clinic visit should be conducted as soon as practicable thereafter.
Dose adjustments should be made based on all available information, including the patient and 
caregiver/adult reports of adverse events and tic reduction, the clinical assessment of safety and 
efficacy by the investigator, and the information from rating scales.
Maximum Daily Dose of IMP by Study Day and Weight Category on Day 1 for Titration at 
Study Initiation
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP 
impairment 
status
Not 
impaired
Impaired
Not 
impaired
Impaired
Not 
impaired
Impaired
Day 1-7
6 mg
6 mg
6 mg
6 mg
6 mg (Days 
1 and 2)
12 mgb
6 mg (Days 
1 and 2)
12 mgb
Day 8-14
12 mg
12 mg
12 mg
12 mg
18 mg
18 mg
Day 15-21
18 mg
18 mg
18 mg
18 mg
24 mg
24 mg
Day 22-28
18 mg
18 mg
24 mg
24 mg
30 mg
30 mg
Day 29-35
24 mg
18 mg
30 mg
24 mg
36 mg
36 mg
Day 36-42
24 mg
18 mg
36 mg
24 mg
42 mg
36 mg
Day 43-49
30 mg
18 mg
42 mg
24 mg
48 mg
36 mg
a Administration of a given dose will take place throughout the days indicated. The new dose starts the morning 
after the telephone contact or the morning after the clinic visit as applicable.
b Patients will receive 6 mg on days 1 and 2, and 12 mg starting on day 3.
CYP=cytochrome P450; IMP=investigational medicinal product.
Note: CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor
metabolizer. The investigator, in consultation with the patient and caregiver/adult, will determine if a dose increase 
is warranted to achieve optimal tic reduction.


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Maintenance period: At the end of the titration period, the patient’s initial dose for the 
maintenance period will be established. Dose adjustments of TEV-50717 (upward or downward) 
may be made during the maintenance period, if necessary, but not more often than every 5 days 
and only in increments of 6 mg. As during titration, dose adjustments should be made based on 
all available information.
During the maintenance period, in-person (in-clinic) study visits will be scheduled at weeks 8, 
15, 34, 41, and 54 for assessments of safety and efficacy and telephone contacts will be 
scheduled for weeks 21 and 47 in order to assess adverse events and tic severity. The randomized 
drug withdrawal and re-titration period (Part B) will occur from the end of week 28 through the 
end of week 33, and then the Part A maintenance period will resume, along with the ability to 
make dose adjustments as described above. At week 54, patients will undergo a complete 
evaluation, including physical and neurological examination, safety laboratory testing, 12-lead 
ECG, CDI-2, and C-SSRS assessments, as well as the YGTSS, TS-CGI, 
, TS-PGII, 
, and C&A-GTS-QOL. 
Washout and follow-up period: All patients will discontinue IMP at the week 54 visit and will 
return 1 week later (week 55) for evaluation of safety and tic reduction. Patients will have a 
follow-up telephone contact for safety evaluation 1 week after the end of the washout period 
(2 weeks after their last dose of IMP) (week 56).
Part B: Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal 
(5 weeks): At the week 28 visit, the patients will be randomized 2:1 to their current dose of 
TEV-50717 or placebo in order to check for the return of symptoms. Because IMP is dispensed 
as enough doses for 2 weeks (current dose level and next dose level), the week 28 visit 
(Day 196) is considered the first day of the randomized withdrawal period, although the patient 
will begin taking blinded IMP the next morning on Day 197. Patients will have a follow-up 
telephone contact for safety evaluation 1 week after the start of the randomized drug withdrawal 
period. At week 30, safety and efficacy will be assessed. At the week 30 visit, patients who 
receive TEV-50717 during the randomized drug withdrawal period will continue at the same
dose in a blinded manner from the start of week 31 to the start of week 34. Any patient who was 
randomized to placebo during the 2-week randomized drug withdrawal period will undergo 
blinded re-titration (titration post-drug withdrawal) to their previously established maintenance
dose over the 3 weeks of treatment following the randomized drug withdrawal period (start of 
week 31 through start of week 34 [Days 211 through 232]). The titration scheme and maximum 
dose will be determined based on the previously established maintenance dose as tabulated 
below. The dose of IMP for each patient who underwent 2 weeks of placebo will be titrated back 
to the maintenance dose that was used by the patient up to week 28 followed by continued 
maintenance therapy at that dose. Patients will have a follow-up telephone contact for safety 
evaluation at weeks 31 and 33. All patients should be back at their maintenance dose on or 
before the start of week 34 and return to open-label treatment for the remainder of the study
(note that, because IMP is dispensed for 2-week periods, patients will use blinded bottles through 
the end of week 34; however, all patients will be known to be on active treatment at the start of 
week 34).


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Daily Dose of IMP by Previously Established Maintenance Dose and Study Week 
(Titration Post-Drug Withdrawal) for Patients Randomized to Placebo During the Blinded, 
Randomized Drug Withdrawal Period
Daily dose (mg) at the start of week
Previously established 
maintenance dosea (mg)
Day 211 
(start of 
week 31)
Day 218 
(start of 
week 32)
Day 225 
(start of 
week 33)
Day 232 (start of 
week 34) 
maintenance dose
6
6
6
6
6
12
12
12
12
12
18
12
18
18
18
24
12
18
24
24
30
12
18
24
30
36
12
24
30
36
42
12
24
36
42
48
12
24
36
48
a The previously established maintenance dose is the dose administered at the end of Part A (Day 196 [end of 
week 28]). The blinded, randomized drug withdrawal period will occur from the start of week 29 through the end 
of week 30.
IMP=investigational medicinal product.
Method of Randomization and Blinding: This is an open-label study that includes a 2-week
double-blind, placebo-controlled, randomized drug withdrawal period followed by a 3-week 
blinded re-titration period (note that, because IMP is dispensed for 2-week periods, patients will 
use blinded bottles for an additional 1 week [4 weeks total after the end of the blinded, 
randomized withdrawal period]; however, all patients will be known to be on active treatment 
during that week). During the blinded drug withdrawal and re-titration period, patients and 
investigators will remain blinded to treatment assignment. In addition, the sponsor’s and 
development partner’s clinical personnel and all vendors (with the exception of the Interactive 
Response Technology (IRT) vendor and the IMP packaging vendor) involved in the study will be 
blinded to the IMP identity until the database has been locked for analysis and the treatment 
assignments are revealed.
IMP Dose, Mode of Administration, and Administration Rate:
IMP will be administered as oral tablets at a starting dose of 6 mg once daily, to be taken in the 
morning (except for day 1, when it should be taken in the evening after the clinic visit). Titration 
schemes based on body weight are shown in the first table above (“Titration period [7 weeks]”
section). The maximum daily dose is determined by body weight and CYP2D6 impairment status 
(see the first table above). Dose adjustments can be made during the titration period and also, if 
clinically indicated, during the maintenance period dosing before and after the randomized drug 
withdrawal and re-titration period.
During the open-label period, TEV-50717 tablets are available in the following dose strengths: 6, 
9, and 12 mg. Each dose strength will have a marking of SD 6, SD 9, and SD 12 corresponding 


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
18
to the dose strength and a distinct color: 6 mg – purple, 9 mg – blue, and 12 mg – beige. IMP
will be supplied in 20-or 60-count tablets per dose strength per bottle.
During the randomized drug withdrawal and re-titration period, TEV-50717 tablets are available 
in the following dose strengths: 6, 9, 12, 15, and 18 mg, all of which are identical in size, shape, 
and color (white). The IMP will be supplied in 20-count bottles. The placebo tablets and 
packaging will match those for TEV-50717. 
Patients who receive TEV-50717 during the randomized drug withdrawal period will remain on 
their maintenance dose of blinded active IMP from the start of week 31 to the start of week 34; 
those assigned to placebo during the randomized drug withdrawal period will undergo blinded 
re-titration from the start of week 31 to the start of week 34 back to their previously established 
maintenance dose from the end of week 28. Note that, because IMP is dispensed for 2-week 
periods, patients will use blinded bottles through the end of week 34; however, all patients will 
be known to be on active treatment at the start of week 34. 
IMP will be administered as follows:

IMP should be swallowed whole and taken with food. Tablets should be taken with 
food (eg, a snack) and should not be taken on an empty stomach.

Dosing will be based on body weight and strong CYP2D6 impairment status, as 
shown in the tables above.

The starting dose is 6 mg in all patients. With the exception of the 6-mg dose 
(administered once daily), doses will be administered twice daily, approximately 
8 to 10 hours apart during the day. A minimum of 6 hours should elapse between 
doses. If a patient misses a dose and it is within 6 hours of their next dose, the missed 
dose should be skipped. 

After week 1, dose increases may not occur more frequently than every 5 days.

Dose reductions, if required, should be in increments of 6 mg. If more than 1 dose 
reduction is required for an adverse event, the medical monitor should be 
notified.

After dose adjustment, if the maintenance dose for a patient is 6 mg, the dose should 
be taken once a day in the morning with food.

During the titration period, the dose of IMP should be adjusted according to the first 
table above (Maximum Daily Dose of IMP by Study Day and Weight Category on 
Day 1 for Titration at Study Initiation) to identify a dose level that optimally reduces 
tics and is well tolerated. A dose cap for impaired patients is prespecified by the IRT.

After week 24, patient dose should be kept stable, if possible, until beginning Part B.

During the randomized drug withdrawal period, the patient will continue to receive 
their current dose of TEV-50717 or receive matching placebo until returning to their 
dose of TEV-50717 at the start of week 31 (patients who receive TEV-50717 during 
the randomized drug withdrawal period will remain on their maintenance dose of 
blinded active IMP from the start of week 31 to the start of week 34; those assigned 
to placebo during the randomized drug withdrawal period will undergo blinded re-


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
19
titration from the start of week 31 to the start of week 34 back to their previously 
established maintenance dose from the end of week 28). 
IMP: TEV-50717
Placebo: Placebo tablets and packaging match TEV-50717 tablets
Duration of Patient Participation: For patients rolling over from Study SD-809-C-17, this 
study will consist of a 4-week screening period (up to 31 days) and up to 54 weeks of treatment. 
All participating patients are expected to participate in this study for its entire duration, which is 
a minimum of 56 weeks. Patients will have a follow-up telephone contact to evaluate safety 
1 week after the end of the washout period (2 weeks after their last dose of IMP). Any patient 
that turns 18 years of age during the course of Study TV50717-CNS-30047 will need to be 
re-consented as an adult. The end of study is defined as the date of the week 56 visit of the last 
participant.
Inclusion Criteria: Patients who have completed Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 have already met the criteria below.
In addition, patients who have completed Study SD-809-C-17 may be included in the study if, 
during screening, they meet all of the following criteria:
a.
Patient is younger than 18 years of age on day 1.
b. Patient weighs at least 44 pounds (20 kg) on day 1. 
c.
Patient is able to swallow IMP whole.
d. Patient and caregiver/adult are willing to adhere to IMP regimen and comply with all 
study procedures.
e.
Patient is in good general health, as indicated by medical and psychiatric history as 
well as physical and neurological examination.
f.
In the investigator’s opinion, the patient and caregiver/adult have the ability to 
understand the nature of the study and its procedures, and the patient is expected to 
complete the study as designed.
g. Patient and caregiver/adult provide written informed consent/assent, depending on the 
child’s age, as appropriate, according to local regulations.
h. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative beta-human chorionic gonadotropin (β-HCG) test on day 1 or are 
sterile. Definitions of sterile are given in Appendix L.
i.
Females who are postmenarchal or ≥12 years of age whose male partners are 
potentially fertile (ie, no vasectomy) must use highly effective birth control methods 
for the duration of the study (ie, starting at screening) and for 30 days or 5 half-lives, 
whichever is longer after last dose of IMP. Further details are included in
Appendix L.


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20
Exclusion Criteria: Patients will not be enrolled in this study if they meet any of the following 
criteria:
Patients who have completed Study TV50717-CNS-30046 or Study TV50717-CNS-30060 have 
already been confirmed to not meet any of the criteria below.
In addition, patients who have completed Study SD-809-C-17 will not be enrolled if, during 
screening, they meet any of the following criteria:
a.
Patient is 18 years of age or older.
b. Patient has a neurologic disorder other than TS that could obscure the evaluation of 
tics.
c.
The patient’s predominant movement disorder is stereotypy (coordinated movements 
that repeat continually and identically) associated with autism spectrum disorder. 
d. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another 
psychotic disorder.
e.
Patient has clinically significant depression at screening or day 1. 
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 6 weeks before screening.
f.
Patient has a history of suicidal intent or related behaviors within 2 years of 
screening:

previous intent to act on suicidal ideation with a specific plan, irrespective of level 
of ambivalence, at the time of suicidal thought

previous suicidal preparatory acts or behavior
g. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
h. Patient has a first-degree relative who has completed suicide.
i.
Patient has clinically significant obsessive-compulsive disorder (OCD) on day 1 that, 
in the opinion of the investigator, is the primary cause of impairment.
j.
Patient has received comprehensive behavioral intervention for tics for TS or 
cognitive behavioral therapy for OCD within 4 weeks of screening.
k. Patient has received any of the following concomitant medications for tics within the 
specified exclusionary windows of screening prior to dosing for washout:

within 3 months: depot neuroleptics, botulinum toxin, or tetrabenazine

within 4 weeks: cannabidiol oil or valbenazine 

within 21 days: reserpine 

within 14 days: neuroleptics (oral), typical and atypical antipsychotics (see
Appendix A, Table 7), metoclopramide, levodopa, and dopamine agonists
Note: Use of stimulant medications, including amphetamine, methylphenidate, 
and lisdexamfetamine, is allowed if primary use is for the treatment of ADHD,
dosing has been stable for at least 2 weeks before screening. 
Note: Use of atomoxetine is allowed if the primary use is for the treatment of 
ADHD, dosing has been stable for at least 4 weeks before screening. 
Note: Use of benzodiazepines is allowed if the primary use is not for tics, and 
dosing has been stable for at least 4 weeks before screening.
Note: Use of topiramate (up to 200 mg/day) is allowed if the dosing has been 
stable for at least 4 weeks before screening. 
Note: Use of guanfacine or clonidine is allowed regardless of indication (ie, if 
prescribed for tics or Tourette syndrome) if the dosing has been stable for at least 


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Study TV50717-CNS-30047
21
4 weeks before screening and no changes to dose or frequency are anticipated 
during the course of the study.
l.
Patient has an unstable or serious medical illness at screening or day 1.
m. Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
interval value >450 msec (males) or >460 msec (females), or >480 msec (with right 
bundle branch block) on 12-lead ECG at screening. Patient requires treatment with 
drugs known to prolong the QT interval (see Appendix A Table 8 for a complete list 
of prohibited QT-prolonging drugs).
n. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart failure.
o. Patient has evidence of hepatic impairment, as indicated by:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the 
upper limit of the normal range (ULN) at screening

alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
Note: Patients with Gilbert’s Syndrome are eligible to participate if approved by 
the medical monitor. 
Note: Patients with abnormalities in 2 or more of the following clinical laboratory 
parameters must be approved for enrollment by the medical monitor: AST, ALT, 
ALP, and Tbil. 
p. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5 × ULN at screening. 
q. Patient has received a monoamine oxidase inhibitor within 14 days of the day 1 visit.
r.
Patient has a known allergy to any of the components of the IMP.
s.
Patient has participated in an investigational drug or device study (with the exception 
of Study SD-809-C-17, Study TV50717-CNS-30046, or Study TV50717-
CNS-30060) and received IMP/intervention within 30 days.
t.
The patient is a pregnant or lactating female or plans to become pregnant during the 
study.
u. Patient has a history of, or acknowledges, alcohol-related disorder in the previous 
12 months, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-V™).
v. Patient has a positive urine drug screen test result or is unable to refrain from 
substance abuse throughout the study.
w. Patient has a DSM diagnosis based on the MINI Kid modules performed at screening 
that, in the opinion of the investigator, makes the patient unsuitable for the study (for 
patients rolling over from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060, these data will be obtained from the screening visit of the parent study).
Measures and Time Points:
Safety Measures and Time Points
Part A:

adverse events and concomitant medications: from the signing of the informed 
consent/assent, depending on the child’s age, as appropriate, through follow-up, 
inclusive of all visits and telephone contacts

physical examination: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients) and week 54


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
22

neurological examination: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients) and week 54

vital signs, height, and weight: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients); day 1; and weeks 2, 4, 6, 8, 
15, 34, 41, 54, and 55
Note: orthostatic blood pressure (BP) and pulse on day 1 and weeks 4, 8, and 54

MINI Kid: screening (only for patients who completed Study SD-809-C-17)

Children’s C-SSRS:

Baseline/screening scale: screening (only for patients who completed 
Study SD-809-C-17)

Since Last Visit (SLV) scale: day 1 (only for patients who completed 
Study SD-809-C-17) and weeks 2, 4, 8, 15, 34, 41, 54, and 55

CDI-2 (Parent and Self-Report Profiles): screening and day 1 (only for patients who 
completed Study SD-809-C-17) and weeks 2, 4, 8, 15, 34, 41, 54, and 55

12-Lead ECG: screening (only for patients who completed Study SD-809-C-17); day 
1; and weeks 4, 8, and 54

clinical laboratory tests (serum chemistry, hematology, and urinalysis): screening 
(only for patients who completed Study SD-809-C-17; data from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 should be used for the remaining 
patients); day 1; and weeks 8 and 54

pregnancy testing (β-HCG): screening (only for patients who completed 
Study SD-809-C-17); day 1; and weeks 4, 8, 15, 34, and 54 (serum tests at screening 
and week 54 and urine tests at other visits) 

drug screen: screening (only for patients who completed Study SD-809-C-17)
Part B:

adverse events and concomitant medications: from the signing of the informed 
consent/assent, depending on the child’s age, as appropriate, through follow-up, 
inclusive of all visits and telephone contacts

physical examination: weeks 28 and 30

vital signs, height, and weight: weeks 28, 30, and 32

Note: orthostatic BP and pulse at week 28

Children’s C-SSRS:

SLV version: weeks 28 and 30

CDI-2 (Parent and Self-Report Profiles): weeks 28 and 30

12-lead ECG: week 28

clinical laboratory tests (serum chemistry, hematology, and urinalysis): week 28

pregnancy testing: week 28


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
23
Efficacy Measures and Time Points:
Part A and Part B:

YGTSS: screening (only for patients who completed Study SD-809-C-17); day 1
(ie, week 13 data from Study TV50717-CNS-30046 or week 9 data from 
Study TV50717-CNS-30060); and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 55

TS-CGI: day 1 (ie, week 13 data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

TS-PGII: day 1 (ie, week 13 data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

C&A-GTS-QOL (ADL subscale): day 1 and weeks 6, 28, 34, and 54
Exploratory Measures and Time Points:
Part A and Part B:
 
 
 
Allowed and Prohibited Medications before and during the Study: 
See Appendix A for details of allowed and disallowed medications. 
Statistical Considerations:
Sample Size Rationale: This is an open-label study. The sample size for this study is not based 
on statistical considerations; hence, only descriptive statistics will be presented and will be 
analyzed by age group at baseline. Up to approximately 227 patients who also meet patient 
exclusion/inclusion criteria will be enrolled (approximately 1 patient is estimated to enroll from 
the Phase 1b Study SD-809-C-17, up to approximately 99 patients are estimated to enroll from the 
Phase 2/3 Study TV50717-CNS-30046, and up to approximately 127 patients are estimated to 
enroll from the Phase 3 Study TV50717-CNS-30060).
For the randomized drug withdrawal period, 190 patients to be included in the analysis will 
provide approximately 90% power to detect a difference between TEV-50717-treated and 
placebo-treated patients assuming a difference in YGTSS TTS of 4.5 with a standard deviation of 
9 using a two-sided test for difference at a significance level of 0.05.
Planned Interim Analysis:
When approximately 100 patients have completed the 28-week clinic visit, an interim analysis,
including data from day 1 and up to week 28 visit only, will be conducted to provide descriptive, 
long-term safety and efficacy data to be used in regulatory submissions. To maintain data 
integrity of Study TV50717-CNS-30047, only a limited number of personnel who do not have 
contact with the sites will have access to this interim data in preparation for the regulatory filing. 


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
24
As no decisions regarding conduct of the study will be made based on the descriptive interim 
analysis, no alpha will be spent.
Analyses of Safety: All adverse events will be coded using the Medical Dictionary for 
Regulatory Activities. Each patient will be counted only once in each preferred term or system 
organ class category for the analyses of safety. Summaries will be presented for all adverse 
events, adverse events determined by the investigator to be related to IMP, serious adverse events, 
and adverse events causing withdrawal from the study. Patient listings of serious adverse events 
and adverse events leading to withdrawal will be presented.
Observed values and changes from day 1 in laboratory results and vital signs will be summarized 
descriptively. 
Observed values in ECG parameters will be summarized, and counts and percentages of abnormal 
findings will be presented. Changes from parent study baseline (for patients rolling over from 
Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or from day 1 (for patient[s] rolling 
over from Study SD-809-C-17) in ECG parameters will be summarized descriptively. In addition, 
the number and percentage of patients with on-treatment QTcF values >450, >480, or >500 msec 
and change from baseline (Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or day 1
(Study SD-809-C-17) >30 or >60 msec will be presented.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with IMP.
Observed values in the Children’s C-SSRS and observed values and changes from day 1 in the 
CDI-2 (Parent and Self-Report Profiles) will be presented for all patients.
 
 
 
 
 
 
 
 
 


Uncontrolled Study–Tourette Syndrome
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25
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............7
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................8
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................34
1.
BACKGROUND INFORMATION...........................................................................37
1.1.
Introduction.................................................................................................................37
1.2.
Name and Description of Investigational Medicinal Product.....................................38
1.3.
Findings from Nonclinical and Clinical Studies.........................................................38
1.3.1.
Nonclinical Studies.....................................................................................................38
1.3.1.1.
Nonclinical Pharmacology..........................................................................................38
1.3.1.2.
Nonclinical Pharmacokinetics and Drug Metabolism................................................39
1.3.1.3.
Toxicology..................................................................................................................39
1.3.2.
Clinical Studies...........................................................................................................40
1.3.2.1.
Clinical Pharmacology Studies...................................................................................40
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................41
1.3.2.3.
Pharmacometrics Analysis of TEV-50717 Active Metabolites to Support 
Dose Selection and Pharmacokinetic Characterization in a Pediatric 
Population...................................................................................................................41
1.4.
Known and Potential Benefits and Risks to Patients..................................................42
1.5.
Selection of Investigational Medicinal Product and Doses........................................42
1.5.1.
Justification for Dose of Active Drug.........................................................................42
1.6.
Compliance Statement................................................................................................42
1.7.
Study Population and Justification .............................................................................43
1.8.
Location and Study Duration......................................................................................43
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................44
2.1.
Purpose of the Study...................................................................................................44
2.2.
Study Objectives.........................................................................................................44


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2.2.1.
Primary Objective.......................................................................................................44
2.2.2.
Secondary Objectives .................................................................................................44
2.3.
Study Endpoints..........................................................................................................44
2.3.1.
Safety Endpoints.........................................................................................................44
2.3.2.
Efficacy Endpoints......................................................................................................45
2.3.3.
Exploratory Endpoints................................................................................................45
3.
STUDY DESIGN .......................................................................................................47
3.1.
General Design and Study Schematic Diagram..........................................................47
3.1.1.
Screening Period (up to 31 days)................................................................................49
3.1.2.
Day 1 Visit (All Patients) ...........................................................................................50
3.1.3.
Titration Period (7 Weeks) .........................................................................................50
3.1.4.
Maintenance Period ....................................................................................................51
3.1.5.
Washout Period and Follow-up ..................................................................................52
3.1.6.
Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug 
Withdrawal Period (5 Weeks) ....................................................................................52
3.2.
Justification for Study Design and Placebo-Controlled Randomized Drug
Withdrawal .................................................................................................................52
3.3.
Safety Measures and Time Points...............................................................................53
3.4.
Efficacy Measures and Time Points ...........................................................................55
3.4.1.
Efficacy Measures and Time Points ...........................................................................55
3.4.2.
Exploratory Measures and Time Points......................................................................55
3.5.
Randomization and Blinding......................................................................................55
3.6.
Maintenance of Randomization and Blinding............................................................56
3.6.1.
Maintenance of Randomization..................................................................................56
3.6.2.
Blinding and Unblinding ............................................................................................56
3.7.
Independent Data Monitoring Committee..................................................................57
3.8.
Investigational Medicinal Product and Placebo Used in the Study............................57
3.9.
Drug Supply and Accountability ................................................................................58
3.9.1.
Drug Storage and Security..........................................................................................58
3.9.2.
Drug Accountability ...................................................................................................58
3.10.
Duration of Patient Participation and Justification.....................................................58
3.11.
Stopping Rules and Discontinuation Criteria .............................................................59
3.12.
Source Data Recorded on the Case Report Form.......................................................59


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3.13.
Study Procedures and Assessments............................................................................59
3.13.1.
Procedures for Screening and Enrollment (Visit 1)....................................................66
3.13.1.1.
YGTSS Rater Certification.........................................................................................67
3.13.2.
Procedures Before Investigational Medicinal Product Treatment (Day 1) ................67
3.13.3.
Procedures During Investigational Medicinal Product Treatment .............................69
3.13.3.1.
Titration Period (Weeks 1 to 7) ..................................................................................69
3.13.3.2.
Maintenance Period (Part A: Weeks 8 to 21 and Weeks 34 to 54/Early 
Termination) and Part B: Weeks 30 to 33 ..................................................................71
3.13.3.3.
Part B: Blinded, Randomized Drug Withdrawal Period/Titration Post-Drug 
Withdrawal Period (Weeks 28 to 33) .........................................................................73
3.13.4.
Procedures After Investigational Medicinal Product Treatment (Follow-Up)...........75
3.13.4.1.
In-Clinic Visit (Week 55)...........................................................................................75
3.13.4.2.
Telephone Contact (Week 56)....................................................................................76
3.13.5.
Unscheduled Visits .....................................................................................................76
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................78
4.1.
Patient Inclusion Criteria ............................................................................................78
4.2.
Patient Exclusion Criteria...........................................................................................78
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................80
4.4.
Withdrawal Criteria and Procedures...........................................................................80
5.
TREATMENT OF PATIENTS..................................................................................82
5.1.
Investigational Medicinal Products Administered During the Study.........................82
5.1.1.
Drug Administration...................................................................................................82
5.2.
Restrictions .................................................................................................................85
5.3.
Prior and Concomitant Medication or Treatment.......................................................85
5.4.
Procedures for Monitoring Patient Compliance .........................................................86
5.5.
Dose Reduction and Temporary Investigational Medicinal Product
Discontinuation...........................................................................................................86
5.6.
Total Blood Volume ...................................................................................................87
6.
ASSESSMENT OF EFFICACY ................................................................................88
6.1.
Efficacy and Exploratory Measures............................................................................88
6.1.1.
Tourette Syndrome–Clinical Global Impression........................................................88
6.1.2.
Tourette Syndrome-Patient Global Impression of Impact..........................................88
6.1.3.
89


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6.1.4.
.89
6.1.5.
Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Scale ...........89
6.1.6.
89
7.
ASSESSMENT OF SAFETY.....................................................................................91
7.1.
Adverse Events ...........................................................................................................91
7.1.1.
Definition of an Adverse Event ..................................................................................91
7.1.2.
Recording and Reporting of Adverse Events .............................................................91
7.1.3.
Severity of an Adverse Event .....................................................................................92
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............93
7.1.5.
Serious Adverse Events..............................................................................................93
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................93
7.1.5.2.
Expectedness...............................................................................................................94
7.1.5.3.
Reporting a Serious Adverse Event............................................................................95
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................96
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................97
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................97
7.2.
Psychometric Rating Scales........................................................................................97
7.2.1.
Mini International Neuropsychiatric Interview for Children and Adolescents, 
(version 6.0)................................................................................................................97
7.2.2.
Columbia-Suicide Severity Rating Scale....................................................................98
7.2.3.
Children’s Depression Inventory, Second Edition, Parent and Self-Report 
Profiles........................................................................................................................99
7.3.
Pregnancy ...................................................................................................................99
7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Product.....................................................................................................100
7.5.
Clinical Laboratory Tests .........................................................................................101
7.5.1.
Serum Chemistry, Hematology, and Urinalysis .......................................................101
7.5.2.
Other Clinical Laboratory Tests ...............................................................................102
7.5.2.1.
Human Chorionic Gonadotropin Tests.....................................................................102
7.5.2.2.
Urine Drug Screen ....................................................................................................102
7.6.
Vital Signs ................................................................................................................102
7.7.
Electrocardiography..................................................................................................103
7.8.
Physical Examinations..............................................................................................103


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7.9.
Assessment of Suicidality.........................................................................................104
7.10.
Neurological Examinations ......................................................................................105
7.11.
Concomitant Medication or Treatment.....................................................................105
7.12.
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data...........................................................................................................................105
8.
ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS............106
9.
STATISTICS ............................................................................................................107
9.1.
Sample Size and Power Considerations ...................................................................107
9.2.
Analysis Sets.............................................................................................................107
9.2.1.
Intent-to-Treat Analysis Set......................................................................................107
9.2.2.
Safety Analysis Set...................................................................................................107
9.2.3.
Randomized Withdrawal ITT Population.................................................................107
9.2.4.
Randomized Withdrawal Safety Population.............................................................108
9.2.5.
Randomized Withdrawal Modified Intent-to-Treat Population ...............................108
9.2.6.
Responder Randomized Withdrawal Modified Intent-to-Treat Population .............108
9.3.
Data Handling Conventions......................................................................................108
9.4.
Study Population.......................................................................................................108
9.4.1.
Patient Disposition....................................................................................................108
9.4.2.
Demographic and Baseline Characteristics ..............................................................108
9.5.
Efficacy Analysis......................................................................................................109
9.5.1.
Efficacy Endpoints....................................................................................................109
9.5.2.
Exploratory Endpoints..............................................................................................109
9.5.3.
Planned Method of Analysis.....................................................................................110
9.5.3.1.
Efficacy Analysis for the Randomized Drug Withdrawal Period ............................110
9.6.
Multiple Comparisons and Multiplicity....................................................................110
9.7.
Safety Endpoints and Analysis .................................................................................110
9.7.1.
Safety Endpoints.......................................................................................................110
9.7.2.
Safety Analysis .........................................................................................................111
9.8.
Tolerability Variables and Analysis .........................................................................111
9.9.
Planned Interim Analysis..........................................................................................111
9.10.
Reporting Deviations from the Statistical Plan ........................................................112
10.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS.............................113
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................114


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11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................114
11.1.1.
Protocol Amendments ..............................................................................................114
11.1.2.
Protocol Violations...................................................................................................114
11.2.
Information to Study Personnel................................................................................114
11.3.
Study Monitoring......................................................................................................115
11.4.
Clinical Product Complaints.....................................................................................115
11.4.1.
Product Complaint Information Needed from the Investigational Center................116
11.4.2.
Handling of Investigational Medicinal Product at the Investigational Center .........116
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................117
11.4.4.
Documenting a Product Complaint ..........................................................................117
11.5.
Audit and Inspection.................................................................................................117
12.
ETHICS ....................................................................................................................118
12.1.
Informed Consent/Assent .........................................................................................118
12.2.
Competent Authorities and Independent Ethics Committees/Institutional 
Review Boards..........................................................................................................118
12.3.
Confidentiality Regarding Study Patients ................................................................118
12.4.
Declaration of the End of Clinical Study..................................................................119
12.5.
Registration of the Clinical Study.............................................................................119
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING .................................................................................................................120
13.1.
Data Collection.........................................................................................................120
13.2.
Data Quality Control.................................................................................................120
13.3.
Archiving of Case Report Forms and Source Documents........................................121
13.3.1.
Sponsor Responsibilities...........................................................................................121
13.3.2.
Investigator Responsibilities.....................................................................................121
14.
FINANCING AND INSURANCE...........................................................................123
15.
REPORTING AND PUBLICATION OF RESULTS..............................................124
16.
REFERENCES .........................................................................................................125
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................127
17.1.
Amendment 01 Dated 22 June 2017.........................................................................127
17.2.
Amendment 02 Dated 15 November 2017 ...............................................................149
17.3.
Amendment 03 Dated 01 February 2018..................................................................209


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17.4.
Amendment 04 Dated 22 May 2019.........................................................................237
APPENDIX A.
ALLOWED AND DISALLOWED MEDICATIONS....................................256
APPENDIX B.
DISTRIBUTION OF AUC BY WEIGHT CATEGORIES AND 
CYP2D6 STATUS....................................................................................................259
APPENDIX C.
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW 
FOR CHILDREN AND ADOLESCENTS ..............................................................260
APPENDIX D.
CHILDREN’S DEPRESSION INVENTORY, SECOND EDITION.............278
APPENDIX E.
.........286
APPENDIX F.
.......292
APPENDIX G.
......305
APPENDIX H.
.........314
APPENDIX I.
 
......315
APPENDIX J.
........317
APPENDIX K.
 
 
........318
APPENDIX L.
FEMALES OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS ...........................................................................................324


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................60
Table 2:
Maximum Daily Dose of IMP by Study Day and Weight Category on Day 1 
for Titration at Study Initiation...................................................................................83
Table 3:
Daily Dose of IMP by Previously Established Maintenance Dose and 
Study Week (Titration Post-Drug Withdrawal) for Patients Randomized to 
Placebo During the Blinded, Randomized Drug Withdrawal Period.........................84
Table 4:
Blood Volumes...........................................................................................................87
Table 5:
Clinical Laboratory Tests .........................................................................................102
Table 6:
Allowed Medications................................................................................................256
Table 7:
Prohibited Antipsychotic Drugs ...............................................................................257
Table 8:
Prohibited QTc Prolonging Drugs............................................................................257
Table 9:
Other Prohibited Drugs.............................................................................................258


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................48
Figure 2:
Study Schematic Diagram (Part B).............................................................................49
Figure 3:
Distribution of AUC of Total (α+β)-HTBZ for Selected Doses Based on 
Weight Categories ....................................................................................................259


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table of Abbreviations
Abbreviation
Term
21CFR
Title 21 Code of Federal Regulations
ADHD
Attention Deficit Hyperactivity Disorder
ADL
activities of daily living
α-HTBZ
alpha-dihydrotetrabenazine
ALP
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase
β-HCG
beta-human chorionic gonadotropin
β-HTBZ
beta-dihydrotetrabenazine
bid
twice daily
BP
blood pressure
CDI-2
Children’s Depression Inventory, Second Edition, Parent and Self-Report 
Profiles
CDMS
clinical data management system
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance and Training
CY-BOCS
Children’s Yale-Brown Obsessive-Compulsive Scale
CYP
cytochrome P450
CYP2D6
cytochrome P450 2D6
C&A-GTS-QOL
Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life
DSM
Diagnostic and Statistical Manual of Mental Disorders
DSM-V™
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text 
Revision
ECG
electrocardiogram
ePRO
electronic patient-reported outcome
FDA
Food and Drug Administration
GCP
Good Clinical Practice


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Abbreviation
Term
GSS
Global Severity Score
HD
Huntington’s disease
IA
interim analysis
IB
Investigator’s Brochure
ICH
International Conference for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IMP
investigational medicinal product
IND
Investigational New Drug
IRT
Interactive Response Technology
ITT
intent-to-treat
LSO
local safety officer
MINI Kid
Mini International Neuropsychiatric Interview For Children and Adolescents
(version 6.0)
mITT
Modified Intention-to-Treat
MTSS
Motor Tic Severity Score 
NDA
New Drug Application
NOAEL
no-observed-adverse-effect level
OCD
obsessive-compulsive disorder
PND
postnatal day
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
red blood cell
RSI
reference safety information
RWITT
Randomized Withdrawal Intent-to-Treat Population
RWmITT
Randomized Withdrawal Modified Intent-to-Treat
RRWmITT
Responder Randomized Withdrawal Modified Intent-to-Treat
RWSAF
Randomized Withdrawal Safety Population
SLV
Since Last Visit
SOP
Standard Operating Procedure
SUSAR
suspected unexpected serious adverse reaction
Tbil
total bilirubin


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Abbreviation
Term
TD
tardive dyskinesia
SD-809/TEV-50717
deutetrabenazine
TS
Tourette syndrome
TS-CGI
Tourette Syndrome-Clinical Global Impression
TS-PGII
Tourette Syndrome-Patient Global Impression of Impact
TTS
Total Tic Score 
UDS
urine drug screen
ULN
upper limit of the normal range
USA
United States of America
VMAT2
vesicular monoamine transporter 2
VTSS
Vocal Tic Severity Score
WBC
white blood cell
YGTSS
Yale Global Tic Severity Scale


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1.
BACKGROUND INFORMATION
1.1.
Introduction
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and 
phonic tics and a variety of behavioral and psychiatric comorbidities (Jankovic 2001, Jankovic 
and Kurlan 2011). Studies have suggested that up to 7% of school children fulfill the diagnostic 
criteria for TS (Kurlan et al 2002). Tics are classified as either simple or complex; simple motor 
tics include eye blinks, shoulder shrugs, while simple vocal tics include grunting, coughing, and 
sniffing. Complex motor tics include touching/tapping and walking in patterns, while complex 
vocal tics include echolalia (repeating another’s speech) and coprolalia (shouting obscenities or 
profanities) (Jankovic 2001, Shaw and Coffey 2014). TS was thought to be a psychogenic 
disorder until improvement with neuroleptics was first observed in the 1960s, leading to the 
theory of central dopaminergic hyperactivity as a possible mechanism of tics associated with TS. 
When the symptoms impair function, most physicians utilize alpha adrenergic drugs (guanfacine, 
clonidine), typical neuroleptics (haloperidol, pimozide, fluphenazine), or atypical neuroleptics 
(olanzapine, ziprasidone, aripiprazole) to control tics (Gilbert and Jankovic 2014, Wijemanne et 
al 2014). In the United States of America (USA), haloperidol and pimozide are approved for the 
treatment of tics associated with TS, while aripiprazole carries a broader indication of “for the 
treatment of TS”. Neuroleptics have the potential for serious adverse effects, including tardive 
dyskinesia (TD), which typically manifests as an irreversible orofacial stereotypy, and other 
forms of hyperkinetic movement disorder (Waln and Jankovic 2013). Up to 25% of adults 
chronically treated with dopamine receptor antagonists (neuroleptics; including the so-called 
“atypical” neuroleptics, such as aripiprazole) eventually develop TD (Jankovic 1995, Pasricha et 
al 2006, Peña et al 2011). Although elderly individuals, especially women, are particularly 
susceptible to developing TD, this iatrogenic condition may also rarely occur in children (Mejia 
and Jankovic 2010). Tetrabenazine, which depletes dopamine presynaptically, has been shown to 
be effective in treating the tics associated with TS (Jain et al 2006, Jankovic 2015, Jankovic and 
Beach 1997, Kenney et al 2007, Paleacu et al 2004, Porta et al 2008) but has not been 
documented to cause TD in clinical use.
While generally effective in reducing the tics of TS, tetrabenazine is associated with frequent 
adverse events, including somnolence, nausea, depression, insomnia, and parkinsonism, that may 
limit its utility. Moreover, tetrabenazine is an immediate-release formulation with the following 
limitations: (1) adverse events of tetrabenazine, such as somnolence, akathisia, and anxiety, are 
often associated with peak concentration after dosing; (2) the active metabolites have short 
half-lives, with the attendant requirement to dose the immediate-release formulation frequently; 
and (3) the active metabolites alpha-dihydrotetrabenazine (α-HTBZ) and 
beta-dihydrotetrabenazine (β-HTBZ) are either primarily (α) or exclusively (β) metabolized by 
cytochrome P450 2D6 (CYP2D6). Polymorphisms in the CYP2D6 gene necessitate genotyping 
to prevent poor metabolizers from experiencing significantly greater exposure to the active drug 
moiety than extensive metabolizers (Mehanna et al 2013).
To address the limitations of commercial tetrabenazine (Xenazine®), Auspex, a wholly owned 
subsidiary of Teva Pharmaceutical Products R&D, Inc, has developed a deuterated tetrabenazine 
(referred to as TEV-50717, previously SD-809) that is eliminated more slowly than 


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tetrabenazine. TEV-50717 has been shown to reduce plasma fluctuation and dosing frequency 
and thus has the potential to improve overall tolerability as compared to that of tetrabenazine. 
Data in patients receiving TEV-50717 for the treatment of chorea associated with Huntington’s
disease (HD) demonstrate a favorable safety profile with low rates of neuropsychiatric adverse 
events. In TS patients with troublesome motor and phonic tics, preliminary efficacy and safety 
data for TEV-50717 have been generated in an open-label, Phase 1b pilot study (SD-809-C-17). 
Results of this study are summarized in Section 1.3.2.2 and support further development of 
TEV-50717 for treatment of tics associated with TS.
TEV-50717 was granted breakthrough status for treatment of TD by the Food and Drug 
Administration (FDA) based on the results of Study SD-809-C-18, and NDA 209885 was 
granted priority review status. TEV-50717 was approved for the treatment of chorea associated 
with HD on 03 April 2017.
1.2.
Name and Description of Investigational Medicinal Product
TEV-50717 (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor with 
the chemical name (RR, SS)-1,3,4,6,7,11b-hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-
2H-benzo[a]quinolizin-2-one. During the open-label period, TEV-50717 tablets are available in 
the following dose strengths: 6, 9, and 12 mg. Each dose strength will have a marking of SD 6, 
SD 9, and SD 12 corresponding to the dose strength and a distinct color: 6 mg – purple, 9 mg –
blue, and 12 mg – beige. The investigational medicinal product (IMP) will be supplied in 20- or 
60-count tablets per dose strength per bottle.
A more detailed description of the product is given in Section 3.8
During the randomized drug withdrawal and re-titration period, TEV-50717 tablets are available 
in the following dose strengths: 6, 9, 12, 15, and 18 mg, all of which are identical in size, shape, 
and color (white). The IMP will be supplied in 20-count bottles.
1.3.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the current Investigator’s Brochure (IB), including the IB supplement for TS (if available).
1.3.1.
Nonclinical Studies
The key nonclinical study findings are provided below, with details available in the IB.
1.3.1.1.
Nonclinical Pharmacology
TEV-50717 is a selectively deuterium-substituted VMAT2 inhibitor structurally related to 
tetrabenazine. The metabolites formed from TEV-50717 (α-HTBZ and β-HTBZ) are potent 
inhibitors of VMAT2 binding, with Ki values of 3.8 and 22 nM, respectively, that are similar to 
previously reported values of their corresponding nondeuterated forms (Scherman et al 1988). 
Off-target binding occurs to a similar extent with deuterated and nondeuterated α-HTBZ and 
β-HTBZ. TEV-50717 and tetrabenazine in male rats at doses resulting in similar systemic 
exposure to the test articles (α-HTBZ and β-HTBZ) produced similar, expected, exaggerated 
central nervous system pharmacological effects. In particular, the adverse event of catalepsy, a 


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known response in rats to drugs that reduce central nervous system dopamine concentrations 
(Fuenmayor and Vogt 1979), was similar in magnitude after TEV-50717 and tetrabenazine 
administration. 
1.3.1.2.
Nonclinical Pharmacokinetics and Drug Metabolism
In human liver S9, the metabolite profile of TEV-50717 overlapped with that of tetrabenazine. In 
a clinical comparative human [14C]-absorption, distribution, metabolism, excretion, and 
mass-balance study, the approximately 22 metabolites of TEV-50717 were also metabolites of 
tetrabenazine. Thus, previous clinical experience with tetrabenazine provides predictive 
information about the safety of TEV-50717 and its metabolites. 
Tetrabenazine, α-HTBZ, and β-HTBZ, and by extension, their deuterated forms, do not inhibit or 
induce cytochrome P450 (CYP) isoenzymes at clinically relevant concentrations (Xenazine 
Prescribing Information 2015). M1, a minor metabolite that may circulate in greater 
concentrations as a metabolite of TEV-50717 as compared to tetrabenazine, is neither an 
inhibitor of major CYP isoenzymes or transporters nor an inducer of CYP isoenzymes.
1.3.1.3.
Toxicology
General and Reproductive Adult Toxicology: Oral administration of TEV-50717 in rats reduced
body weight gain, increased mammary hyperplasia, and produced estrus cycle changes, all of 
which occurred with tetrabenazine at doses that produced similar systemic exposures to test 
articles and metabolites. Mammary and estrus effects are likely consequences of reduced central 
dopamine and subsequently increased prolactin, consistent with information in the Xenazine®
(tetrabenazine) label. Oral administration of TEV-50717 in pregnant rats did not produce test 
article-related embryofetal toxicities, even at doses that led to reduced body weight gain in dams. 
Oral administration of metabolite M1 to pregnant rats from gestational days 6 to 17 produced no 
test article-related maternal or fetal toxicities.
Genetic Toxicology: TEV-50717 and its α-HTBZ and β-HTBZ metabolites were negative in 
in vitro studies for mutagenicity (bacterial reverse mutation, or the Ames test) and for 
chromosomal structural aberrations in human peripheral blood lymphocytes. Oral doses of 
TEV-50717 were negative for inducing micronuclei in the bone marrow of treated mice. 
Juvenile Toxicology: The effects of TEV-50717 on juvenile development was assessed in male 
and female rats with oral dosing from weaning (postnatal day [PND] 21) to PND 71, similar to 
human dosing from Year 2 through early adolescence and overlapping with TEV-50717 oral 
dosing in a general adult toxicology study. The effects of M1 were assessed in male and female 
juvenile rats from PND 25 to PND 70 with a recovery phase and postdosing reproductive 
assessment.
TEV-50717 produced no test-article-related effects on learning and memory functions, on 
histopathology assessments, on reproductive capacity (male and female fertility, estrus cyclicity),
or on intrauterine survival of embryos from matings during recovery from test article 
administration. Adversely reduced body weight gain and adverse clinical observation of tremors 
and in-cage hyperactivity were all noted in previous studies with adult rats; these effects have not 
predicted adult clinical intolerance to TEV-50717. The highest dose level of M1 (50 mg/kg/day) 
produced no test article-related toxicities (clinical observations, changes in body weight gain, 


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clinical pathology, histopathology, ophthalmology, and performance in learning and memory 
tests).
The no-observed-adverse-effect level (NOAEL) for toxicities in juvenile rats is lower than that in 
adults; however, the total (α+β)-HTBZ exposure multiples or safety margins comparing rat to 
humans at the adult and juvenile age categories are similar. The potential for increased 
sensitivity to the effects of TEV-50717 in pediatric patients is mitigated by 2 factors. First, the 
effects of TEV-50717 on behavior and weight gain recovered with cessation of test article 
administration in the juvenile rat toxicology study. Second, the clinical significance of tremors 
and reduced body weight gain in rats dosed with TEV-50717 are unclear because these findings 
were not adverse events of note in adults or adolescent patients. While hypoactivity in rats has 
the potential to relate to clinical observations of somnolence, this adverse effect is controlled 
with dose reduction. In clinical comparison, the adverse event profile of tetrabenazine in adult 
patients is qualitatively similar to patients from approximately 22 months to 18 years of age (Jain 
et al 2006, Kenney et al 2007, Porta et al 2008).
1.3.2.
Clinical Studies
The clinical development plan for TEV-50717 to date includes:

7 completed Phase 1 studies in healthy adult volunteers

2 ongoing Phase 1 studies in healthy adult volunteers

1 completed Phase 3 pivotal study for the treatment of chorea associated with HD

1 completed Phase 3 long-term safety study in patients with HD

2 completed Phase 2/3 study in patients with TD

1 ongoing Phase 3 long-term safety study in patients with TD

1 completed Phase 1b study in patients with TS

2 ongoing Phase 2/3 and Phase 3 studies in patients with TS

1 ongoing Phase 3 long-term safety study in patients with TS
Further details may be found in the IB. 
1.3.2.1.
Clinical Pharmacology Studies
Seven Phase 1 clinical pharmacology studies were conducted in healthy adult volunteers. In 
addition, sparse pharmacokinetic sampling was included in the Phase 3 studies with HD 
patients where population pharmacokinetic analyses were performed to extensively evaluate 
the pharmacokinetics and pharmacokinetics/pharmacodynamics relationship of TEV-50717. A 
summary of the clinical pharmacology findings is provided in the IB.
Pharmacometric analyses of TEV-50717’s active metabolites based on the Phase 1 clinical 
pharmacology in healthy adult volunteers were performed to support dose selection and 
pharmacokinetic characterization in a pediatric population. Subsequently, a further 
pharmacometric analysis of TEV-50717’s active metabolites following administration of 
TEV-50717 to adolescent TS patients with tics (Study SD-809-C-17) was recently completed. 
The results of these analyses are described in Section 1.3.2.3.


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1.3.2.2.
Clinical Safety and Efficacy Studies
TEV-50717 has pharmacologic activity indistinguishable from tetrabenazine, a VMAT2 inhibitor 
with established efficacy in treating the motor and phonic tics associated with TS. Preliminary 
efficacy of TEV-50717 has been evaluated in an open-label, Phase 1b pilot study in patients with 
troublesome motor and phonic tics associated with TS (Study SD-809-C-17). Twenty-three 
patients were enrolled in this study across 9 centers in the USA. Patients who completed the 
study received treatment with TEV-50717 for a total of 8 weeks and had a safety follow-up 
assessment 4 weeks after treatment. The following efficacy observations were made in this 
study:

TEV-50717 was effective in reducing both motor and vocal tics from baseline to 
week 8 (end of treatment), demonstrating a 37.60% reduction in the Yale Global Tic 
Severity Scale (YGTSS) Total Tic Score (TTS) from baseline (p<0.0001).

The reduction in tic severity was associated with significant improvement (from 
baseline to week 8) in the YGTSS Impairment score (-35.32%; p<0.0001), the 
Tourette Syndrome-Clinical Global Impression (TS-CGI) score (-1.2 points; 
p<0.0001), and in the Patient Global Impression of Change score. For example, 
compared to baseline, 76% of patients completing the study reported that they were 
“much” or “very much” improved at week 8.

Between week 8 (end of treatment) and week 9 (1 week post-treatment), an increase 
in YGTSS and TS-CGI scores were observed following discontinuation of treatment 
with TEV-50717 at week 8, indicating a re-emergence of symptoms, thus providing 
further evidence of efficacy.
The safety profile of TEV-50717 has been characterized to date in healthy volunteers as well as 
in patients with chorea associated with HD and TD (as detailed in the IB). Study SD-809-C-17
also evaluated the safety of TEV-50717 in patients with TS. Results of the safety analyses 
indicate that treatment with TEV-50717 at dosages up to 36 mg daily given in 2 divided doses is 
generally safe and well tolerated for up to 8 weeks in patients with TS. No serious treatment-
emergent adverse events (TEAEs) or severe TEAEs occurred in this study. The most frequently 
observed TEAEs during the entire treatment period were fatigue and headache, each reported in 
4/23 (17.4%) patients, followed by irritability which was reported in 3/23 (13.0%) patients. 
There were no clinically meaningful trends in mean changes from baseline for any clinical 
laboratory variable or any other observations related to safety.
1.3.2.3.
Pharmacometrics Analysis of TEV-50717 Active Metabolites to Support Dose 
Selection and Pharmacokinetic Characterization in a Pediatric Population
Population pharmacokinetics modeling of the TEV-50717 active metabolites -HTBZ and 
β-HTBZ has been performed throughout the clinical development program. Based on sequential 
pharmacokinetics sampling data obtained in healthy volunteers in the Phase 1 program, a 
structural population pharmacokinetics model was developed to guide dose selection for HD 
patients with chorea (Study SD-809-CLN-076) and subsequently optimized to better describe the 
absorption/bioconversion profile of -HTBZ and β-HTBZ (Study SD-809-CLN-077). 


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Employing the structural model defined in Study SD-809-CLN-077, sequential and sparse 
pharmacokinetics sampling data obtained from Study SD-809-C-17 were combined with the 
Phase 1 data employed in Study SD-809-CLN-077 to estimate the exposure total of (+β)-HTBZ 
in adolescent patients (age 12 to 18 years) with TS and to simulate exposure in adolescent and 
pediatric patients (age 6 to 11 years) with and without concomitant use of a strong CYP2D6 
inhibitor across a range of doses (Appendix B). Population model parameters were re-estimated 
for the combined Phase 1 and adolescent data obtained from patients in Study SD-809-C-17. The 
model was used to simulate total (+β)-HTBZ exposures across a range of body weights 
corresponding to a pediatric and adolescent population according to the Centers for Disease 
Control growth charts. 
This analysis indicated that exposure to total (+β)-HTBZ is influenced by body weight, and a 
reduction in dose for pediatric and adolescent patients weighing <40 kg is necessary in order to 
provide comparable exposure to doses up to 48 mg per day in adults, a level previously 
demonstrated to be safe and well tolerated in treated patients with chorea associated with HD. 
This analysis provides the basis for the dosing recommendations in Section 5.1. 
1.4.
Known and Potential Benefits and Risks to Patients
Additional information regarding benefits and risks to patients may be found in the current IB
and in the United States prescribing information for AUSTEDO™(deutetrabenazine).
1.5.
Selection of Investigational Medicinal Product and Doses
A detailed description of IMP administration is presented in Section 5.1.
1.5.1.
Justification for Dose of Active Drug
The dose ranges to be evaluated in this study, based on body weight and CYP2D6 impairment 
status on day 1, were selected on the basis of the safety, preliminary efficacy, and population 
pharmacokinetics data generated from Study SD-809-C-17 (Table 2). In Study SD-809-C-17, 
TEV-50717 up to 18 mg twice daily (bid [36 mg/day]) was well tolerated and demonstrated a 
clinically meaningful benefit in adolescents with TS-associated tics. The dosages proposed in the 
present study aim to match the exposure achieved in adults receiving up to 48 mg/day (24 mg 
bid), a level previously demonstrated to be efficacious, safe, and well tolerated in patients with 
HD-associated chorea. 
Similar to one of the parent studies (TV50717-CNS-30046), IMP will be titrated based on 
investigator, patient, and parent/guardian assessments of tic reduction and adverse events. This 
dosing strategy is practical in a clinical study setting and affords sufficient time between dose 
steps for safety and efficacy to be assessed. It is also consistent with the clinical application of 
tetrabenazine, another VMAT2 inhibitor with accepted efficacy in this population. 
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6 and 
any applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament 


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and of the Council on the approximation of the laws, regulations, and administrative provisions 
of the Member States relating to the implementation of GCP in the conduct of clinical studies on 
medicinal products for human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMP as described in the IB.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the Independent Ethics Committee/Institutional Review Board 
(IEC/IRB), and with competent authorities.
1.7.
Study Population and Justification
The population to be studied includes male and female patients who have previously completed 
participation in Study SD-809-C-17, Study TV50717-CNS-30046, or Study TV50717-
CNS-30060. Per selection criteria in these previous studies, these patients were children and 
adolescents, 6 through 16 years of age, with TS with tics troublesome enough to cause distress or 
impairment based on the assessment of the patient, parent/guardian, and investigator.
1.8.
Location and Study Duration
This study is planned to be conducted globally (per Study SD-809-C-17, Study TV50717-
CNS-30046, and Study TV50717-CNS-30060) at approximately 120 centers. It is expected to 
start in May 2018 and conclude in January 2021, with a duration of approximately 32 months.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
This is an open-label Phase 3 study with a 2-week, double-blind, placebo-controlled, randomized 
drug withdrawal period to evaluate the safety and efficacy of TEV-50717 tablets in patients who 
have previously completed participation in Study SD-809-C-17, Study TV50717-CNS-30046, or 
Study TV50717-CNS-30060.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to evaluate the safety and tolerability of long-term therapy 
with TEV-50717.
2.2.2.
Secondary Objectives
The secondary objectives of this study are as follows:

to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the 
severity of TS tics

to confirm long-term maintenance of effect by means of a double-blind, 
placebo-controlled, randomized drug withdrawal period after 28 weeks of open-label 
treatment
2.3.
Study Endpoints
2.3.1.
Safety Endpoints
The following safety endpoints will be assessed in Part A: 

incidence of adverse events 

observed values and changes from day 1 in vital signs

observed values and changes from day 1 in the Children’s Depression Inventory, 
Second Edition, Parent and Self-Report Profiles (CDI-2)

observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS)

observed values in electrocardiogram (ECG) parameters and shifts from parent study 
baseline (for patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060) or from day 1 (for patient[s] rolling over from 
Study SD-809-C-17) for clinically significant abnormal findings

observed values and changes from day 1 in clinical laboratory parameters 
(hematology, serum chemistry, and urinalysis)


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The following safety endpoint will be assessed in Part B: 

incidence of adverse events
In addition to routine monitoring of adverse events, clinical laboratory parameters, 12-lead 
ECGs, and safety scales, an Independent Data Monitoring Committee (IDMC) will monitor 
safety during the conduct of the study.
2.3.2.
Efficacy Endpoints
The following efficacy endpoints will be assessed in Part A:

change in the YGTSS TTS from day 1 to each visit in which the scale is administered

change in the TS-CGI score from day 1 to each visit in which the scale is 
administered

change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) 
score from day 1 to each visit in which the scale is administered

change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life 
(C&A-GTS-QOL) activities of daily living (ADL) subscale score from day 1 to each 
visit in which the scale is administered
The following efficacy endpoint will be assessed in Part B: 

change in the TTS of the YGTSS from week 28 to week 30, with the primary 
analyses and sensitivity testing done as described in Section 9.5.3.1
2.3.3.
Exploratory Endpoints
The following exploratory endpoints will be assessed in Part A:

 

 

 

 

 

 

 


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
 

 

 


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3.
STUDY DESIGN
3.1.
General Design and Study Schematic Diagram
This is a 56-week, open-label, single-arm study that includes a 2-week, double-blind, 
placebo-controlled, randomized drug withdrawal period followed by a 3-week blinded 
re-titration period to evaluate the safety of TEV-50717 in children and adolescents with tics 
associated with TS after they have successfully completed any of the parent studies (SD-809-C-
17 [Phase 1b], TV50717-CNS-30046 [Phase 2/3], or TV50717-CNS-30060 [Phase 3]). Patients 
rolling over from Study SD-809-C-17 will need to undergo all day 1 assessments. For patients 
rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, the week 13 visit 
(Study TV50717-CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) will be the day 
1 visit for Study TV50717-CNS-30047. If the patient does not wish to enroll in Study TV50717-
CNS-30047 at that visit, they can enroll up to 1 week following the week 13 or week 9 visits, 
respectively.
For patients rolling over from Study SD-809-C-17, this study will consist of a 4-week screening 
period (up to 31 days) and up to 54 weeks of treatment. All participating patients are expected to 
participate in this study for its entire duration, which is a minimum of 56 weeks. Patients will 
have a follow-up telephone contact to evaluate safety 1 week after the end of the washout period 
(2 weeks after their last dose of IMP). The end of study is defined as the date of the week 56 visit 
of the last participant.
Informed consent/assent, depending on the child’s age, as appropriate, will be obtained before 
any study procedures are performed. For patients rolling over from Study TV50717-CNS-30046 
or Study TV50717-CNS-30060, informed consent/assent, as appropriate, may be obtained prior 
to the day 1 visit, up to 4 weeks in advance of open-label study participation. Any patient that 
turns 18 years of age during the course of Study TV50717-CNS-30047 will need to be 
re-consented as an adult.
Patients who have successfully completed any of the parent studies may be eligible to enroll in 
the current study after they complete a 1-week washout period and the final evaluation (week 13 
in Study TV50717-CNS-30046 or week 9 in Study TV50717-CNS-30060) in the parent study. 
To reduce patient burden, after obtaining informed consent/assent, depending on the child’s age, 
as appropriate, some data collected in Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 will be used to provide corresponding day 1 data in the current open-label study (see 
Table 1). 
All screening procedures will be performed for patients rolling over from Study SD-809-C-17, as 
they will have been off IMP for several months at the time of enrollment into the current study. 
Site-administered scales include the YGTSS, 
, Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI Kid, version 6.0), and the C-SSRS and 
self-administered scales include the TS-PGII, 
, CDI-2, and C&A-
GTS-QOL. For the YGTSS, input from the caregiver/adult is required. For 
 the TS-PGII 
 
, input from the caregiver/adult is permitted. For all other scales, children 13 years of 
age and under, interviews may be performed separately or jointly with the caregiver/adult as 
appropriate or as defined by the scale. For children over 13 years of age, caregiver/adult 


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involvement is strongly encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information.
The assessments and procedures performed during each study visit are detailed in Table 1 and 
Section 3.13.
Up to approximately 227 patients are planned to be enrolled (approximately 1 patient is
estimated to enroll from the Phase 1b Study SD-809-C-17, up to approximately 99 patients are 
estimated to enroll from the Phase 2/3 Study TV50717-CNS-30046, and up to approximately 
127 patients are estimated to enroll from the Phase 3 Study TV50717-CNS-30060).
When approximately 100 patients have completed the 28-week clinic visit, an interim analysis, 
including data from day 1 and up to week 28 visit only, will be conducted to provide descriptive, 
long-term safety and efficacy data to be used in regulatory submissions. To maintain data 
integrity of Study TV50717-CNS-30047, only a limited number of personnel who do not have 
contact with the sites will have access to this interim data in preparation for the regulatory filing. 
As no decisions regarding conduct of the study will be made based on the descriptive interim 
analysis, no alpha will be spent.
Patients who complete all scheduled visits will have procedures and assessments performed at 
the final visit (week 54). Patients who withdraw from the study before completing the week 54
evaluation period will have the week 54 procedures and assessments performed at their final 
visit, and a follow-up telephone contact for safety evaluation 2 weeks after their last dose of 
IMP. 
The study schematic diagram is presented in Figure 1. An additional diagram that details the 
blinded, randomized drug withdrawal/titration post-drug withdrawal period (Part B of the study) 
is presented in Figure 2.
Figure 1:
Overall Study Schematic Diagram


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a Maximum total daily dose for patients ≥40 kg is 48 mg/day (24 mg bid), 30 to <40 kg is 42 mg/day (21 mg bid), 
and 20 to <30 kg is 30 mg/day (15 mg bid). For those considered CYP2D6 impaired, maximum daily dose for 
patients ≥40 kg is 36 mg/day, 30 to <40 kg is 24 mg/day, and 20 to <30 kg is 18 mg/day (Table 2).
b If a stable dose is reached before the indicated time, the patient should continue taking that dose for the remainder 
of the titration period and throughout the maintenance therapy dosing.
c Dose adjustments may be made, as necessary, except for Part B.
d See Figure 2.
Note: Screening visit is required only for patients rolling over from Study SD-809-C-17.
bid=twice daily; CYP=cytochrome P450; ET=early termination visit.
Figure 2:
Study Schematic Diagram (Part B)
a Ranges account for different dosing schedules for patients based on their previously established maintenance dose 
in Part A. Re-titration only applies to patients who were randomized to placebo during the withdrawal period.
b Dose adjustments may be made, as necessary.
In the study period descriptions below, “week X” refers to the end of that week, which coincides 
with the study visit, unless stated otherwise. Some dose changes will occur at the start of a week 
rather than at the end of a week and will be indicated as such.
3.1.1.
Screening Period (up to 31 days)
For patients from Study SD-809-C-17:
Screening period (up to 31 days): All screening procedures will be performed for patients rolling 
over from Study SD-809-C-17, as they will have been off IMP for several months at the time of 
enrollment into this study (TV50717-CNS-30047). 
After informed consent/assent, depending on the child’s age, as appropriate, is obtained, patients 
who are stable from a medical and psychiatric standpoint will undergo a screening evaluation, 
including medical history, physical and neurological examination, assessment of vital signs, 
laboratory testing, and 12-lead ECG, along with rating scales to assess comorbid TS symptoms 
and behavioral status. 


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At the discretion of the investigator, the screening visit may be divided into 2 visits if the visit 
length is deemed to be too burdensome for the patient. Patients may be rescreened 1 time if there 
is a change in the patient’s medical background, a modification of study entry criteria, or other 
relevant change. (Note: Details of a patient’s rescreening must be approved and documented by 
the medical monitor and/or Clinical Surveillance and Training [CST] team.)
For patients from Study TV50717-CNS-30046 or Study TV50717-CNS-30060:
The screening evaluation for this open label study occurs at the end of the treatment period in the 
double-blind study. To reduce patient burden and not collect duplicate information, after 
obtaining informed consent/assent, depending on the child’s age, as appropriate, relevant data 
collected in Study TV50717-CNS-30046 or Study TV50717-CNS-30060 will be used to provide 
corresponding data in this open-label study (see Table 1).
Part A:
3.1.2.
Day 1 Visit (All Patients)
For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, the 
week 13 visit (Study TV50717-CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) 
will be the day 1 visit for Study TV50717-CNS-30047. Patients rolling over from 
Study SD-809-C-17 will need to undergo all day 1 assessments. Day 1 assessments for 
Study TV50717-CNS-30047 that are identical to Study TV50717-CNS-30046 week 13 or 
Study TV50717-CNS-30060 week 9 assessments do not need to be repeated. Additionally, 
Study TV50717-CNS-30047 required evaluations will be completed at Study TV50717-
CNS-30046 week 13 visit or Study TV50717-CNS-30060 week 9 visit (see Table 1). For all 
patients, the day 1 visit will occur on or as close as possible to the week 13 or week 9 visit from 
Study TV50717-CNS-30046 and Study TV50717-CNS-30060, respectively, but not >7 days 
beyond those respective visits.
For patients with clinically significant laboratory abnormalities at week 12 in Study TV50717-
CNS-30046 or at week 8 in Study TV50717-CNS-30060, Study TV50717-CNS-30046 week 13 
value(s) or Study TV50717-CNS-30060 week 9 value(s) will serve as day 1 laboratory values in 
this study. Rollover for such patients must be approved and documented by the medical monitor 
and may be delayed.
3.1.3.
Titration Period (7 Weeks)
As patients from Study SD-809-C-17 will have been off IMP for several months at the time of 
enrollment, and since patients from Study TV50717-CNS-30046 or Study TV50717-CNS-30060 
will have discontinued IMP (TEV-50717 or placebo) for at least 1 week at completion of the 
parent study, all patients will undergo TEV-50717 dose titration in this study. Patients will 
receive 6 mg of TEV-50717 with food on the evening of day 1. Tablets should be taken with 
food (eg, a snack) and should not be taken on an empty stomach. The titration scheme and 
maximum dose will be determined by body weight and CYP2D6 impairment status from the 
parent study. Patients will be classified as CYP2D6 impaired if they are receiving a strong 
CYP2D6 inhibitor or are a CYP2D6 poor metabolizer based on blinded assessment of CYP2D6 
genotype at baseline of the parent study. Patients who are CYP2D6 impaired will have a dose 
cap in the open-label study, as shown in Table 2. Patients and their caregiver/adult will interact 
weekly with the clinical research staff, either by telephone contact or in-clinic visits from week 1 


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through week 7 of the titration period, in order to evaluate safety and establish a dose of 
TEV-50717 that optimally reduces tics and is well tolerated (optimal dose). Safety evaluations 
during the titration period include assessment of vital signs, monitoring for adverse events and 
concomitant medications, 12-lead ECGs, and rating scales for depression and suicidality.
In-person (in-clinic) study visits will be scheduled at weeks 2, 4, and 6, and telephone contacts 
will be scheduled for weeks 1, 3, 5, and 7 in order to assess adverse events and tic severity. 
The dose of the IMP should be increased on a weekly basis until one of the following occurs:

The investigator determines that there has been a clinically meaningful reduction in 
tics.

The patient experiences a protocol-defined “clinically significant” adverse event
(defined as an adverse event that is related to IMP and is either moderate or severe in 
intensity or meets the criteria for a serious adverse event).

The maximum allowable dose is reached, based on the patient’s weight and use of 
strong CYP2D6 impairment status.
If a stable dose is reached before the week 7 telephone call, the patient should continue on that 
dose (ie, the dose should not be increased further) for the remainder of the titration period. If a 
patient experiences depression, suicidal ideation or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes with daily activity, or adverse event that is 
related to IMP, the investigator will determine if a dose reduction or suspension is necessary. If 
the determination is made during a telephone contact that a patient requires a dose reduction or 
suspension, an unscheduled in-clinic visit should be conducted as soon as practicable thereafter.
Dose adjustments should be made based on all available information, including the patient and 
caregiver/adult reports of adverse events and tic reduction, the clinical assessment of safety and 
efficacy by the investigator, and the information from rating scales.
3.1.4.
Maintenance Period
At the end of the titration period, the patient’s initial dose for the maintenance period will be 
established. Dose adjustments of TEV-50717 (upward or downward) may be made during the 
maintenance period, if necessary, but not more often than every 5 days and only in increments of 
6 mg. As during titration, dose adjustments should be made based on all available information.
After dose adjustment, if the maintenance dose for a patient is 6 mg, the dose should be taken 
once a day in the morning with food (other dose levels are taken twice daily).
During the maintenance period, in-person (in-clinic) study visits will be scheduled at weeks 8, 
15, 34, 41, and 54 for assessments of safety and efficacy and telephone contacts will be 
scheduled for weeks 21 and 47 in order to assess adverse events and tic severity. The randomized 
drug withdrawal and re-titration period (Part B) will occur from the end of week 28 through the 
end of week 33, and then the Part A maintenance period will resume, along with the ability to 
make dose adjustments as described above. At week 54, patients will undergo a complete 
evaluation, including physical and neurological examination, safety laboratory testing, 12-lead 
ECG, CDI-2, and C-SSRS assessments, as well as the YGTSS, TS-CGI, 
 TS-PGII, 
, and C&A-GTS-QOL.


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3.1.5.
Washout Period and Follow-up
All patients will discontinue IMP at the week 54 visit and will return 1 week later (week 55) for 
evaluation of safety and tic reduction. Patients will have a follow-up telephone contact for safety 
evaluation 1 week after the end of the washout period (2 weeks after their last dose of IMP)
(week 56).
See Table 1 for study procedures and assessments.
See Figure 1 and Figure 2 for study schema.
Part B:
3.1.6.
Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug 
Withdrawal Period (5 Weeks)
At the week 28 visit, the patients will be randomized 2:1 to their current dose of TEV-50717 or
placebo in order to check for return of symptoms. Because IMP is dispensed as enough doses for 
2 weeks (current dose level and next dose level), the week 28 visit (Day 196) is considered the 
first day of the randomized withdrawal period, although the patient will begin taking blinded 
IMP on Day 197. Patients will have a follow-up telephone contact for safety evaluation 1 week 
after the start of the randomized drug withdrawal period. At week 30, safety and efficacy will be 
assessed. At the week 30 visit, patients who receive TEV-50717 during the randomized drug 
withdrawal period will continue at the same dose in a blinded manner from the start of week 31 
to the start of week 34. Any patient who was randomized to placebo during this 2-week period
will undergo blinded re-titration. Patients will have a follow-up telephone contact for safety 
evaluation at weeks 31 and 33.
Titration Post-Drug Withdrawal (Weeks 31, 32, and 33)
Any patient who was randomized to placebo between the week 28 and week 30 visits will 
undergo re-titration to their previously established maintenance dose over the 3 weeks of 
treatment following the randomized drug withdrawal period (start of week 31 to the start of week 
34 [Days 211 through 232]). The titration scheme and maximum dose will be determined based 
on the previously established maintenance dose according to Table 3. The dose of IMP for each 
patient who underwent 2 weeks of placebo will be titrated back to the maintenance dose that was 
used by the patient up to week 28 followed by continued maintenance therapy at that dose.
All patients should be back at their maintenance dose on or before the start of week 34 and return 
to open-label treatment for the remainder of the study (note that, because IMP is dispensed for 
2-week periods, patients will use blinded bottles through the end of week 34; however, all 
patients will be known to be on active treatment at the start of week 34).
3.2.
Justification for Study Design and Placebo-Controlled Randomized 
Drug Withdrawal
At the present time, effective treatment options for TS are suboptimal and limited. As a chronic 
condition impairing major life activities during childhood, such as occupational, social, and 
educational activities, TS presents an area of significant unmet medical need in the pediatric 
population.


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Preliminary efficacy and safety data for TEV-50717 as a treatment for TS have been generated in 
an open-label, Phase 1b pilot study (SD-809-C-17) in patients. Results of Study SD-809-C-17
support further development of TEV-50717 as a treatment of TS.
Two parent studies, TV50717-CNS-30046 and TV50717-CNS-30060, are underway. They are 
randomized, double-blind, placebo-controlled studies of the efficacy and safety of TEV-50717 
on the tics in patients with TS. This is an open-label, single-arm study that includes a 2-week, 
double-blind, placebo-controlled, randomized drug withdrawal period in which patients with TS 
may be eligible to participate after successful completion of any of the parent studies (SD-809-C-
17 [Phase 1b], TV50717-CNS-30046 [Phase 2/3], or TV50717-CNS-30060 [Phase 3]). Patients 
who have successfully completed a parent study may be eligible to enroll in this study after they 
complete a 1-week washout period and the final evaluation in the parent study. For patients 
rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, the week 13 visit 
(Study TV50717-CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) will be the 
day 1 visit for Study TV50717-CNS-30047. If the patient does not wish to enroll in 
Study TV50717-CNS-30047 at that visit, they can enroll up to 1 week following the week 13 or 
week 9 visits, respectively. The end of study is defined as the date of the week 56 visit of the last 
participant.
Inclusion and exclusion criteria have been designed to minimize the risk to patients while 
maintaining a consistent level of TS symptoms to allow detection and analysis of a drug effect. 
Exclusion criteria were designed to exclude patients with concomitant conditions that may 
increase their risk to drug treatment.
The open-label study design (ie, no placebo or comparator) was selected to allow further 
evaluation and review long-term safety of TEV-50717 in this patient population. Patients will 
receive twice daily dosing for up to 54 weeks (those on the 6-mg dose will receive once-daily 
dosing), with an initial 7-week titration period to allow for optimal dose selection. At the 
week 28 visit, patients will begin a 2-week blinded, randomized drug withdrawal period. The 
randomized drug withdrawal period will rigorously assess the long-term maintenance of effect. 
Patients will be randomized to their current dose of TEV-50717 or placebo for 2 weeks. After 
completing the 2 weeks, patients will continue their same dose of TEV-50717 in a blinded 
manner or will be re-titrated (patients receiving placebo only) in a blinded manner for 3 weeks. 
At week 34, all patients will resume their maintenance dose. This is a classic ABA study design
(ie, drug, placebo, drug) that allows for a more rigorous test of the intervention. In the traditional 
AB design, changes in symptoms (particularly in a long trial) could be attributed to other factors 
(eg, life changes, societal issues, and regression to the mean); however, an acute change 
demonstrated only in a placebo group among subjects that have been maintained for several 
months would reduce the likelihood of any other explanations for changes in symptoms.
3.3.
Safety Measures and Time Points
A description of the safety measures is provided in Section 7.
Part A:

adverse events and concomitant medications: from the signing of the informed 
consent/assent, depending on the child’s age, as appropriate, through follow-up, 
inclusive of all visits and telephone contacts


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
physical examination: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients) and week 54

neurological examination: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients) and week 54

vital signs, height, and weight: screening (only for patients who completed 
Study SD-809-C-17; data from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients); day 1; and weeks 2, 4, 6, 8,
15, 34, 41, 54, and 55

Note: orthostatic blood pressure (BP) and pulse on day 1 and weeks 4, 8, and 54

MINI Kid: screening (only for patients who completed Study SD-809-C-17)

Children’s C-SSRS:

Baseline/screening scale: screening (only for patients who completed 
Study SD-809-C-17)

Since Last Visit (SLV) scale: day 1 (only for patients who completed 
Study SD-809-C-17) and weeks 2, 4, 8, 15, 34, 41, 54, and 55

CDI-2 (Parent and Self-Report Profiles): screening and day 1 (ie, only for patients 
who completed Study SD-809-C-17) and weeks 2, 4, 8, 15, 34, 41, 54, and 55

12-lead ECG: screening (ie, only for patients who completed Study SD-809-C-17); 
day 1; and weeks 4, 8, and 54

clinical laboratory tests (serum chemistry, hematology, and urinalysis): screening (ie, 
only for patients who completed Study SD-809-C-17; data from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 should be used for the remaining 
patients); day 1; and weeks 8 and 54

pregnancy testing (beta-human chorionic gonadotropin [β-HCG]): screening (ie, only 
for patients who completed Study SD-809-C-17); day 1 and weeks 4, 8, 15, 34, and 
54 (serum tests at screening and week 54 and urine tests at other visits)

drug screen: screening (ie, only for patients who completed Study SD-809-C-17)
Part B: 

adverse events and concomitant medications: from the signing of the informed 
consent/assent, depending on the child’s age, as appropriate, form through follow-up, 
inclusive of all visits and telephone contacts

physical examination: weeks 28 and 30

vital signs, height, and weight: weeks 28, 30, and 32

Note: orthostatic BP and pulse at week 28

Children’s C-SSRS:


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
SLV version: weeks 28 and 30

CDI-2 (Parent and Self-report Profiles): weeks 28 and 30

12-lead ECG: week 28

clinical laboratory tests (serum chemistry, hematology, and urinalysis): week 28

pregnancy testing: week 28
3.4.
Efficacy Measures and Time Points
A description of the efficacy measures is provided in Section 6.
3.4.1.
Efficacy Measures and Time Points
Part A and Part B:

YGTSS: Screening (only for patients who completed Study SD-809-C-17); day 1 (ie, 
week 13 data from Study TV50717-CNS-30046 or week 9 data from 
Study TV50717-CNS-30060); and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 55

TS-CGI: Day 1 (ie, week 13 data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

TS-PGII: Day 1 (ie, week 13 data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

C&A-GTS-QOL (ADL subscale): Day 1 and weeks 6, 28, 34, and 54
3.4.2.
Exploratory Measures and Time Points
Part A and Part B:

 

 

 




3.5.
Randomization and Blinding
This is an open-label study that includes a 2-week, double-blind, placebo-controlled, randomized 
drug withdrawal period followed by a 3-week blinded re-titration period. At the start of the 
randomized drug withdrawal period (end of week 28), the patients will be randomized 2:1 to the 


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current dose or placebo in order to check for return of symptoms. During the entire 5-week 
period, patients randomized to TEV-50717 will stay on their established maintenance dose of 
blinded active IMP. Patients who receive placebo during the randomized drug withdrawal period 
will undergo blinded re-titration post-drug withdrawal. All patients will return to open-label 
dosing at week 34 (note that, because IMP is dispensed for 2-week periods, patients will use 
blinded bottles through the end of week 34; however, all patients will be known to be on active 
treatment at the start of week 34).
During the blinded drug withdrawal and re-titration period, patients and investigators will remain 
blinded to treatment assignment. In addition, the sponsor’s and development partner’s clinical 
personnel and all vendors (with the exception of the Interactive Response Technology [IRT]
vendor and the IMP packaging vendor) involved in the study will be blinded to the IMP identity 
until the database has been locked for analysis and the treatment assignments are revealed.
Patients will be centrally randomly assigned to the treatment groups by means of a 
computer-generated randomization list. The creation of the randomization list will be under the 
responsibility and oversight of Syneos Health.
The randomized treatment and medication allocation will be assigned to the relevant treatment 
groups through a qualified service provider (ie, via IRT). The management of the IRT system 
will be done by a qualified service provider under the oversight of Nuvelution TS Pharma, Inc.
(referred to hereafter as Nuvelution TS Pharma).
The staff member at the investigational center who will dispense the IMP will not know the 
treatment given to each patient during the blinded drug withdrawal and re-titration period.
3.6.
Maintenance of Randomization and Blinding
3.6.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location within Syneos Health. At the 
time of analysis, when treatment codes are needed, the Syneos Health statistician assigned to the 
study will make a request to unblind and will receive the unblinded codes and unblinded IMP 
assignment according to the processes defined in the relevant Standard Operating Procedure 
(SOP).
3.6.2.
Blinding and Unblinding
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations. The patient’s randomized 
treatment will be made available to the investigator(s) via the IRT system. If possible, the 
medical monitor should be notified of the event before breaking of the code. If this is not 
possible, the medical monitor should be notified immediately afterward, and the patient’s 
randomized treatment should not be communicated to the medical monitor. Breaking of the 
randomization code can always be performed by the investigational center without prior approval 
by the medical monitor.
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded on the case report form (CRF). However, if a patient is unblinded by mistake, the 


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57
investigator should discuss with the medical monitor whether or not the patient should be 
withdrawn. The circumstances leading to the breaking of the code should be fully documented in 
the investigator’s study files and in the patient’s source documentation. Assignment of IMP 
should not be recorded in any study documents or source document.
In studies with blinding, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance may independently request that the blind code be broken (on a case-by-case 
basis) to comply with regulatory requirements. The report will be provided in an unblinded 
manner for regulatory submission. If this occurs, blinding will be maintained for the investigator 
and for other personnel involved in the conduct of the study and analysis and reporting of the 
data.
3.7.
Independent Data Monitoring Committee
An IDMC will review accumulating safety data on a regular basis to ensure the continuing safety 
of the study patients and to review any study conduct issues.
The IDMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician. The IDMC will receive safety data 
periodically, which will be presented by masked treatment groups. They will have the right to 
recommend modification of the study for safety reasons. 
IDMC sessions can be open or closed. During open sessions, representatives of the sponsor and 
development partner may be present, and information is provided and discussed in a blinded 
manner. During closed sessions, the only participants are members of the IDMC and the 
designated unblinded statistician (if approved to be present). 
If there is a request to unblind any individual treatment assignment, a written request from the 
IDMC (as a committee), signed by the IDMC chairperson, should be made to the unblinded 
statistician. The appropriate medical and operational personnel will be notified but will not 
receive the unblinded treatment information. Any use of unblinded treatment assignments should 
be clearly documented and reported to the sponsor at study termination.
The IDMC chairperson will communicate with Nuvelution TS Pharma in regard to issues 
resulting from the conduct and clinical aspects of the study. Nuvelution TS Pharma and Syneos 
Health will work closely with the committee to provide the necessary data for review.
The conduct and specific details regarding the IDMC sessions and requests to unblind any 
blinded treatment assignment are outlined in the IDMC charter.
3.8.
Investigational Medicinal Product and Placebo Used in the Study
The IMP is a matrix formulation and is designed as a gastro-erosional tablet to be administered 
with food and should not be taken on an empty stomach. The IMP is coated with a white 
polymer coating to aid in swallowing. TEV-50717 tablets have been manufactured according to 
current Good Manufacturing Practice regulations. 
During the open-label period, TEV-50717 tablets are available in the following dose strengths: 6, 
9, and 12 mg. Each dose strength will have a marking of SD 6, SD 9, and SD 12 corresponding 


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58
to the dose strength and a distinct color: 6 mg – purple, 9 mg – blue, and 12 mg – beige. The 
IMP will be supplied in 20- or 60-count tablets per dose strength per bottle.
Each bottle will contain a sufficient supply of drug until the next specified visit/telephone 
contact, plus overage to account for potential delays in study visits. 
A more detailed description of administration procedures is given in Section 5.1.
During the randomized drug withdrawal and re-titration periods, TEV-50717 tablets are available 
in the following dose strengths: 6, 9, 12, 15, and 18 mg, all of which are identical in size, shape, 
and color (white). The IMP will be supplied in 20-count bottles.
Patients who receive TEV-50717 during the randomized drug withdrawal period will remain on 
their maintenance dose of blinded active IMP from the start of week 31 to the start of week 34; 
those assigned to placebo during the randomized drug withdrawal period will undergo blinded 
re-titration from the start of week 31 to the start of week 34 back to their previously established 
maintenance dose from the end of week 28. Note that, because IMP is dispensed for 2-week 
periods, patients will use blinded bottles through the end of week 34; however, all patients will 
be known to be on active treatment at the start of week 34. 
3.9.
Drug Supply and Accountability
3.9.1.
Drug Storage and Security
The IMP (TEV-50717) should be stored protected from light, at a controlled room temperature, 
20°C to 25°C (68°F to 77°F); however, storage between 15°C and 20°C (59°F to 68°F) is 
acceptable if there is no alternative. The IMP should be stored in a dry, securely locked, 
substantially constructed cabinet or enclosure, with access limited to authorized staff.
3.9.2.
Drug Accountability
Each IMP shipment to the site will include a packing slip listing the contents of the shipment, 
drug return instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMP and other study materials from 
the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the local regulations, and used in accordance with this protocol. 
A record of IMP accountability (ie, IMP and other materials received, used, retained, returned, or 
destroyed) must be prepared and signed by the principal investigator or designee, with an 
account given for any discrepancies. Empty, partially used, and unused IMP will be disposed of, 
as agreed with the sponsor/development partner.
3.10.
Duration of Patient Participation and Justification
For patients rolling over from Study SD-809-C-17, this study will consist of a 4-week screening 
period (up to 31 days) and up to 54 weeks of treatment. All participating patients are expected to 
participate in this study for its entire duration, which is a minimum of 56 weeks (for those rolling 
over from Study SD-809-C-17, this can be up to 60 weeks). Patients will have a follow-up 
telephone contact to evaluate safety 1 week after the end of the washout period (2 weeks after 
their last dose of IMP). 


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See Section 12.4 for the definition of the end of the study.
3.11.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational center to identify safety concerns. The study may be terminated by the sponsor at 
any time. 
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event); every effort should be undertaken to find out 
the reason for discontinuation. The investigator and/or sponsor can withdraw a patient from the 
study at any time for any reason (eg, protocol violation or deviation as defined in Section 11.1.2, 
noncompliance, or adverse event). 
3.12.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the sponsor provides written instructions specifying 
which data are permitted to be recorded directly onto the CRF, such as eScales. 
If patient data are processed from other vendors (eg, clinical laboratory, central ECG, diary data), 
the results will be sent to the investigational center, where they will be retained but not entered 
into the CRF. These data may also be sent electronically to the sponsor (or organization 
performing data management) for direct use with the clinical database (see Section 13.1). All 
clinical patient data from other vendors will be available to the investigator.
The CRFs are filed in the sponsor’s central file after study completion. 
3.13.
Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 1. During a visit, 
study procedures and assessments should be performed in the order specified in the study 
manual.
Detailed by-visit information is provided in the sections following the table. Detailed 
descriptions of each assessment are provided in Section 6 (efficacy assessments) and Section 7
(safety assessments).


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60
Table 1:
Study Procedures and Assessments
Part A
Screeninga
Titration
Maintenance
Study weekb
Parent study
Day 1c
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
5
(Day 
35)
6
(Day 
42)
7
(Day 
49)
8
(Day 
56)
15
(Day 
105)
21
(Day 
147)
C-17
046 or 060
Visit window (days)
<31 days
<31 days
0
±3 days
In-clinic visit
Xd
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
Evaluate/Adjust IMP
Xe
X
Xe
X
Xe
X
X
X
Informed consent/assent
X
Xf
Eligibility criteria
X
X
Medical history and psychiatric history
X
[g]
Demographics
X
[g]
Vital signs and weighth
X
Xi
X
Xi
X
Xi
X
Physical examination
X
[j]
Neurological examination
X
[j]
Height
X
[j]
X
X
X
X
X
X
12-lead ECGk
X
X
X
X
Chemistry/Hematology/Urinalysis
X
[j]
Xj,l
X
Urine drug screen
X
CYP2D6 genotype
[m]
[m]
β-HCG testn
X
X
X
X
X
MINI Kido, p
X
[g]
CDI-2 (Parent and Self-Report)q
X
Xr
X
X
X
X
Children’s C-SSRS (Baseline/Screen)p
X
Children’s C-SSRS (Since Last Visit) p
Xr
X
X
X
X


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Part A
Screeninga
Titration
Maintenance
Study weekb
Parent study
Day 1c
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
5
(Day 
35)
6
(Day 
42)
7
(Day 
49)
8
(Day 
56)
15
(Day 
105)
21
(Day 
147)
C-17
046 or 060
Visit window (days)
<31 days
<31 days
0
±3 days
YGTSSs, t
X
Xr
Xu
X
Xu
Xu
TS-CGIt
Xr
X
X
X
TS-PGIIt
Xr
X
X
X
t
Xr
X
X
X
Xr
X
X
X
p
Xr, v
Xw
C&A-GTS-QOL (including VAS)p
X
X
Contact IRT and dispense IMP and patient diary
Xx
Xx
Xx
Xx
Xy
Xy
Collect IMP
X
X
X
X
X
Assess IMP accountability/compliance/supply
Xz
X
Xz
X
Xz
X
Xz
X
X
Xz
Assess adverse events
X
Xr
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsaa
X
Xr
X
X
X
X
X
X
X
X
X
X
a Full screening visit is required for patients who previously completed Study SD-809-C-17. This visit is not required for patients who completed Study TV50717-CNS-30046 
or Study TV50717-CNS-30060.
b Assessment to occur at the end of study week (±3 days).
c For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, the week 13 visit (Study TV50717-CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) will be the day 1 visit for Study TV50717-CNS-30047, and patients will continue to enter dosing times in the diary through completion of 
Study TV50717-CNS-30047. Patients rolling over from Study SD-809-C-17 will need to undergo all day 1 assessments. Study TV50717-CNS-30047 day 1 assessments that are 
identical to Study TV50717-CNS-30046 week 13 or Study TV50717-CNS-30060 week 9 visit assessments do not need to be repeated. 
d The screening visit may be conducted over 2 separate visits at the discretion of the investigator.
e Dose adjustment will be made by the investigator after telephone contact with the patient and caregiver/adult to evaluate tic reduction and adverse events (Table 2).
f For patients enrolled from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, informed consent/assent, depending on the child’s age, as appropriate, may be obtained 
up to 4 weeks in advance.
g For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, these data will be obtained from the screening visit of the parent study.
h Weight must be measured with shoes and outerwear off. Before pulse and BP are measured, the patient must be in a supine or semi erect/seated position and resting for at least 
5 minutes (the same position and arm should be used each time vital signs are measured for a given patient).
i Orthostatic BP and pulse will be measured after patient is in a standing position for at least 3 minutes.


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j For patients rolling over from Study TV50717-CNS-30046, these data will be obtained from the week 12 visit of the parent study. For patients rolling over from Study TV50717-
CNS-30060, these data will be obtained from the week 8 visit of the parent study.
k All ECGs will be performed after at least 5 minutes rest in a supine or semi-supine position.
l For patients with clinically significant laboratory abnormalities at week 12 in Study TV50717-CNS-30046, the week 13 value will serve as the day 1 in this study. For patients 
with clinically significant laboratory abnormalities at week 8 in Study TV50717-CNS-30060, the week 9 value will serve as the day 1 in this study. Rollover for such patients 
must be approved by the medical monitor and may be delayed.
m Genotype data will be obtained from the relevant parent study. For the patients rolling over from Study SD-809-C-17, these data will come from the CSR and will be 
communicated to the relevant investigator.
n For females who are postmenarchal or ≥12 years of age, a urine test will be administered on day 1 and weeks 4, 8, 15, 28, and 34. A serum test will be administered at screening, 
week 54, and if clinically indicated.
o MINI Kid modules to be used are as follows: Major Depressive Episode (Module A), (Hypo) Manic Episode (Module D), OCD (Module J), Alcohol Dependence/Abuse 
(Module L), Substance Dependence/Abuse (Non-alcohol; Module M), ADHD (Module O), Conduct Disorder (Module P), and Psychotic Disorders and Mood Disorders with 
Psychotic Features (Module R).
p For children 13 years of age and under, interviews may be performed separately or jointly with the caregiver/adult as appropriate or defined by the scale. For children over 
13 years of age, caregiver/adult involvement is strongly encouraged. Questions should be directed to the child, but the caregiver/adult should be encouraged to add relevant 
information.
q Children 6 years of age at day 1 will not complete the Self-Report version; the caregiver/adult will complete the Parent version.
r For patients rolling over from Study TV50717-CNS-30046, these data will be obtained from the week 13 visit of the parent study. For patients rolling over from Study TV50717-
CNS-30060, these data will be obtained from the week 9 visit of the parent study.
s Input from the caregiver/adult is required.
t The YGTSS, TS-CGI, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG assessments.
u Perform assessment of “Severity Ratings” of the questionnaire. Inventory portions (ie, “Motor Tic Symptom Checklist” and “Phonic Tic Symptom Checklist”) do not need to be 
performed.
v A complete assessment will be performed for patients who completed Study SD-809-C-17. For patients who completed Study TV50717-CNS-30046 or Study TV50717-
CNS-30060, only perform the Severity Ratings of OCD symptoms (Questions 1 through 10); checklist does not need to be performed.
w Perform the Severity Ratings of OCD symptoms (Questions 1 through 10) only. Checklist does not need to be performed.
x Study drug will be dispensed in the clinic; patients will receive doses for 2 weeks (current dose level and next dose level) to cover the telephone contacts. The site will determine 
titration (ie, starting the next dose) for the patient by telephone. See Table 2 for weight-based dosing titration.
y Patients will receive enough doses to cover treatment until the following in-clinic visit.
z The site needs to discuss the drug status during the telephone contacts to ensure the patient has adequate tablets, inform the patient if they should titrate (only during the titration 
period), and remind them to bring completed bottles to the next in-clinic visit.
aa Parents/Patients will be instructed during the course of the study to notify the investigator if any new medication is prescribed/administered, including over-the-counter 
medications. Any prescribed medication should be reviewed with the investigator.
ADHD=Attention Deficit Hyperactivity Disorder; β-HCG=beta-human chorionic gonadotropin; BP=blood pressure; CDI-2=Children’s Depression Inventory, Second Edition, 
Parent and Self-Report Profiles; CSR=clinical study report; C-SSRS=Columbia-Suicide Severity Rating Scale; CY-BOCS=Children’s Yale-Brown Obsessive-Compulsive Scale; 
CYP2D6=cytochrome P450 2D6; ECG=electrocardiogram; ET=early termination visit; C&A-GTS-QOL=Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life; 
IMP=Investigational Medicinal Product; IRT=Interactive Response Technology; MINI Kid=Mini International Neuropsychiatric Interview For Children and Adolescents
(version 6.0); TS-CGI=Tourette Syndrome-Clinical Global Impression; OCD=obsessive-compulsive disorder; TS-PGII=Tourette Syndrome-Patient Global Impression of Impact; 
TS-PGIS=Tourette Syndrome-Patient Global Impression of Severity; U=unscheduled visit; UA=urinalysis; VAS=visual analog scale; YGTSS=Yale Global Tic Severity Scale.


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Table 1 Study Procedures and Assessments (continued)
Part B: Blinded, randomized drug 
withdrawal/titration post-drug withdrawal period
Part A resumed
Randomized 
drug 
withdrawal
Maintenance (resumed) or 
titration post-drug withdrawal
Maintenance
Follow-up
U
Study weeka
28b
(Day 
196)
29
(Day 
203)
30
(Day 
210)
31
(Day 
217)
32
(Day 
224)
33
(Day 
231)
34
(Da
y 
238
)
41
(Da
y 
287)
47
(Da
y 
329)
54/E
Tc
(Day 
378)
55
(Day 
385)
56d
(Day 
392)
Visit window (days)
±3 days
±3 
days
±3 days
±3 days from 
week 54
In-clinic visit
X
X
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
Evaluate/Adjust IMP
X
X
X
X
X
Informed consent/assent
Vital signs and weighte
Xf
X
X
X
X
Xf
X
X
Physical examination
X
X
X
Xg
Neurological examination
X
Xg
Height
X
X
X
X
X
X
X
Xg
12-lead ECGh
X
X
Xg
Chemistry/Hematology/Urinalysis
X
X
Xg
Urine drug screen
Xg
β-HCG testi
X
X
X
Xg
CDI-2 (Parent and Self-Report)j
X
X
X
X
X
X
Xg
Children’s C-SSRS (Baseline/Screening)k
Children’s C-SSRS (Since Last Visit)k
X
X
X
X
X
X
Xg
YGTSSl, m
X
X
X
Xn
X
Xn


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Part B: Blinded, randomized drug 
withdrawal/titration post-drug withdrawal period
Part A resumed
Randomized 
drug 
withdrawal
Maintenance (resumed) or 
titration post-drug withdrawal
Maintenance
Follow-up
U
Study weeka
28b
(Day 
196)
29
(Day 
203)
30
(Day 
210)
31
(Day 
217)
32
(Day 
224)
33
(Day 
231)
34
(Da
y 
238
)
41
(Da
y 
287)
47
(Da
y 
329)
54/E
Tc
(Day 
378)
55
(Day 
385)
56d
(Day 
392)
Visit window (days)
±3 days
±3 
days
±3 days
±3 days from 
week 54
TS-CGIm
X
X
X
X
X
TS-PGIIm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xo
C&A-GTS-QOL (including VAS)k
X
X
X
Contact IRT and dispense IMP and patient diary
Xp
Xp
Xp
Xq
Xq
Xg,r
Collect IMP
X
X
X
X
X
X
Xg
Assess IMP accountability/compliance/supply
X
Xs
X
Xs
X
X
Xs
X
Xs
X
Xg
Assess adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationst
X
X
X
X
X
X
X
X
X
X
X
X
X
a Assessments to occur at end of study week (±3 days).
b At the week 28 visit, the patients will be randomized 2:1 to their current dose of TEV-50717 or placebo in order to check for return of symptoms.
c For patients who withdraw prematurely, an early termination visit should be conducted as soon as possible after the last dose of IMP. All patients who discontinue early will 
have a follow-up telephone contact for safety evaluation 2 weeks after their last dose of IMP; evaluations will be as described for week 54 visit.
d This visit is a telephone contact for safety evaluation.
e Weight must be measured with shoes and outerwear off. Before pulse and BP are measured, the patient must be in a supine or semi erect/seated position and resting for at least 
5 minutes (the same position and arm should be used each time vital signs are measured for a given patient).
f Orthostatic BP and pulse will be measured after patient is in a standing for at least3 minutes.
g Assessment to be completed at investigator's discretion.
h All ECGs will be performed after at least 5 minutes rest in a supine or semi-supine position.


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i For females who are postmenarchal or ≥12 years of age, a urine test will be administered on day 1 and weeks 4, 8, 15, 28, and 34. A serum test will be administered at screening, 
week 54, and if clinically indicated.
j Children 6 years of age at day 1 will not complete the Self-Report version; the caregiver/adult will complete the Parent version.
k For children 13 years of age and under, interviews may be performed separately or jointly with the caregiver/adult as appropriate or defined by the scale. For children over 
13 years of age, caregiver/adult involvement is strongly encouraged. Questions should be directed to the child, but the caregiver/adult should be encouraged to add relevant 
information.
l Input from the caregiver/adult is required.
m The YGTSS, TS-CGI, TS-PGIS, and TS-PGII questionnaires should be performed before any blood draws or ECG assessments.
n Perform assessment of “Severity Ratings” of the questionnaire. Inventory portions (ie, “Motor Tic Symptom Checklist” and “Phonic Tic Symptom Checklist”) do not need to be 
performed.
o Perform the Severity Ratings of OCD symptoms (Questions 1 through 10) only. Checklist does not need to be performed.
p IMP will be dispensed in the clinic; patients will receive doses for 2 weeks (current dose level and next dose level, when applicable [week 30 and week 32 visits]) to cover the 
telephone contacts. Because IMP for Part B is dispensed then, the week 28 visit (Day 196) is considered the first day of the randomized withdrawal period, although the patient 
will begin taking blinded IMP on Day 197. When applicable, the site will determine titration (ie, starting the next dose) for the patient by telephone. See Table 3 for dosing 
titration based on the patient’s previously established maintenance dose at the end of Part A.
q Patients will receive enough doses to cover treatment until the following in-clinic visit.
r Contact IRT if IMP assignment or adjustment is required.
s The site needs to discuss the drug status during the telephone contacts to ensure the patient has adequate tablets, inform the patient if they should titrate (only during the titration 
period), and remind them to bring completed bottles to the next in-clinic visit.
t Parents/patients will be instructed during the course of the study to notify the investigator if any new medication is prescribed/administered, including over-the-counter 
medications. Any prescribed medication should be reviewed with the investigator.
ADHD=Attention Deficit Hyperactivity Disorder; β-HCG=beta-human chorionic gonadotropin; BP=blood pressure; CDI-2=Children’s Depression Inventory, Second Edition, 
Parent and Self-Report Profiles; C-SSRS=Columbia-Suicide Severity Rating Scale; 
; CYP2D6=cytochrome 
P450 2D6; ECG=electrocardiogram; ET=early termination visit; C&A-GTS-QOL=Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life; IMP=Investigational 
Medicinal Product; IRT=Interactive Response Technology; MINI Kid=Mini International Neuropsychiatric Interview For Children and Adolescents (version 6.0); 
TS-CGI=Tourette Syndrome-Clinical Global Impression; OCD=obsessive-compulsive disorder; TS-PGII=Tourette Syndrome-Patient Global Impression of Impact; 
 U=unscheduled visit; UA=urinalysis; VAS=visual analog scale; YGTSS=Yale Global Tic Severity Scale.


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3.13.1.
Procedures for Screening and Enrollment (Visit 1)
Informed consent/assent, depending on the child’s age, as appropriate, will be obtained before 
any study procedures are performed. For patients rolling over from Study TV50717-CNS-30046 
or Study TV50717-CNS-30060, informed consent/assent, as appropriate, may be obtained prior 
to the day 1 visit, up to 4 weeks in advance of open-label study participation.
For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, 
screening data will be obtained from the parent study (see Table 1). Informed consent/assent, as 
appropriate, must be given before any procedures related solely to Study TV50717-CNS-30047 
are performed.
For patients from Study SD-809-C-17: 
All screening procedures will be performed for patients rolling over from Study SD-809-C-17, as 
they will have been off IMP for several months at the time of enrollment into this study 
(TV50717-CNS-30047). A signed and dated informed consent form will be obtained from the
parent/legally acceptable representative, and a signed and dated assent, depending on the child’s 
age, as appropriate, will be obtained from each patient before any screening procedures 
commence, according to national laws and local IEC/IRB requirements. Parents/legally 
acceptable representatives will acknowledge and agree to the possible use of this information for 
the study by giving informed consent.
A patient who is screened but not enrolled may be rescreened 1 time if there is a change in the 
patient’s medical background, a modification of study entry criteria, or other relevant change. 
(Note: Details of rescreening must be approved and documented by the medical monitor and/or 
CST team.)
The screening visit will take place not more than 31 days before the day 1 visit. The screening 
visit may be conducted over 2 separate visits at the discretion of the investigator. The following 
procedures will be performed at the screening visit for patients from Study SD-809-C-17:

obtain written informed consent (and assent, depending on the child’s age, as 
appropriate) before any other study-related procedures are performed

conduct clinic visit

review eligibility (inclusion and exclusion) criteria

inform patients of study restrictions and compliance requirements

review medical and psychiatric history

review demographics information

measure vital signs (pulse, BP, body temperature, and respiratory rate)

perform full physical and neurological examinations (including height and weight; 
note: weight must be measured with shoes and outerwear off)

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.).


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
perform clinical laboratory tests, including serum chemistry, hematology, and urine 
analyses

perform urine drug screen (UDS)

perform a serum pregnancy (β-HCG) test (only in females who are postmenarchal or 
≥12 years of age)

administer the following questionnaires (Note: For MINI Kid and Children’s 
C-SSRS, children 13 years of age and under may be interviewed separately or jointly 
with the caregiver/adult as appropriate or defined by the scale. For children over 13 
years of age, caregiver/adult involvement is strongly encouraged. Questions should be 
directed to the child, but the caregiver/adult should be encouraged to add relevant 
information. The YGTSS questionnaire should be performed before any blood draws 
or ECG assessments.):

MINI Kid (Note: The following modules will be used: Major Depressive Episode 
[Module A], [Hypo] Manic Episode [Module D], Obsessive-Compulsive Disorder 
[OCD; Module J], Alcohol Dependence/Abuse [Module L], Substance 
Dependence/Abuse [Non-alcohol; Module M], Attention Deficit Hyperactivity 
Disorder [ADHD; Module O], Conduct Disorder [Module P], and Psychotic 
Disorders and Mood Disorders with Psychotic Features [Module R].)

CDI-2, Parent and Self-Report Profiles (Note: Children 6 years of age on day 1
will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

C-SSRS (children’s baseline/screening)

YGTSS (Input from the caregiver/adult is required.)

review medication history and concomitant medications

inquire about adverse events
3.13.1.1.
YGTSS Rater Certification
All investigators and subinvestigators who will be administering the YGTSS from screening 
through the end of study visit must undergo and pass a Rater Certification Program which will be 
provided separately from this protocol. Every effort must be made to ensure that the same 
certified rater administers the YGTSS to a specific patient at all visits where this scale is 
administered, especially at day 1 and at weeks 28, 30, and 54/early termination visits. However, 
if due to unforeseen circumstances the same rater is absolutely unavailable to complete a visit 
rating, the YGTSS can be administered only by another certified individual from that study site.
3.13.2.
Procedures Before Investigational Medicinal Product Treatment (Day 1)
For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, the 
week 13 visit (Study TV50717-CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) 
will be the day 1 visit for Study TV50717-CNS-30047. Patients rolling over from 
Study SD-809-C-17 will need to undergo all day 1 assessments. Day 1 assessments for 


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Study TV50717-CNS-30047 that are identical to Study TV50717-CNS-30046 week 13 or 
Study TV50717-CNS-30060 week 9 visit assessments do not need to be repeated.
The following procedures will be performed at the day 1 visit, as they:

conduct clinic visit

review eligibility (inclusion and exclusion) criteria (required for all patients)

measure vital signs (orthostatic pulse and BP after standing for at least 3 minutes), 
height, and weight

perform 12-lead ECG (required for all patients). Note: ECG will be performed after at 
least 5 minutes rest in a supine or semi-supine position.

perform clinical laboratory tests, including serum chemistry, hematology, and urine 
analyses

perform a urine pregnancy (β-HCG) test (required for all females who are 
postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: For C-SSRS,
 
 and C&A-GTS-QOL, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined by 
the scale. For children over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information. The YGTSS, TS-CGI, 
 and 
TS-PGII questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-Report Profiles (Note: Children 6 years of age on day 1
will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

C-SSRS (children’s SLV)

YGTSS; a complete assessment will be performed for patients who completed 
Study SD-809-C-17. For patients who completed Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, perform assessment of “Severity Ratings” of the 
questionnaire; inventory portions (ie, “Motor Tic Symptom Checklist” and 
“Phonic Tic Symptom Checklist”) do not need to be performed (Input from the 
caregiver/adult is required).

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)
 
 


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
C&A-GTS-QOL (including VAS) (required for all patients)

dispense IMP (sufficient doses for 2 weeks [current dose level and next dose level] to 
cover the telephone contacts) and patient diary

patients will continue to enter dosing times in the diary through completion of the 
study

review concomitant medications

inquire about adverse events
A patient who is not enrolled in the study on the basis of results of day 1 assessments (eg, 
because inclusion and exclusion criteria were not met or enrollment did not occur within the 
specified time) may be rescreened if there is a change in the patient’s medical background, a 
modification of study inclusion and exclusion criteria, or other relevant change. (Note: Details of 
rescreening must be approved and documented by the medical monitor and/or CST team.)
Patients from Study SD-809-C-17 who continue to meet the inclusion and exclusion criteria will 
be assigned a permanent unique treatment number. This assigned number will be entered in the 
CRF.
3.13.3.
Procedures During Investigational Medicinal Product Treatment
3.13.3.1.
Titration Period (Weeks 1 to 7)
3.13.3.1.1. Telephone Contacts (Weeks 1, 3, 5, and 7)
Patients will be contacted by telephone to evaluate tic reduction and adverse events. Dose 
adjustment will be made by the investigator after telephone contact with the patient and 
caregiver/adult. The following procedures/assessments will be performed via telephone contact
at weeks 1, 3, 5, and 7:

assess IMP accountability/compliance/supply status to ensure the patient has adequate 
tablets, inform the patient if they should titrate, and remind them to bring used and 
unused IMP bottles to the next in-clinic visit

inquire about adverse events

review concomitant medications
If a patient experiences an adverse event that is reported during a telephone contact and is 
probably related to the IMP, he or she will be brought to the clinic for evaluation (see 
Section 3.13.5). Based on the telephone evaluation, the investigator will determine whether, with 
the medication already provided, the patient should titrate up, stay at that dose, or reduce the 
dose. If additional IMP is required, it would be ordered from the distributor and provided to the 
patient at an unscheduled visit.


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3.13.3.1.2. In-Clinic Visits (Weeks 2, 4, and 6)
The following procedures/assessments will be performed at in-clinic visits at weeks 2, 4, and 6:

conduct clinic visit

evaluate and, if required, adjust IMP dose (see Section 5.1)

measure vital signs (pulse, BP, body temperature, and respiratory rate); at week 4, 
orthostatic BP and pulse should be measured after the patient is in a standing position
for at least 3 minutes 

measure height and weight (Note: Weight must be measured with shoes and 
outerwear off)

at week 4 only, perform 12-lead ECG (Note: ECG will be performed after at least 
5 minutes rest in a supine or semi-supine position)

perform a urine pregnancy (β-HCG) test (required for all females who are 
postmenarchal or ≥12 years of age) at week 4

administer the following questionnaires (Note: For C-SSRS, 
 
, and C&A-GTS-QOL, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined by 
the scale. For children over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information. The YGTSS, TS-CGI, 
, and 
TS-PGII questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-Report Profiles at weeks 2 and 4 only (Note: Children 6 
years of age on day 1 will not complete the Self-Report version; the 
caregiver/adult will complete the Parent version.)

C-SSRS (children’s SLV) at weeks 2 and 4 only

YGTSS at weeks 2 and 4 only (Note: at week 2, only perform assessment of 
“Severity Ratings” of the questionnaire only. Inventory portions [ie, “Motor Tic 
Symptom Checklist” and “Phonic Tic Symptom Checklist”] do not need to be 
performed. Input from the caregiver/adult is required.)

TS-CGI at week 4

TS-PGII at week 4 (Input from the caregiver/adult is permitted.)
 
[Questions 1 through 10] only; checklist does not need to be performed.)

C&A-GTS-QOL (including VAS); week 6 only


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
dispense IMP (sufficient doses for 2 weeks [current dose level and next dose level]) 
and patient diary

collect used and unused IMP bottles

assess drug accountability/compliance/supply

inquire about adverse events

review concomitant medications
3.13.3.2.
Maintenance Period (Part A: Weeks 8 to 21 and Weeks 34 to 54/Early 
Termination) and Part B: Weeks 30 to 33
3.13.3.2.1. In-Clinic Visits (Weeks 8, 15, 30, 32, 34, 41, and 54/Early Termination Visits)
The following procedures/assessments will be performed at weeks 8, 15, 30, 32, 34, 41, 
and 54/ET:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate); at weeks 8 
and 54, orthostatic BP and pulse should be measured after the patient is in a standing 
position for at least 3 minutes

measure height and weight (Note: weight must be measured with shoes and outerwear 
off)

perform full physical examination (including height) at weeks 30 and 54 

perform neurological examination at week 54 

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.) at weeks 8 and 54

perform clinical laboratory tests, including serum chemistry, hematology, and urine 
analyses at weeks 8 and 54

perform a urine pregnancy (β-HCG) test (required for all females who are 
postmenarchal or ≥12 years of age) at weeks 8, 15, and 34. A serum test will be 
administered at week 54.

administer the following questionnaires (Note: For C-SSRS, 
 
 and C&A-GTS-QOL, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined by 
the scale. For children over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information. The YGTSS, TS-CGI, 
, and 
TS-PGII questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-Report Profiles at weeks 8, 15, 30, 34, 41, and 54 (Note: 
Children 6 years of age on day 1 will not complete the Self-Report version; the 
caregiver/adult will complete the Parent version.)


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
C-SSRS (children’s SLV) at weeks 8, 15, 30, 34, 41, and 54

YGTSS at weeks 8, 15, 30, 34, 41, and 54 (at weeks 8, 15, and 41, only perform 
assessment of “Severity Ratings” of the questionnaire; inventory portions [ie, 
“Motor Tic Symptom Checklist” and “Phonic Tic Symptom Checklist”] do not 
need to be performed. Input from the caregiver/adult is required.)

TS-CGI at weeks 8, 15, 34, 41, and 54

TS-PGII at weeks 8, 15, 34, 41, and 54 (Input from the caregiver/adult is 
permitted.)
 

C&A-GTS-QOL (including VAS) at weeks 34 and 54

dispense IMP (sufficient doses to cover treatment until the following in-clinic visit) 
and patient diary at weeks 8, 15, 30, 32, 34, and 41

assess drug accountability/compliance/supply 

collect used and unused IMP bottles

inquire about adverse events

review concomitant medications
3.13.3.2.2. Telephone Contacts (Weeks 21, 31, 33, and 47)
Patients will be contacted by telephone to evaluate tic reduction and adverse events. The 
following procedures/assessments will be performed via telephone contact at weeks 21, 31, 33, 
and 47:

assess IMP accountability/compliance/supply status to ensure the patient has adequate 
tablets and remind them to bring used and unused IMP bottles to the next in-clinic 
visit

inquire about adverse events

review concomitant medications
If a patient experiences an adverse event that is reported during a telephone contact and is 
probably related to the IMP, he or she will be brought to the clinic for evaluation (see 
Section 3.13.5). Based on the telephone evaluation, the investigator will determine whether, with 
the medication already provided, the patient should titrate up, stay at that dose, or reduce the 
dose. If additional IMP is required, it would be ordered from the distributor and provided to the 
patient at an unscheduled visit.


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3.13.3.3.
Part B: Blinded, Randomized Drug Withdrawal Period/Titration Post-Drug 
Withdrawal Period (Weeks 28 to 33)
3.13.3.3.1. In-Clinic Visit (Week 28)
The following procedures/assessments will be performed at week 28:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate); orthostatic BP 
and pulse should be measured after the patient is in a standing position for at least
3 minutes

measure height and weight (Note: weight must be measured with shoes and outerwear 
off)

perform full physical examination (including height) 

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)

perform clinical laboratory tests, including serum chemistry, hematology, and urine
analyses

perform a urine pregnancy (β-HCG) test (required for all females who are 
postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: For C-SSRS, 
 
, and C&A-GTS-QOL, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined by 
the scale. For children over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information. The YGTSS, TS-CGI, 
, and 
TS-PGII questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-Report Profiles (Note: Children 6 years of age on day 1
will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

C-SSRS (children’s SLV)

YGTSS (only perform assessment of “Severity Ratings” of the questionnaire; 
inventory portions [ie, “Motor Tic Symptom Checklist” and “Phonic Tic 
Symptom Checklist”] do not need to be performed. Input from the caregiver/adult 
is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)


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
C&A-GTS-QOL (including VAS) 

dispense IMP (sufficient doses to cover treatment until the following in-clinic visit)
and patient diary

assess drug accountability/compliance/supply 

collect used and unused IMP bottles

inquire about adverse events

review concomitant medications
3.13.3.3.2. In-clinic Visit (Weeks 30 and 32):

conduct clinic visit

evaluate IMP

measure vital signs (pulse, BP, body temperature, and respiratory rate)

measure height and weight (Note: weight must be measured with shoes and outerwear 
off)

perform physical examination (week 30)

CDI-2, Parent and Self-Report Profiles at week 30 (Note: Children 6 years of age on 
day 1 will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

Children’s C-SSRS (SLV version) at week 30

YGTSS at week 30

dispense IMP (sufficient doses to cover treatment until the following in-clinic visit)
and patient diary

collect used and unused IMP bottles

assess IMP accountability/compliance/supply status to ensure that the patient has 
adequate tablets and remind them to bring used and unused IMP bottles to the next 
in-clinic visit

inquire about adverse events

review concomitant medications
3.13.3.3.3. Telephone Contacts (Weeks 29, 31, and 33)
Patients will be contacted by telephone to evaluate tic reduction and adverse events. Dose 
adjustment will be made by the investigator after telephone contact with the patient and 
caregiver/adult. The following procedures/assessments will be performed via telephone contact 
at weeks 29, 31, and 33:


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
assess IMP accountability/compliance/supply status to ensure the patient has adequate 
tablets, inform the patient if they should titrate, and remind them to bring used and 
unused IMP bottles to the next in-clinic visit

inquire about adverse events

review concomitant medications 
3.13.4.
Procedures After Investigational Medicinal Product Treatment (Follow-Up)
3.13.4.1.
In-Clinic Visit (Week 55)
The following procedures/assessments will be performed at week 55:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate)

measure height and weight (Note: weight must be measured with shoes and outerwear 
off)

administer the following questionnaires (Note: For C-SSRS, 
 
, children 13 years of age and under may be interviewed separately or 
jointly with the caregiver/adult as appropriate or defined by the scale. For children 
over 13 years of age, caregiver/adult involvement is strongly encouraged. Questions 
should be directed to the child, but the caregiver/adult should be encouraged to add 
relevant information. The YGTSS, TS-CGI, 
, and TS-PGII questionnaires 
should be performed before any blood draws or ECG assessments.):

CDI-2, Parent and Self-Report Profiles (Note: Children 6 years of age on day 1
will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

C-SSRS (children’s SLV)

YGTSS (only perform assessment of “Severity Ratings” of the questionnaire; 
inventory portions [ie, “Motor Tic Symptom Checklist” and “Phonic Tic 
Symptom Checklist”] do not need to be performed. Input from the caregiver/adult 
is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)
 

inquire about adverse events

review concomitant medications


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3.13.4.2.
Telephone Contact (Week 56)
The following procedures/assessments will be performed at week 56:

inquire about adverse events

review concomitant medications
Patients who participate in the study in compliance with the protocol for at least 54 weeks of 
treatment will be considered to have completed the study. See Section 12.4 for the definition of 
the end of study.
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at an end-of-treatment visit or on the last day the patient receives the IMP, or as soon 
as possible thereafter. Procedures for patients who withdraw prematurely from the study are 
described in Section 4.4. Patients should be treated with standard of care after termination of the 
study as appropriate.
Patients with ongoing adverse events will be monitored as described in Section 7.1.2. Otherwise, 
the follow-up visit will be the last study visit.
3.13.5.
Unscheduled Visits
An unscheduled telephone contact may be performed at the discretion of the investigator.
An in-clinic unscheduled visit should be performed if a patient requires a dose adjustment for 
adverse events reported during a telephone contact. An unscheduled visit may be performed at 
any time during the study at the patient’s request and as deemed necessary by the investigator. 
The date and reason for the unscheduled visit will be recorded on the CRF as well as any other 
data obtained (eg, adverse events, concomitant medications and treatments, and results from 
procedures or tests).
The following procedures/assessments will be performed at all in-clinic unscheduled visits:

conduct clinic visit

evaluate and, if required, adjust IMP dose (see Section 5.1)

measure vital signs (pulse, BP, body temperature, and respiratory rate)

measure weight (Note: weight must be measured with shoes and outerwear off) 

inquire about adverse events

review concomitant medications
The following procedures/assessments may be performed at unscheduled visits per the 
investigator’s discretion:

measure height

perform physical examination 

perform neurological examination 

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)


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
perform clinical laboratory tests, including chemical, hematological, and urine 
analyses 

perform UDS

perform a urine/serum pregnancy (β-HCG) test (required for all females who are 
postmenarchal or ≥12 years of age)

administer the following questionnaires

CDI-2, Parent and Self-Report Profiles (Note: Children 6 years of age on day 1
will not complete the Self-Report version; the caregiver/adult will complete the 
Parent version.)

C-SSRS (children’s SLV; Note: Children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined 
by the scale. For children over 13 years of age, caregiver/adult involvement is 
strongly encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information.)

if applicable, dispense additional IMP

collect used and unused IMP bottles

assess drug accountability/compliance/supply 
Other procedures may also be performed at the discretion of the investigator.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by the sponsor/development partner (see Section 11.1.2).
4.1.
Patient Inclusion Criteria
Patients who have completed Study TV50717-CNS-30046 or Study TV50717-CNS-30060 have 
already met the criteria below.
In addition, patients who have completed Study SD-809-C-17 may be included in the study if,
during screening, they meet all of the following criteria:
a.
Patient is younger than 18 years of age on day 1.
b. Patient weighs at least 44 pounds (20 kg) on day 1.
c.
Patient is able to swallow IMP whole.
d. Patient and caregiver/adult are willing to adhere to IMP regimen and comply with all 
study procedures.
e.
Patient is in good general health, as indicated by medical and psychiatric history as 
well as physical and neurological examination.
f.
In the investigator’s opinion, the patient and caregiver/adult have the ability to 
understand the nature of the study and its procedures, and the patient is expected to 
complete the study as designed.
g. Patient and caregiver/adult provide written informed consent/assent, depending on the 
child’s age, as appropriate, according to local regulations.
h. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative β-HCG test on day 1 or are sterile. Definitions of sterile are given 
in Appendix L.
i.
Females who are postmenarchal or ≥12 years of age whose male partners are 
potentially fertile (ie, no vasectomy) must use highly effective birth control methods 
for the duration of the study (ie, starting at screening) and for 30 days or 5 half-lives, 
whichever is longer after last dose of IMP. Further details are included 
in Appendix L.
4.2.
Patient Exclusion Criteria
Patients who have completed Study TV50717-CNS-30046 or Study TV50717-CNS-30060 have 
already been confirmed to not meet any of the below criteria.
In addition, patients who have completed Study SD-809-C-17 will not be enrolled if, during 
screening, they meet any of the following criteria:
a.
Patient is 18 years of age or older.
b. Patient has a neurologic disorder other than TS that could obscure the evaluation of 
tics.
c.
The patient’s predominant movement disorder is stereotypy (coordinated movements 
that repeat continually and identically) associated with autism spectrum disorder. 
d. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another 
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e.
Patient has clinically significant depression at screening or day 1. 
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 6 weeks before screening.
f.
Patient has a history of suicidal intent or related behaviors within 2 years of 
screening, defined as:

previous intent to act on suicidal ideation with a specific plan, irrespective of level 
of ambivalence, at the time of suicidal thought

previous suicidal preparatory acts or behavior
g. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
h. Patient has a first-degree relative who has completed suicide.
i.
Patient has clinically significant OCD on day 1 that, in the opinion of the investigator, 
is the primary cause of impairment.
j.
Patient has received comprehensive behavioral intervention for tics for TS or 
cognitive behavioral therapy for OCD within 4 weeks of screening.
k. Patient has received any of the following concomitant medications for tics within the 
specified exclusionary windows of screening prior to dosing for washout:

within 3 months: depot neuroleptics, botulinum toxin, or tetrabenazine

within 4 weeks: cannabidiol oil and Valbenazine

within 21 days: reserpine 

within 14 days: neuroleptics (oral), typical and atypical antipsychotics 
(see Appendix A, Table 7), metoclopramide, levodopa, and dopamine agonists 
Note: Use of stimulant medications, including amphetamine, methylphenidate, 
and lisdexamfetamine, is allowed if primary use is for the treatment of ADHD and 
dosing has been stable for at least 2 weeks before screening.
Note: Use of atomoxetine is allowed if the primary use is for the treatment of 
ADHD, dosing has been stable for at least 4 weeks before screening.
Note: Use of benzodiazepines is allowed if the primary use is not for tics and 
dosing has been stable for at least 4 weeks before screening.
Note: Use of topiramate (up to 200 mg/day) is allowed if the dosing has been 
stable for at least 4 weeks before screening. 
Note: Use of guanfacine or clonidine is allowed regardless of indication (ie, if 
prescribed for tics or Tourette syndrome) if the dosing has been stable for at least 
4 weeks before screening and no changes to dose or frequency are anticipated 
during the course of the study.
l.
Patient has an unstable or serious medical illness at screening or day 1.
m. Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
interval value >450 msec (males) or >460 msec (females) or >480 msec (with right 
bundle branch block) on 12-lead ECG at screening. Patient requires treatment with 


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drugs known to prolong the QT interval (see Appendix A Table 8 for a complete list 
of prohibited QT-prolonging drugs).
n. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart failure.
o. Patient has evidence of hepatic impairment, as indicated by:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the 
upper limit of the normal range (ULN) at screening

alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
Note: Patients with Gilbert’s Syndrome are eligible to participate if approved by 
the medical monitor. 
Note: Patients with abnormalities in 2 or more of the following clinical laboratory 
parameters must be approved for enrollment by the medical monitor: AST, ALT, 
ALP, and Tbil. 
p. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5 × ULN at screening. 
q. Patient has received a monoamine oxidase inhibitor within 14 days of the day 1 visit.
r.
Patient has a known allergy to any of the components of the IMP.
s.
Patient has participated in an investigational drug or device study (with the exception 
of Study SD-809-C-17 or Study TV50717-CNS-30046 or Study TV50717-
CNS-30060) and received IMP/intervention within 30 days.
t.
The patient is a pregnant or lactating female, or has plans to become pregnant during 
the study.
u. Patient has a history of or acknowledges alcohol-related disorder in the previous 
12 months, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition, Text Revision (DSM-V™).
v. Patient has a positive UDS test result or is unable to refrain from substance abuse 
throughout the study.
w. Patient has a DSM diagnosis based on the MINI Kid modules performed at screening 
that, in the opinion of the investigator, makes the patient unsuitable for the study (for 
patients rolling over from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060, these data will be obtained from the screening visit of the parent study).
4.3.
Justification for Key Inclusion and Exclusion Criteria
Inclusion and exclusion criteria have been designed to minimize the risk to patients while 
maintaining a consistent level of TS symptoms to allow detection and analysis of a drug effect. 
Exclusion criteria were designed to exclude patients with concomitant conditions that may 
increase their risk to drug treatment.
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (and in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study if any of the following events occur:
a.
intercurrent illness


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b. adverse events (any patient who experiences an adverse event may be withdrawn 
from the study or from study treatment at any time at the discretion of the investigator 
or sponsor as indicated in Section 7.1.7)
c.
pregnancy (see Section 7.3)
d. other reasons concerning the health or well-being of the patient
e.
lack of cooperation
f.
post-baseline QTcF value >500 msec or change from baseline >60 msec (as described 
in Section 7.1.7). The investigator should repeat the ECG assessment twice and 
compare the average of the 2 pre-treatment QTcF values (ie, the parent study baseline 
and screening values for patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 or the day 1 and screening values from the current study 
for patient[s] who completed Study SD-809-C-17) to the average of the 3 post-
baseline QTcF values. The IMP must be stopped for any confirmed post-day 1 QTcF 
value >500 msec or increase from baseline >60 msec.
g. when a blind is broken due to safety concerns (see Section 3.6.2). If a patient is 
unblinded by mistake, the investigator should discuss with the medical monitor 
whether or not the patient should be withdrawn.
h. if the investigator or the sponsor determines that the patient is not in compliance with 
the study protocol, the investigator and the sponsor should determine whether the 
patient should be withdrawn from the study (Section 5.4).
In addition, a patient may be withdrawn from the study as described in 
Sections 3.11, 3.6, 5.4, 7.1.7, and 3.13. 
Should a patient decide to withdraw after administration of IMP, or should the investigator 
decide to withdraw the patient, all efforts will be made to complete and report all observations up 
to the time of withdrawal. A complete final evaluation of the patient’s withdrawal should be 
made as soon as possible after the last dose of IMP, and an explanation should be given as to 
why the patient is withdrawing or being withdrawn from the study. Assessments to be conducted 
at the early termination visit are described in Section 3.13.3.2.1.
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed onto the CRF. If a patient withdraws consent, every attempt will 
be made to determine the reason. If the reason for withdrawal is an adverse event or a potentially 
clinically significant abnormal laboratory test result, monitoring will be continued at the 
discretion of the investigator (eg, until the event has resolved or stabilized, until the patient is 
referred to the care of a health care professional, or until a determination of a cause unrelated to 
the IMP or study procedure is made). The specific event or test result must be recorded on the 
source documentation and transcribed onto the CRF. 
All patients who discontinue early will have a follow-up telephone contact for safety evaluation 
2 weeks after their last dose of IMP (Section 3.13.4.2).


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5.
TREATMENT OF PATIENTS
5.1.
Investigational Medicinal Products Administered During the Study
During the open-label period, TEV-50717 tablets are available in the following dose strengths: 6, 
9, and 12 mg. Patients will receive twice daily dosing for up to 54 weeks (those on the 6-mg dose 
will receive once-daily dosing), with an initial 7-week titration period to allow for optimal dose 
selection. 
During the randomized drug withdrawal and re-titration period, TEV-50717 tablets are available 
in the following dose strengths: 6, 9, 12, 15, and 18 mg, all of which are identical in size, shape, 
and color (white). The IMP will be supplied in 20-count bottles. The placebo tablets and 
packaging will match those for TEV-50717. 
Patients who receive TEV-50717 during the randomized drug withdrawal period will remain on 
their maintenance dose of blinded active IMP from the start of week 31 to the start of week 34; 
those assigned to placebo during the randomized drug withdrawal period will undergo blinded 
re-titration from the start of week 31 to the start of week 34 back to their previously established 
maintenance dose from the end of week 28. Note that, because IMP is dispensed for 2-week 
periods, patients will use blinded bottles through the end of week 34; however, all patients will 
be known to be on active treatment at the start of week 34. 
5.1.1.
Drug Administration
IMP (see Section 3.9) will be administered as oral tablets at a starting dose of 6 mg once daily. 
Titration schemes based on body weight on day 1 are shown in Table 2. The maximum daily 
dose is determined by body weight and CYP2D6 impairment status on day 1 (see Table 2). 
Although dose adjustments can be made up to and including the week 7 telephone call, if a stable 
dose is reached before then, the patient should continue taking that dose for the remainder of the 
titration period. If a patient experiences depression, suicidal ideation or behavior, anxiety, 
akathisia, parkinsonism, somnolence, any other adverse event that interferes with daily activity, 
or adverse event that is related to IMP, the investigator will determine if a dose reduction or 
suspension is necessary. At the end of the titration period, the patient’s dose will be established 
for the maintenance period. If a patient experiences an adverse event during the maintenance 
period and the investigator believes a dose reduction is warranted, the dose may be reduced.
Dose adjustments of TEV-50717 (upward or downward) may be made during the maintenance 
period, if necessary, but not more often than every 5 days and only in increments of 6 mg.
IMP will be dispensed in the clinic. Patients should take their first dose in the evening on day 1 
after their day 1 clinic visit. Patients will receive sufficient doses to last until the next visit.
IMP will be administered as follows:

IMP should be swallowed whole and taken with food. Tablets should be taken with 
food (eg, a snack) and should not be taken on an empty stomach.

Dosing will be based on body weight and CYP2D6 impairment status, as shown in 
Table 2.


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
The total daily dose, as provided in Table 2, is divided into a twice daily 
administration. The starting dose is 6 mg in all patients. Daily doses will be 
administered twice daily, approximately 8 to 10 hours apart during the day (those on 
the 6-mg dose will have once-daily dosing). A minimum of 6 hours should elapse 
between doses. If a patient misses a dose and it is within 6 hours of their next dose, 
the missed dose should be skipped.

After week 1, dose increases may not occur more frequently than once every 5 days.

Dose reductions, if required, should be in increments of 6 mg. If more than 1 dose 
reduction is required for an adverse event, the medical monitor should be 
notified.

After dose adjustment, if the maintenance dose for a patient is 6 mg, the dose should 
be taken once a day in the morning with food.

During the titration period, the dose of the IMP should be adjusted according to 
Table 2 to identify a dose level that optimally reduces tics (as determined by the 
investigator, in consultation with the patient and caregiver/adult) and is well tolerated.
A dose cap for impaired patients is prespecified by the IRT and presented in Table 2.

After week 24, patient dose should be kept stable, if possible, until beginning Part B.

During the randomized drug withdrawal period, the patient will continue to receive 
their current dose of TEV-50717 or receive matching placebo until returning to their
dose of TEV-50717 at the start of week 31 (patients who receive TEV-50717 during 
the randomized drug withdrawal period will remain on their maintenance dose of 
blinded active IMP from the start of week 31 to the start of week 34; those assigned 
to placebo during the randomized drug withdrawal period will undergo blinded 
re-titration from the start of week 31 to the start of week 34 back to their previously 
established maintenance dose from the end of week 28). During the re-titration
period, the dose of the IMP should be adjusted according to Table 3.

Following re-titration, the dose of IMP should be kept stable, if possible, but changes 
can be made as described for Part A.
IMP will be packaged in bottles and provided for patients to take at home (see Section 3.8). 
Table 2:
Maximum Daily Dose of IMP by Study Day and Weight Category on Day 1
for Titration at Study Initiation
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP impairment 
status
Not 
impaired
Impaired Not 
impaired
Impaired Not impaired
Impaired
Day 1-7
6 mg
6 mg
6 mg
6 mg
6 mg (Days 1
and 2)
12 mgb
6 mg (Days 1 
and 2)
12 mgb
Day 8-14
12 mg
12 mg
12 mg
12 mg
18 mg
18 mg


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Table 2:
Maximum Daily Dose of IMP by Study Day and Weight Category on Day 1 
for Titration at Study Initiation (Continued)
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP impairment 
status
Not 
impaired
Impaired Not 
impaired
Impaired Not impaired
Impaired
Day 15-21
18 mg
18 mg
18 mg
18 mg
24 mg
24 mg
Day 22-28
18 mg
18 mg
24 mg
24 mg
30 mg
30 mg
Day 29-35
24 mg
18 mg
30 mg
24 mg
36 mg
36 mg
Day 36-42
24 mg
18 mg
36 mg
24 mg
42 mg
36 mg
Day 43-49
30 mg
18 mg
42 mg
24 mg
48 mg
36 mg
a Administration of a given dose will take place throughout the days indicated. The new dose starts the morning 
after the telephone contact or the morning after the clinic visit as applicable.
b Patients will receive 6 mg on days 1 and 2, and 12 mg starting on day 3.
CYP=cytochrome P450; IMP=investigational medicinal product.
Note: CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor
metabolizer. The investigator, in consultation with the patient and caregiver/adult, will determine if a dose increase 
is warranted to achieve optimal tic reduction.
Table 3:
Daily Dose of IMP by Previously Established Maintenance Dose and 
Study Week (Titration Post-Drug Withdrawal) for Patients Randomized to 
Placebo During the Blinded, Randomized Drug Withdrawal Period
Daily dose (mg) at the start of week
Previously established 
maintenance dose
a (mg)
Day 211 
(start of 
week 31)
Day 218 
(start of 
week 32)
Day 225 
(start of 
week 33)
Day 232 (start of 
week 34) 
maintenance dose
6
6
6
6
6
12
12
12
12
12
18
12
18
18
18
24
12
18
24
24
30
12
18
24
30
36
12
24
30
36
42
12
24
36
42
48
12
24
36
48
a The previously established maintenance dose is the dose administered at the end of Part A (Day 196 [end of 
week 28]). The blinded, randomized drug withdrawal period will occur from the start of week 29 through the end 
of week 30.
IMP=investigational medicinal product.


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5.2.
Restrictions
Medications prohibited before or during the study are described in Section 5.3. 
While patients receiving strong CYP2D6 inhibitors such as paroxetine, fluoxetine, and 
bupropion on day 1 may be enrolled into this study, the removal of strong CYP2D6 inhibitors 
during treatment is discouraged as this would have an effect on exposure to active circulating 
drug. If the removal of a strong CYP2D6 inhibitor is required from a clinical perspective, the 
medical monitor should be contacted so an appropriate change in IMP can be made. The use of 
quinidine and terbinafine are prohibited (see Appendix A, Table 9).
Restrictions in regard to sexual activity and required laboratory values are provided in the 
inclusion and exclusion criteria.
As with other VMAT2 inhibitors (tetrabenazine, reserpine), patients should be advised that the 
concomitant use of alcohol or other sedating drugs with TEV-50717 may have additive effects 
and cause or worsen somnolence. Given the age of the study population, the use of alcohol 
during this study is prohibited. 
Patients should be advised not to drive a car or operate dangerous machinery until they 
understand how TEV-50717 affects them.
Use of illicit drugs is prohibited from the time of signing of the informed consent/assent form 
and throughout study participation.
Patients may not donate blood from the time of informed consent/assent, while taking the IMP, 
and for 14 days after the last dose.
5.3.
Prior and Concomitant Medication or Treatment
Any prior or concomitant therapy, medication, or procedure a patient receives during IMP
administration and up to the end of the study period, including follow-up, will be recorded on the 
CRF. Generic or trade name, indication, and dosage will be recorded. In addition, only for 
patients who completed Study SD-809-C-17, any prior or concomitant therapy, medication, or 
procedure a patient has had within 3 months before IMP administration will be recorded on the 
CRF. The sponsor will encode all therapy and medication according to the World Health 
Organization drug dictionary.
At each clinic visit after the screening visit, the investigator will ask patients whether they have 
taken any medications (other than IMP), including over-the-counter medications, vitamins, or 
herbal or nutritional supplements, since the previous visit. Parents/patients will be instructed 
during the course of the study to notify the investigator if any new medication is 
prescribed/administered, including over-the-counter medications. Any prescribed/administered
medication should be reviewed with the investigator. Indication, dosage, and start and end dates 
should be entered on the CRF. 
Medications that are allowed, provided that conditions outlined in the table are met, are shown 
in Appendix A, Table 6.
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving
during the study) a medication that is associated with QTc prolongation or that is a known strong 
CYP inhibitor. Addition of a strong CYP inhibitor is prohibited.


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Prohibited antipsychotic drugs medications are listed in Appendix A, Table 7, while prohibited 
medications that are associated with QTc prolongation are listed in Appendix A, Table 8.
5.4.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. A check of IMP
compliance will be performed during each visit after the initial dispensation of IMP, and IMP
accountability records will be completed. If the investigator or the sponsor determines that the 
patient is not in compliance with the study protocol, the investigator and the sponsor should 
determine whether the patient should be withdrawn. The IEC/IRB should be notified as required 
by national and local regulations.
5.5.
Dose Reduction and Temporary Investigational Medicinal Product
Discontinuation
Dose Reduction
If a patient experiences a “clinically significant” adverse event that is attributed to IMP, the 
investigator will determine if a dose reduction or suspension is necessary. Dose adjustments 
should be made based on all available information, including the patient and caregiver/adult
reports of adverse events and tic reduction, the clinical assessment of safety and efficacy by the 
investigator, and information from rating scales. If more than 1 dose reduction is required for 
an adverse event, the medical monitor must be notified. After dose adjustment, if the 
maintenance dose for a patient is 6 mg, the dose should be taken once a day in the morning with 
food (other dose levels are taken twice daily).
If the determination that a patient requires a dose reduction or suspension is made during a 
telephone contact, an unscheduled clinic visit should be conducted as soon as practicable 
thereafter.
Dose Suspension
Suspension of study medication for up to 1 week, if warranted for patient safety, is allowed. If 
the patient restarts study medication within 7 days of suspension, the full dose of TEV-50717 
may be resumed without titration. Suspensions of study medication for adverse events must 
be reviewed with the medical monitor before therapy is restarted. If a subject’s serum 
potassium or magnesium were tested and found to be below the lower limit of normal and 
clinically significantly, the laboratory test should be repeated at least once. If the abnormality in 
the repeated laboratory test is consistent with the prior laboratory test, the IMP must be 
suspended. The medical monitor must be contacted to determine the appropriate investigation 
and treatment. TEV-50717 may only be restarted once serum potassium or magnesium have 
normalized.
The reason for a dose reduction or suspension must be clearly documented.
If a dose reduction or suspension occurs before a scheduled clinic visit, the clinic visit will 
be postponed so that efficacy evaluations can be performed at least 5 days after the change.
The patients who restart IMP treatment will follow the visit schedule as outlined in Table 1. 
Patients who withdraw from the study will proceed as described in Section 4.4.


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5.6.
Total Blood Volume
The total volume of blood to be collected for each patient in this study is approximately 30 to 
60 mL, as detailed in Table 4.
Table 4:
Blood Volumes
Type of samples
Volume per sample
(mL)
Total number of 
samples
Total volume (mL)
Clinical laboratory 
(chemistry/hematology)
10
3a to 6b
30a to 60b
a For patients who completed Study TV50717-CNS-30046 or Study TV50717-CNS-30060, 30 to 40 mL will be 
collected.
b For patients who completed Study SD-809-C-17, 50 to 60 mL will be collected.
Note: Beta-human chorionic gonadotropin testing (in females who are postmenarchal or ≥12 years of age) is 
included in the clinical laboratory sample.


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6.
ASSESSMENT OF EFFICACY
Site-administered efficacy scales include the YGTSS and 
 and self-administered 
efficacy scales include the 
 TS-PGII, 
 and C&A-GTS-QOL.
6.1.
Efficacy and Exploratory Measures
 
 
 
 
 
 
 
 
 
6.1.1.
Tourette Syndrome–Clinical Global Impression
TS-CGI is administered on day 1 (ie, week 13 data from Study TV50717-CNS-30046 or week 9 
data from Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55. The TS-CGI 
scale is a 7-point Likert scale that allows the clinician to use all available information to assess 
the impact of tics on the patient’s quality of life. The TS-CGI is rated as follows: 1 (normal), 
2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme).
A reference sample is provided in Appendix H.
6.1.2.
Tourette Syndrome-Patient Global Impression of Impact
The TS-PGII is administered on day 1 (ie, week 13 data from Study TV50717-CNS-30046 or 
week 9 data from Study TV50717 CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55. Input 
from the caregiver/adult is permitted.
The TS-PGII is a single-item questionnaire that asks the patient to assess the degree of impact 
due to current tics. The TS-PGII uses a 5-point scale, ranging from not at all (1) to very 
much (5), to assess overall response to therapy. In general, patient-rated global measures of 
change have face validity and have been shown to correlate with disability for a number of 
chronic conditions.


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6.1.3.
 
 
 
 
 
6.1.4.
 
 
 
 
 
 
 
6.1.5.
Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Scale
The C&A-GTS-QOL is administered on day 1 and weeks 6, 28, 34, and 54. Children 13 years of 
age and under must be interviewed in conjunction with the caregiver/adult. Children 13 years of 
age and under may be interviewed separately or jointly with the caregiver/adult as appropriate or 
defined by the scale. Questions should be directed to the child, but the caregiver/adult should be 
encouraged to add relevant information.
The C&A-GTS-QOL is a 27-item questionnaire specific to TS patients that asks the patient to 
assess the extent to which their quality of life is impacted by their symptoms. The C&A-
GTS-QOL contains 4 subscales (psychological, physical, obsessional, and cognitive) and uses a 
5-point Likert scale ranging from no problem to extreme problem. Patients will also be asked 
how satisfied they feel overall with their life at that moment by using a VAS scale between 0 and 
100 (Su et al 2017).
A reference sample is provided in Appendix K.
6.1.6.
 
 
 


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight and height measurements), use of concomitant 
medication, neurological examination, C-SSRS, and CDI-2.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the IMP, TEV-50717. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during this study will not be considered adverse 
events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions

drug interactions

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant (Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving IMP
are not considered adverse events.)
7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse events, the study period is defined for each patient as that time period 
from signature of the informed consent/assent form to the end of the follow-up period. The 
follow-up period is defined as 2 weeks after the last dose of IMP.


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All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the serious adverse event form must be completed, and 
the serious adverse event must be reported immediately (see Section 7.1.5.3.1). The investigator 
does not need to actively monitor patients for adverse events after the defined period. Serious 
adverse events occurring to a patient after the treatment of that patient has ended should be 
reported to the sponsor if the investigator becomes aware of them, following the procedures 
described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe”. All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved,
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF.
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
Further details are given in the Safety Monitoring Plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities


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7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of an adverse event to the IMP is characterized as follows:
Term
Definition
Clarification
No 
reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be 
unrelated to the IMP.
The relationship of an adverse event may be 
considered “no reasonable possibility” if it is clearly 
due to extraneous causes or if at least 2 of the 
following apply:

It does not follow a reasonable temporal 
sequence from the administration of the 
IMP.

It could readily have been produced by the 
patient’s clinical state, environmental or 
toxic factors, or other modes of therapy 
administered to the patient.

It does not follow a known pattern of 
response to the IMP.

It does not reappear or worsen when the 
IMP is re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection 
with the administration of IMP
cannot be ruled out with certainty.
The relationship of an adverse event may be 
considered “reasonable possibility” if at least 2 of 
the following apply:

It follows a reasonable temporal sequence 
from administration of the IMP.

It cannot be reasonably explained by the 
known characteristics of the patient’s 
clinical state, environmental or toxic factors,
or other modes of therapy administered to 
the patient.

It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does not 
disappear after discontinuation of the IMP, 
yet an IMP relationship clearly exists.

It follows a known pattern of response to the 
IMP.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as the time 
period from signing of the informed consent/assent form to the end of the follow-up period as 
defined in Section 7.1.2. Serious adverse events occurring in a patient after the end of the follow-
up period should be reported to the sponsor if the investigator becomes aware of them, following 
the procedures described in Section 7.1.5.3.1.
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:


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
results in death

is life threatening (ie, the patient was at risk of death at the time of the event); it does 
not refer to an event which hypothetically might have caused death if it were more 
severe

requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled before the patient signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
preexisting condition during the patient’s participation in this study.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

is an important medical event that may not result in death, be life-threatening, or 
require hospitalization, but may jeopardize the patient and may require medical 
intervention to prevent one of the outcomes listed in this definition
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3 × the upper limit of normal (ULN)

total bilirubin increase of >2 × ULN

absence of initial findings of cholestasis (ie, no substantial increase of ALP)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB.
A serious adverse event that is not included in the Listing of Adverse Reactions in the RSI by its 
specificity, severity, outcome, or frequency is considered an unexpected adverse event.
The sponsor’s Global Patient Safety and Pharmacovigilance will determine the expectedness for 
all serious adverse events.


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For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events that occur during the study,
regardless of judged relationship to administration of the IMP, must be reported by the 
investigator according to the instructions provided on the serious adverse event form. The event 
must be reported within 24 hours of when the investigator learns about it. Completing the serious 
adverse event form and reporting the event must not be delayed, even if not all the information is 
available. The investigator does not need to actively monitor patients for adverse events once this 
study has ended.
Serious adverse events occurring to a patient after the last administration of IMP should be 
reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
contract research organization in a country without a sponsor LSO) (contact information is in the 
Clinical Study Personnel Contact Information section); the LSO will forward the report to the 
sponsor’s Global Patient Safety and Pharmacovigilance.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility)
Additional information includes:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data


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
medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death:

cause of death (whether or not the death was related to IMP)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease.
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report.
For all countries, the sponsor’s Global Patient Safety and Pharmacovigilance will distribute the 
Council for International Organizations of Medical Sciences (CIOMS) form/Extensible Markup 
Language (XML) file to the LSO/Syneos Health for submission to the competent authorities,
IEC/IRBs, and investigators, according to regulations. The investigator must ensure that the 
IEC/IRB is also informed of the event, in accordance with national and local regulations.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.3).
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of TEV-50717 and the appropriate competent authorities (and IEC/IRB, as 
appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other actions may be required, including:

altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-50717
7.1.6.
Protocol-Defined Adverse Events of Special Interest 
No protocol-defined adverse events of special interest were identified for this study.


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7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from the study or from IMP at 
any time at the discretion of the investigator. If a post-day 1 QTcF value >500 msec or change 
from baseline (Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or day 1 (Study 
SD-809-C-17), as appropriate (see Section 9.7.2) >60 msec is found, the investigator should 
repeat the ECG assessment twice and compare the average of the 2 pre-treatment QTcF values 
(ie, the parent study baseline and screening values for patients rolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 or the day 1 and screening values from the current 
study for patient[s] who completed Study SD-809-C-17) to the average of the 3 post-day 1 QTcF 
values. The IMP must be stopped for any confirmed post-day 1 QTcF value >500 msec or 
increase from baseline (Study TV50717-CNS-30046 or Study TV50717-CNS 30060) or day 1 
(Study SD-809-C-17) >60 msec. If a patient is withdrawn wholly or in part because of an 
adverse event, both the adverse events page and termination page of the CRF will be completed 
at that time.
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the IMP or study procedure is made). The 
investigator must inform the clinical project physician (CPP)/clinical leader as soon as possible 
of any patients who are being considered for withdrawal due to adverse event(s). Additional 
reports must be provided when requested.
If a patient is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event that, in the opinion 
of the investigator, is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be need to take a prohibited medication, not the adverse event.
7.1.8.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Psychometric Rating Scales
Site-administered safety scales include the MINI Kid and C-SSRS, and self-administered safety 
scales include the CDI-2. 
7.2.1.
Mini International Neuropsychiatric Interview for Children and Adolescents, 
(version 6.0)
Select MINI Kid modules are administered at screening (only for patients who completed 
Study SD-809-C-17). Children 13 years of age and under may be interviewed separately or 
jointly with the caregiver/adult as appropriate or defined by the scale. For children over 13 years 


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of age, caregiver/adult involvement is strongly encouraged. Questions should be directed to the 
child, but the caregiver/adult should be encouraged to add relevant information.
The MINI Kid is a short questionnaire to be administered by a trained clinician. The MINI Kid 
assesses symptoms of psychiatric disorders as outlined in the International Classification of 
Diseases-10 and the DSM in children 6 to 17 years of age by self-report. For children under 
13 years old, the patient may be interviewed separately or jointly with the caregiver/adult as 
appropriate or defined by the scale, and the caregiver/adult is encouraged to participate when 
needed. The MINI Kid (version 6.0) is composed of 24 modules overall, and questions are 
largely yes-or-no questions. The current study will focus on 8 modules: Major Depressive 
Episode (Module A), (Hypo) Manic Episode (Module D), OCD (Module J), Alcohol 
Dependence/Abuse (Module L), Substance Dependence/Abuse (Non-alcohol; Module M), 
ADHD (Module O), Conduct Disorder (Module P), and Psychotic Disorders and Mood 
Disorders with Psychotic Features (Module R).
A reference sample is provided in Appendix C.
7.2.2.
Columbia-Suicide Severity Rating Scale
The C-SSRS children’s baseline/screening version assesses past and current suicidal ideations
and behaviors to determine suicide risk and is administered at screening. The C-SSRS children’s 
SLV scale is administered on day 1 (only for patients who completed Study SD-809-C-17) and 
weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 55. Children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as appropriate or defined by the scale. 
For children over 13 years of age, caregiver/adult involvement is strongly encouraged. Questions 
should be directed to the child, but the caregiver/adult should be encouraged to add relevant 
information. The C-SSRS is administered through an interview by trained study personnel.
Suicidal ideation

Patients with a positive C-SSRS suicidal ideation score on either items 1 or 2 or a change 
on the CDI-2 Parent or Self-Report Profiles consistent with increasing depressive 
symptoms must be 1) discussed with the medical monitor, 2) re-evaluated within 2 to 3 
days in a clinic visit, and 3) treated according to the investigator’s medical judgment. 
Consultation with a child and adolescent psychiatrist or licensed child/adolescent mental 
health provider is advised, followed by close ongoing monitoring.

If patients endorse or report a C-SSRS suicidal ideation level of 3, 4, or 5, patients will be 
evaluated immediately by the study investigator and referred for psychiatric evaluation. 
The medical monitor will be immediately consulted. If it is determined by the 
investigator, after consultation with the medical monitor and the consulting psychiatrist, 
that exposure to the IMP may have contributed to this change in C-SSRS and/or 
increased depressive symptoms, IMP will be immediately discontinued and the patient 
terminated from the study. In cases where it is determined that IMP did not contribute to 
changes in depression or suicidality, the investigator will consult with the medical 
monitor, the consulting psychiatrist, and/or sponsor to determine whether the patient 
should continue in the study.


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Suicidal behavior

Actual attempt: 

If patients report any suicidal behavior that is an actual attempt as assessed in the 
C-SSRS, they will be evaluated immediately by the study investigator, referred 
for psychiatric evaluation, and terminated from the study.

Interrupted attempt, aborted attempt, or Preparatory Acts or Behavior: 

If patients report any suicidal behavior that is interrupted, aborted, or preparatory 
as assessed in the C-SSRS, they will be evaluated immediately by the study 
investigator and referred for psychiatric evaluation. In cases where it is 
determined in the psychiatric evaluation that IMP did not contribute to changes in 
suicidal behavior, the investigator will consult with the medical monitor, the 
consulting psychiatrist, and/or sponsor to determine whether the patient should 
continue in the study.
A reference sample is provided in Appendix E.
7.2.3.
Children’s Depression Inventory, Second Edition, Parent and Self-Report 
Profiles
CDI-2 (Parent and Self-Report Profiles) is administered at screening and day 1 (only for patients 
who completed Study SD-809-C-17) and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 55. As the 
CDI-2 is designed for children 7 to 17 years of age, children 6 years of age on day 1 will not 
complete the Self-Report version; the caregiver/adult will complete the Parent version.
The CDI-2 Self-Report is a 28-item, self-report questionnaire assessing depressive symptoms in 
children 7 to 17 years of age with basic reading and comprehension skills. In the CDI-2, children 
are asked to choose 1 of 3 statements that most closely aligns with their feelings in the previous 
2 weeks. The questionnaire covers both the major and minor symptoms of depression as outlined 
in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (Sun 
and Wang 2015).
The CDI-2 Parent is a 17-item questionnaire administered to parents to assess depression-related 
behaviors observed in their children. In the CDI-2 Parent, parents are asked to rate their child’s 
behaviors in the past 2 weeks on a 4-point Likert scale from “not at all” to “much or most of the 
time”. The questionnaire allows for the division of depressive symptoms into functional 
problems and emotional problems (Sun and Wang 2015).
A reference sample is provided in Appendix D.
7.3.
Pregnancy
Any female patient becoming pregnant during the study will discontinue IMP.
All pregnancies of female patients participating in the study that occur during the study, or 
within 14 days after the end of the study, are to be reported immediately to the physician 
identified in the Clinical Study Personnel Contact Information section of this protocol, and the 
investigator must provide the sponsor (LSO/Syneos Health) with the completed pregnancy form.


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The process for reporting a pregnancy is the same as that for reporting a serious adverse event 
but using the pregnancy form (see Section 7.1.5.3).
The investigator is not required to report patients who are found to be pregnant between 
screening and day 1, provided no IMP was given. All female patients who become pregnant will 
be monitored for the outcome of the pregnancy (including spontaneous, elective, or voluntary 
abortion). If the pregnancy continues to term, the outcome (health of the infant up to 8 weeks of 
age), including details of birth and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy during the study and any complication of pregnancy that the 
investigator becomes aware of after withdrawal from the study will be reported as an adverse 
event or serious adverse event, as appropriate.
If the pregnancy in the female patient participating in the study does not continue to term, 1 of 
the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.4.
Medication Error and Special Situations Related to the 
Investigational Medicinal Product
Any administration of IMP that is not in accordance with the study protocol should be reported
on the CRF either as a violation, if it meets the violation criteria specified in the protocol
(Section 11.1.2), or as a deviation, in the patients source documents, regardless of whether or not 
an adverse event occurs as a result. All instances of incorrect medication administration should 
be categorized on the CRF as “Non-Compliance with IMP”.
The following are types of medication errors and special situations:
2. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
3. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP or placebo), whether taken intentionally or unintentionally, in 
excess of that prescribed must be immediately reported to the sponsor.
4. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
5. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects.


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6. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
7. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
8. Breastfeeding: Suspected adverse reactions that occur in infants following exposure to a 
medicinal product from breast milk.
7.5.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
The clinical significance of the laboratory values will be evaluated by the criteria described in 
the study laboratory manual and by the judgment of the investigator. A laboratory test result that 
is judged by the investigator as clinically significant will be recorded both on the source 
documentation and the CRF as an adverse event, and monitored as described in Section 7.1.2. An 
event may include a laboratory or diagnostic test abnormality (once confirmed by repeated
testing) that results in the withdrawal of the patient from the study, the temporary or permanent 
cessation of administration of IMP or medical treatment, or further diagnostic work-up.
Abnormal laboratory tests can be repeated without approval from the medical monitor. (Note: 
Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from 
entering the study or receiving IMP are not considered adverse events).
7.5.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (eg, serum chemistry, hematology and urinalysis) will be performed at 
the time points detailed in Table 1. Clinical laboratory tests will be performed using the central 
laboratory. Specific laboratory tests to be performed are provided in Table 5.


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Table 5:
Clinical Laboratory Tests
Serum Chemistry
Hematology
Urinalysis
calcium
phosphate
sodium
potassium
chloride
creatinine
glucose
magnesium
blood urea nitrogen (BUN)
total cholesterol 
uric acid
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
lactate dehydrogenase (LDH)
alkaline phosphatase (ALP)
bicarbonate or carbon dioxide
total protein
albumin
total bilirubin
direct bilirubin
hemoglobin
hematocrit
red blood cell (RBC) count
mean cell volume
platelet count
white blood cell (WBC) count, and 
differential count 
absolute neutrophil count (ANC)
polymorphonuclear leukocytes 
(neutrophils)
lymphocytes
eosinophils
monocytes
basophils
protein
glucose
ketones
blood (hemoglobin)
pH
specific gravity
microscopic
bacteria
RBCs
WBCs
casts
crystals
7.5.2.
Other Clinical Laboratory Tests
7.5.2.1.
Human Chorionic Gonadotropin Tests
Human chorionic gonadotropin tests in urine or serum will be performed for all females who are 
postmenarchal or ≥12 years of age as detailed in Table 1 and if clinically indicated. Any female 
patient who becomes pregnant during the study will be withdrawn. Procedures for reporting the 
pregnancy are provided in Section 7.3.
7.5.2.2.
Urine Drug Screen
A UDS will be performed at the time points specified in Table 1. A positive result for any of the 
specified drugs or their metabolites, without medical explanation, will preclude the patient from 
enrollment or continued participation in the study.
7.6.
Vital Signs
Vital signs (BP, respiratory rate, body temperature, and pulse) will be measured at the time 
points detailed in Table 1. All vital signs results outside of the reference ranges will be judged by 
the investigator as belonging to one of the following categories:

abnormal and not clinically significant 


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
abnormal and clinically significant
Before BP and pulse are measured, the patient must rest in a supine or semi-erect/seated position 
and resting for at least 5 minutes. (The same position and arm should be used each time vital 
signs are measured for a given patient.)
For any abnormal vital sign finding, the measurement should be repeated as soon as possible. 
Any vital sign value that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event, and monitored as described 
in Section 7.1.2.
On day 1 and weeks 4, 8, 28, and 54, orthostatic BP and pulse will be measured after the patient 
is in a standing position for at least 3 minutes.
7.7.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 1. All ECGs will be 
performed after at least 5 minutes rest in a supine or semi-supine position. A qualified physician 
at a central diagnostic center will be interpreting the ECG.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event, recorded on the source documentation and 
in the CRF, and monitored as described in Section 7.1.2.
If a post-day 1 QTcF value >500 msec or change from baseline (Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060) or day 1 (Study SD-809-C-17), as appropriate (see 
Section 9.7.2)>60 msec is found, the investigator should repeat the ECG assessment twice and 
compare the average of the 2 pre-treatment QTcF values (ie, the parent study baseline and 
screening values for patients rolling over from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060; or the day 1 and screening values from the current study for patient[s] who 
completed Study SD-809-C-17) to the average of the 3 post-day 1 QTcF values. The IMP must 
be stopped for any confirmed post-day 1 QTcF value >500 msec or increase from baseline
(Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or day 1 (Study SD-809-C-17) 
>60 msec.
7.8.
Physical Examinations
Physical examinations, including height and weight, general appearance, skin, head, eyes, ears, 
nose, throat, neck, lymph nodes, cardiovascular, respiratory, musculoskeletal, abdominal, and 
extremities will be performed at the time points detailed in Table 1. 
Weight must be measured with shoes and outerwear off.


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Any physical examination finding that is judged by the investigator as clinically significant 
(except at the screening visit) will be considered an adverse event, recorded on the CRF, and 
monitored as described in Section 7.1.2.
7.9.
Assessment of Suicidality
TEV-50717 is considered to be central nervous system (CNS)-active. In addition, there have 
been some reports of suicidal ideation or behavior as reported in the product label when it has 
been given to some patients with certain conditions. The sponsor considers it important to 
monitor for such events before and during this clinical study.
Some CNS-active IMPs may be associated with an increased risk of suicidal ideation or behavior 
when given to some patients with certain conditions. Although this IMP or other similar 
medicinal products in this class have not been shown to be associated with an increased risk of 
suicidal thinking or behavior when given to this study population, the sponsor considers it 
important to monitor for such events before or during this clinical study.
The study population being administered TEV-50717 should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing TEV-50717 in participants who experience signs 
of suicidal ideation or behavior, and detailed recommendations are provided in Section 7.2.2.
The day 1 assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation 
and behavior will be assessed during the study using the Children’s C-SSRS described in 
Section 7.2.2.
Depression and Suicidality as an Adverse Event 
Families and caregivers of patients will be instructed to monitor patients for any changes in or 
new onset of depressive symptoms; unusual changes in mood, cognition, or behavior; or onset of 
and/or changes in suicidal ideation or behavior, and to report such symptoms immediately to the 
study investigator. Telephone contacts and clinic visits also allow opportunities for investigators 
to assess adverse events.
If a relevant change in status is identified, patients will be seen immediately for an unscheduled 
visit by the study investigator and discussed with the medical monitor. The patient will be 
referred for further psychiatric evaluation if there is any suspected suicidal ideation with any 
level of intent, suicidal behavior, or clinical findings suggesting that the patient may be 
dangerous to self or others, and/or experiencing depression. The investigator will record these 
symptoms as an adverse event of depression and/or suicidality. If it is determined by the 
investigator, after consultation with the medical monitor and the consulting psychiatrist, that 
exposure to the IMP may have contributed to the adverse event of depression or suicidality, IMP 
will be immediately discontinued and the patient will be terminated from the study. Follow up 
with a pediatric psychiatrist or licensed child and adolescent mental health clinician will be 
arranged.
In cases where it is determined that IMP did not contribute to the adverse event of depression or 
suicidality, the investigator will consult with the medical monitor and/or sponsor to determine 
whether the patient should continue in the study.
A reference sample is provided in Appendix E.


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7.10.
Neurological Examinations
Neurological examination, including mental status, cranial nerves, motor system (strength, tone, 
and posture), coordination, gait and balance, tendon reflexes, and sensation, will be performed at 
the time points detailed in Table 1. Any neurological examination finding that is judged by the 
investigator as a potentially clinically significant change (worsening) compared with the 
screening value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2. 
7.11.
Concomitant Medication or Treatment
Concomitant therapy or medication usage will be monitored throughout the study. 
Parents/patients will be instructed during the course of the study to notify the investigator if any 
new medication is prescribed/administered, including over-the-counter medications. Any 
prescribed/administered medication should be reviewed with the investigator.
Medications that are allowed, provided that conditions outlined in the table are met, are shown in 
Table 6. The tables for allowed and prohibited medications are not comprehensive and may not 
include all possible concomitant medications.
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving 
during the study) a medication that is associated with QTc prolongation or that is a known strong
CYP inhibitor, or if there are any questions regarding any medication not listed in Appendix A. 
Prohibited medications that are associated with QTc prolongation are listed in Table 8, while 
prohibited antipsychotic drugs are listed in Table 7.
7.12.
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data
All adverse events will be reviewed on a periodic basis by the CPP/medical monitor according to 
the safety monitoring plan (eg, scheduled safety reviews for TEV-50717) as preliminary safety 
databases become available.
Methods and time points of assessing safety data are discussed in Section 3.13. Procedures for 
recording safety data are discussed in Section 13.1, and methods of analyses are discussed in 
Section 9.7.2.
Information about the IDMC used for this study is provided in Section 3.7.


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8.
ASSESSMENT OF 
PHARMACOKINETICS/PHARMACODYNAMICS
Pharmacokinetic and pharmacodynamic assessments will not be performed as part of 
Study TV50717-CNS-30047.


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9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report 
(CSR).
9.1.
Sample Size and Power Considerations
This study is safety-oriented in nature; therefore, no formal hypothesis testing is planned for 
Part A. Based on the number of patients in the previous studies, up to approximately 227 patients 
(approximately 1 patient from the Phase 1b Study SD-809-C-17, up to approximately 99 patients 
from the Phase 2/3 Study TV50717-CNS-30046, and up to approximately 127 patients from the 
Phase 3 Study TV50717-CNS-30060) are estimated to enroll.
All patients who complete Study TV50717-CNS-30060 or Study TV50717-CNS-30046 are 
eligible to participate in Study TV50717-CNS-30047. As the number of patients to be 
randomized in parent Study TV50717-CNS-30046 has increased, the number of patients 
anticipated to be randomized into Study TV50717-CNS-30047 has also increased. The rationale 
for the increased sample size in Study TV50717-CNS-30046 is provided that protocol.
For the randomized drug withdrawal period, 190 patients to be included in the analysis will 
provide approximately 90% power to detect a difference between TEV-50717-treated and 
placebo-treated patients assuming a difference in YGTSS TTS of 4.5 with a standard deviation 
of 9 using a two-sided test for difference at a significance level of 0.05.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all enrolled patients, regardless of whether or 
not a patient took any IMP. Enrolled subjects who are not randomized will be summarized 
separately as “Not randomized,” and randomized subjects will be analyzed based on their 
randomized treatment. A patient is considered enrolled according to the status reported in the 
database. All efficacy analyses will be based on the ITT analysis set.
9.2.2.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of IMP. 
The safety analysis set will be used for all safety analyses.
9.2.3.
Randomized Withdrawal ITT Population
The Randomized Withdrawal ITT (RWITT) Population will include all patients enrolled in the 
randomized drug withdrawal period of the study.


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9.2.4.
Randomized Withdrawal Safety Population
The Randomized Withdrawal Safety (RWSAF) Population will include all patients enrolled in 
the randomized drug withdrawal period who are administered any study drug. All summaries of 
safety measures in the randomized withdrawal period will be summarized descriptively in the 
RWSAF Population.
9.2.5.
Randomized Withdrawal Modified Intent-to-Treat Population
The Randomized Withdrawal Modified Intent-to-Treat (RWmITT) Population will include all 
patients enrolled in the randomized drug withdrawal period who receive study drug and have a 
YGTSS TTS at both the randomized drug withdrawal week 28 visit and the week 30 visit.
Efficacy measures in the randomized drug withdrawal period will be analyzed as described in 
Section 9.5.3.1.
9.2.6.
Responder Randomized Withdrawal Modified Intent-to-Treat Population
The Responder Randomized Withdrawal mITT (RRWmITT) Population will include all patients 
enrolled in the randomized drug withdrawal period who receive study drug and have a YGTSS 
TTS at both the week 28 visit and the week 30 visit and a ≥25% reduction in the TTS from 
baseline in the parent protocol to week 28. Efficacy measures in the randomized drug withdrawal 
period will be analyzed as described in Section 9.5.3.1. 
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses.
9.4.
Study Population
The ITT analysis set (see Section 9.2.1) will be used for all open-label efficacy summaries and 
analyses unless otherwise noted. The safety analyses set will be used for all safety summaries. 
Summaries will be presented for all patients.
The RRWmITT or RWmITT analysis set (see Section 9.2.5) will be used for all randomized 
withdrawal efficacy summaries and analyses unless otherwise noted. The RWSAF analysis set 
will be used for all randomized-withdrawal safety summaries.
9.4.1.
Patient Disposition
Data from patients who are enrolled, patients enrolled but not treated (and the reason), patients in 
the ITT, safety, and other analysis sets, patients who enter the randomized drug withdrawal 
period, patients who complete the randomized drug withdrawal period, patients who complete 
the study, and patients who withdraw from the study will be summarized using descriptive 
statistics. Data from patients who withdraw from the study will also be summarized by reason for 
withdrawal using descriptive statistics.
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics (day 1), including medical history, prior 
medications and treatments, and ECG findings, will be summarized using descriptive statistics
and will be analyzed by age group. For continuous variables, descriptive statistics (number [n], 


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mean, standard deviation, median, minimum, and maximum) will be provided. For categorical 
variables, patient counts and percentages will be provided. Categories for missing data will be 
presented if necessary.
9.5.
Efficacy Analysis
No formal inferential statistics will be applied to the efficacy endpoints in Part A; however, 
inferential statistics will be applied to the efficacy endpoint in Part B (see Section 9.5.1).
9.5.1.
Efficacy Endpoints
The following efficacy endpoints will be assessed in Part A: 

change in the TTS of the YGTSS from day 1 to each visit in which the scale is 
administered

change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from 
day 1 to each visit in which the scale is administered

change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) 
score from day 1 to each visit in which the scale is administered

change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life 
(C&A-GTS-QOL) activities of daily living (ADL) subscale score from day 1 to each 
visit in which the scale is administered
The following efficacy endpoint will be assessed in Part B: 

change in the TTS of the YGTSS from week 28 to week 30, with the primary 
analyses and sensitivity testing done as described in Section 9.5.3.1
9.5.2.
Exploratory Endpoints
The following exploratory endpoints will be assessed in Part A:
 
 
 
 
 
 


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9.5.3.
Planned Method of Analysis
The ITT analysis set (see Section 9.2.1) will be used for all efficacy analyses in Part A. 
Summaries will be presented for all patients.
9.5.3.1.
Efficacy Analysis for the Randomized Drug Withdrawal Period
For the randomized drug withdrawal portion of the study, an analysis of covariance model will 
be used as the primary analysis model with the change from randomized-withdrawal week 28 to 
week 30 in YGTSS TTS as the dependent variable, and treatment group, randomized-withdrawal 
week 28 TTS, and age group at baseline as covariates. The least squares mean of the change in 
TTS from week 28 to week 30 will be compared (the active treatment arm and placebo arm) 
using a 2-sided test at the alpha=0.05 level of significance.
The primary analysis will be in the RRWmITT population (see Section 9.2.6). In addition, 
sensitivity testing will be done using the same model in the RWmITT population and in a 
subpopulation of the RRWmITT who had a ≥35% reduction in the TTS from baseline in the 
parent protocol to week 28.
9.6.
Multiple Comparisons and Multiplicity
This does not apply to this study.
9.7.
Safety Endpoints and Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.2) for the open-label 
study and the RWSAF set for the randomized drug withdrawal portion.
9.7.1.
Safety Endpoints
The following safety endpoints will be assessed in Part A (Day 1, Titration, and Maintenance):

incidence of adverse events 

observed values and changes from day 1 in vital signs

observed values and changes from day 1 in the CDI-2 (Parent and Self-Report 
Profiles)

observed values in the C-SSRS

observed values in electrocardiogram (ECG) parameters and shifts from parent study 
baseline (for patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060) or from day 1 (for patient[s] rolling over from 
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
observed values and changes from day 1in clinical laboratory parameters 
(hematology, serum chemistry, and urinalysis)
The following safety endpoint will be assessed in Part B (Blinded, Randomized Drug 
Withdrawal Period and Titration Post-Drug Withdrawal Period): 

incidence of adverse events 
In addition to routine monitoring of adverse events, clinical laboratory parameters, 12-lead 
ECGs, and safety scales, an IDMC will monitor safety during the conduct of the study.
9.7.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to IMP (ie, reasonable possibility [see 
Section 7.1.4] defined as related or with missing relationship) (overall and by severity), serious 
adverse events, and adverse events causing withdrawal from the study. Patient listings of serious 
adverse events and adverse events leading to withdrawal will be presented.
Changes in laboratory and vital signs measurement data will be summarized descriptively. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with IMP.
Observed values in ECG parameters will be summarized, and counts and percentages of 
abnormal findings will be presented. Changes from parent study baseline (for patients rolling 
over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or from day 1 (for 
patient[s] rolling over from Study SD-809-C-17) in ECG parameters will be summarized 
descriptively. In addition, the number and percentage of patients with on-treatment QTcF values 
>450, >480, or >500 msec and change from baseline (Study TV50717-CNS-30046 or Study 
TV50717-CNS-30060) or day 1 (Study SD-809-C-17) >30 or >60 msec will be presented.
Observed values in the C-SSRS and observed values and changes from baseline in the CDI-2 
(Parent and Self-Report Profiles) will be presented for all patients.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
9.8.
Tolerability Variables and Analysis
Tolerability was not specifically defined.
9.9.
Planned Interim Analysis
When approximately 100 patients have completed the 28-week clinic visit, an interim analysis, 
including data from day 1 and up to week 28 visit only, will be conducted to provide descriptive, 
long-term safety and efficacy data to be used in regulatory submissions. To maintain data 
integrity of Study TV50717-CNS-30047, only a limited number of personnel who do not have 
contact with the sites will have access to this interim data in preparation for the regulatory filing. 


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As no decisions regarding conduct of the study will be made based on the descriptive interim 
analysis, no alpha will be spent.
9.10.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations.


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10.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, IMP label records, diary data, protocol-required worksheets, and CRFs that are used 
as the source (see Section 3.12).
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.


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11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients or when the change involves only nonsubstantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment.
11.1.2.
Protocol Violations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to the administration of 
IMP; use of prohibited medications. Protocol violations will be identified and recorded by 
investigational center personnel in a log or as part of the CRF. All protocol violations will be 
reported to the responsible IEC/IRB, as required.
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol violation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 


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made available during the study when new personnel members become involved in the study and 
as otherwise agreed upon with either the investigator or the study monitor.
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol; that all data are correctly and completely recorded and 
reported; and that informed consent/assent, depending on the child’s age, as appropriate, is 
obtained and recorded for all patients before they participate in the study and when changes to 
the consent form are warranted, in accordance with IEC/IRB approvals.
The study monitor will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source document [see Section 3.12]) relating to the study to verify adherence to the protocol and 
to ensure the completeness, consistency, and accuracy of the data being recorded. If electronic 
CRFs are used for the study, the study monitor will indicate verification by electronically 
applying source document verification flags to the CRF and will ensure that all required 
electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected in the course of these 
monitoring visits or provided in follow-up written communication.
11.4.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside)

incorrect packaging, or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor, or both


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
device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving a drug product, all relevant samples (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible.
11.4.1.
Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will obtain the 
following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to protocol Yes/No

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling of Investigational Medicinal Product at the Investigational Center
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP.
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return.


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11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively).
11.4.4.
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint,
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.
11.5.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Clinical Development, is responsible for 
determining the need for (and timing of) an investigational center audit.
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines.


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12.
ETHICS
Details of compliance with regulatory requirements and applicable laws are provided in 
Section 1.6.
12.1.
Informed Consent/Assent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and parent/legally acceptable representative of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB. All written and oral information 
about the study will be provided in a language as nontechnical as practical to be understood by 
the parent/legally acceptable representative and the patient. The patient and parent/legally 
acceptable representative should be given ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study. The above should be detailed in 
the source documents.
A personally signed and dated informed consent form will be obtained from parent/legally 
acceptable representative, and a signed and dated assent, depending on the child’s age, as 
appropriate, will be obtained from each patient (if the patient is able) before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained; according to national and local IEC/IRB requirements. The 
forms will be signed and dated also by the person who conducted the informed consent 
discussion. The investigator will keep the original informed consent/assent forms, depending on 
the child’s age, as appropriate, and copies will be given to the patients. It will also be explained 
to the patients (and parent/legally acceptable representative) that they are free to refuse 
participation in the study and free to withdraw from the study at any time without prejudice to 
future treatment. Any patient that turns 18 years of age during the course of Study TV50717-
CNS-30047 will need to be re-consented as an adult.
For patients rolling over from Study TV50717-CNS-30046 or Study TV50717-CNS-30060, 
informed consent/assent, as appropriate, may be obtained prior to the day 1 visit, up to 4 weeks 
in advance of open-label study participation.
12.2.
Competent Authorities and Independent Ethics 
Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national and local competent 
authority and to each IEC/IRB for review. As required, the study will not start at a given 
investigational center before the IEC/IRB and competent authority (where applicable) for the
investigational center give written approval or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number.


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Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance, or competent authorities. 
Personal medical information will always be treated as confidential.
12.4.
Declaration of the End of Clinical Study
The end of study is defined as the date of the week 56 visit of the last participant.
For investigational centers located in the European Union, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/EC, Article 10(c); 
for other countries, national and local regulations will be followed.
12.5.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study may be registered on clinical studies registry websites.


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13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and study-specific training. After they are trained, users will be provided with individual 
system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent/assent. 
Patient identity should not be discernible from the data provided on the CRF. Data will be 
verified by the study monitor using the data source, and reviewed for consistency by Data 
Management using both automated logical checks and manual review. All data collected will be 
approved by the investigator at the investigational center. This approval acknowledges the 
investigator’s review and acceptance of the data as being complete and accurate.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
ECG center, diary data, electronic patient-reported outcome [ePRO] Tablet), the results will be 
sent to the investigational center, where they will be retained but not entered in the CRF, unless 
otherwise specified in the protocol. These data may also be sent electronically to the sponsor (or 
organization performing data management) for direct entry in the clinical database. Laboratory 
test results will not be entered in the CRF unless otherwise specified in the protocol. All data 
from other sources will be available to the investigators.
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening
failure reason, demography, and adverse events from the time of informed consent/assent will be 
entered in the CRF.
13.2.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality control, will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data quality control, will be described in a data management 
plan.
CRFs received will be processed and reviewed for completeness, consistency, and the presence 
of mandatory values. Applicable terms will be coded according to the coding conventions for 
this study. Logical checks will be implemented to ensure data quality and accuracy. Any 
necessary changes will be made in the clinical database, and data review and validation 
procedures will be repeated as needed. Data from external sources will be compared with the 
information available in the CDMS. Discrepancies found will be queried.


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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates, and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate.
13.3.
Archiving of Case Report Forms and Source Documents
13.3.1.
Sponsor Responsibilities
The sponsor will have final responsibility for the processing and quality control of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies.
Day to day data management tasks for this study are delegated to a contract organization, and
these functions may be carried out as described in the SOPs for clinical studies at that 
organization. These SOPs will be reviewed by the sponsor before the start of data management 
activities. The original CRFs will be archived by the sponsor. Investigational center-specific 
CRFs will be provided to the respective investigational centers for archiving.
13.3.2.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to:

full case histories

signed informed consent/assent forms

patient identification lists

CRFs for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, diary)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the IMP

copies of all correspondence with sponsor, the IEC/IRB, and any competent authority
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until Syneos Health
or sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational center closing or going out of 
business, the investigator reasonably determines that study record retention has become unduly 
burdensome, and sponsor has not provided written notification of destruction, then the 
investigator may submit a written request to sponsor at least 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 


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for appropriate archival or disposition, including requiring that the investigator deliver such 
records to the sponsor. The investigator shall notify the sponsor of any accidental loss or 
destruction of study records.


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14.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and Syneos Health before the IMP is delivered.
This clinical study is insured in accordance with applicable legal provisions. The policy coverage 
is subject to the full policy terms, conditions, extensions, and exclusions. Excluded from the 
insurance coverage are inter alia, damages to health, and worsening of previous existing disease 
that would have occurred or continued if the patient had not taken part in the clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.


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15.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to national, local, and regional requirements and regulations for 
registration and posting of results.
The sponsor is responsible for the preparation of a CSR, in cooperation with the coordinating
investigator. The final report is signed by the sponsor and, if applicable, by the coordinating 
investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
competent authorities, drafts may be circulated to the principal investigator for comments and 
suggestions. An endorsement of the final report will be sought from the principal investigator.
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. Authorship will be based on meeting all the following 
4 criteria:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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16.
REFERENCES
Fuenmayor LD, Vogt M. The influence of cerebral 5-hydroxytryptamine on catalepsy induced by 
brain-amine depleting neuroleptics or by cholinomimetics. B J Pharmacol 1979;67(2):309-18.
Gilbert D, Jankovic J. Pharmacological treatment of Tourette syndrome. J Obsessive Compuls 
Rel Disord 2014;3:407–14.
Jain S, Greene PE, Frucht SJ. Tetrabenazine therapy of pediatric hyperkinetic movement 
disorders. Mov Disord 2006;21(11):1966-72.
Jankovic J. Therapeutic developments for tics and myoclonus. Mov Disord 
2015;30(11):1566-73.
Jankovic J. Tardive syndromes and other drug-induced movement disorders. Clin 
Neuropharmacol 1995;18(3):197-214.
Jankovic J. Tourette’s syndrome. N Engl J Med 2001;345(16):1184-92.
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement. Neurology 
1997;48(2):358-62.
Jankovic J, Kurlan R. Tourette syndrome: evolving concepts. Mov Disord 2011;26(6):1149.
Kenney C, Hunter C, N M, Jankovic J. Tetrabenazine in the treatment of Tourette syndrome. J 
Pediatric Neurol 2007;5(1):9-13.
Kurlan R, Como PG, Miller B, Palumbo D, Deeley C, Andresen EM, et al. The behavioral 
spectrum of tic disorders: a community-based study. Neurology 2002;59(3):414-20.
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.
Mejia NI, Jankovic J. Tardive dyskinesia and withdrawal emergent syndrome in children. Expert 
Rev Neurother 2010 Jun;10(6):893-901.
Mehanna R, Hunter C, Davidson A, Jimenez-Shahed J, Jankovic J. Analysis of CYP2D6 
genotype and response to tetrabenazine. Mov Disord 2013 Feb;28(2):210-5.
Paleacu D, Giladi N, Moore O, Stern A, Honigman S, Badarny S. Tetrabenazine treatment in 
movement disorders. Clin Neuropharmacol 2004;27(5):230-3.
Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: from disturbed motility to 
disordered movement—a review of the clinical benefits and medicolegal risks of 
metoclopramide. Nat Clin Pract Gastroenterol Hepatol 2006;3(3):138-48.
Peña MS, Yaltho TC, Jankovic J. Tardive dyskinesia and other movement disorders secondary to 
aripiprazole. Mov Disord 2011 Jan;26(1):147-52.
Porta M, Sassi M, Cavallazzi M, Fornari M, Brambilla A, Servello D. Tourette’s syndrome and 
role of tetrabenazine: review and personal experience. Clin Drug Investig 2008;28(7):443.


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Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WL, et al. Children’s 
Yal-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc 
Psychiatry 1997;36(6):844-52.
Scherman D, Gasnier B, Jaudon P, Henry JP. Hydrophobicity of the tetrabenazine-binding site of 
the chromaffin granule monoamine transporter. Mol Pharmacol 1988;33(1):72-7.
Shaw Z, Coffey B. Tics and Tourette syndrome. Psychiatr Clin North Am 2014 Sep;37(3):269-
86.
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.
Sun S, Wang S. The Children’s Depression Inventory in worldwide child development research: 
a reliability generalization study. J Child Fam Stud 2015;24(8):2352-63.
Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor 
and other hyperkinetic movements. Tremor Other Hyperkinet Mov 2013;3.
Wijemanne S, Wu LJ, Jankovic J. Long-term efficacy and safety of fluphenazine in patients with 
Tourette syndrome. Mov Disord 2014 Jan;29(1):126-30.
Xenazine: Highlights of Prescribing Information. 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf. Accessed 27 
Oct 2015.
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available
at http://www.icmje.org/recommendations/.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 01 Dated 22 June 2017
The primary reason for this amendment is to change aspects of the conduct, include concomitant 
medications, titration instructions, number of patients randomized, acceptable contraceptive 
methods, analysis of the data, and clinical study personnel.
This amendment is considered to be substantial (ie, requires approval by CA, IEC, and/or IRB) 
by the sponsor’s Authorized Representative. Other nonsubstantial changes have been made to the 
protocol (and protocol synopsis, as appropriate). These changes are unlikely to affect the safety 
or rights (physical or mental integrity) of the patients in this clinical study or the scientific value 
of the clinical study.
Original text with changes shown
New wording
Reason/Justificati
on for change
Global
Study drug
Investigational Medicinal Product 
(IMP)
“Study drug” to 
“IMP” for
consistency 
throughout the 
document.
TITLE PAGE
Not applicable
Teva’s Development Partner
Nuvelution Pharma, Inc.
601 Gateway Boulevard
Suite 1270
South San Francisco, California 
94080
United States of America
Title page was 
updated to add 
Teva’s 
Development 
Partner Nuvelution 
Pharma, Inc.
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS
Electronic Data Capture
Medidata RAVE (through PRA 
InternationalINC Research)
Contract Research Organization; Safety 
and Efficacy Data Analysis
PRA International
4130 ParkLake Avenue, Suite 400
Raleigh, NC 27612 
USA
INC Research
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604-1547
USA
Electronic Data Capture
Medidata RAVE (through INC 
Research)
Contract Research 
Organization; Safety and 
Efficacy Data Analysis
INC Research
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604-1547
USA
Integrated Response 
The administrative 
changes made to 
this section were 
completed for 
accuracy of 
laboratories, other 
departments, and 
institutions.


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
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Integrated Response Technology
Y Prime
263 Great Valley Parkway
Malvern, PA 19355
USA
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA
ePRO, eCOA, and Scales Training
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA
Bioanalytical Pharmacokinetics Evaluation 
Data Analysis
Information will be included in the Trial 
Master File.
Technology
Bracket Global, LLC
575 East Swedesford Road, Suite 
200
Wayne, PA 19087 
USA
ePRO, eCOA, and Scales 
Training
Bracket Global, LLC
575 East Swedesford Road, Suite 
200
Wayne, PA 19087 
USA
Bioanalytical Pharmacokinetics 
Evaluation Data Analysis
Information will be included in 
the Trial Master File.
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
 
Tel: 
Email: 
Medical Director, Medical Affairs
INC Research
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604
USA
Office:
Mobile:
Email:
For operational issues, contact the 
operational lead listed below:
, Teva 
Branded Pharmaceutical Products R&D, Inc.
Tel: +
Fax: 
Cell: 
Email: S
, Nuvelution Pharma
Medical Director, Medical Affairs
INC Research
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604
USA
Office:
Mobile:
For operational issues, contact 
the operational lead listed 
below:
 
Nuvelution Pharma
Tel: 
Email: 
These changes were
made to update the 
clinical study 
personnel.


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
129
Tel: +
Email: 
For protocol issues, contact the study 
leader listed below:
 
 
Teva Branded Pharmaceutical Products R&D, 
Inc.
Tel: + 
Fax: + 
Cell: +1 202 494 6059 
Email: 
, Nuvelution Pharma
Tel: +
Email: 
Nuvelution Pharma
Tel: + 
Email: 
For protocol issues, contact the 
study leader listed below:
, 
Nuvelution Pharma
Tel: + 
Email: 
Nuvelution Pharma
Tel: +
Email: 
1.1.
Introduction
Not applicable
TEV-50717 was granted 
breakthrough status for treatment 
of TD by the Food and Drug 
Administration (FDA) based on 
the results of Study SD-809-C-18, 
and NDA 209885 was granted 
priority review status. TEV-
50717 was approved for the 
treatment of chorea associated 
with HD on 03 April 2017.
Addition based on 
recent granting of 
breakthrough status 
of TEV-50717 for 
the treatment of TD 
by the FDA 
1.2.Name and Description of Investigational Medicinal Product (Other Sections that apply to this 
change: 3.7., 5.1.)
TEV-50717 tablets are available in the 
following dose strengths: 6, 9, and 12, 15, and 
18 mg. Each dose strength will have a 
marking of SD 6, SD 9, and SD 12, SD 15, 
and SD 18 corresponding to the dose strength 
and a distinct color: 6 mg – purple, 9 mg –
blue, and 12 mg – beige, 15 mg white, and 
18 mg yellow. Study drug will be supplied in 
TEV-50717 tablets are available 
in the following dose strengths: 6, 
9, and 12 mg. Each dose strength 
will have a marking of SD 6, SD 
9, and SD 12 corresponding to the 
dose strength, and a distinct color: 
6 mg – purple, 9 mg – blue, and 
12 mg – beige. Study drug will be 
This change reflects 
the correct dosages 
and strengths of 
IMP available for 
the study.


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Study TV50717-CNS-30047
130
20- or 760-count tablets per dose strength per 
bottle.
supplied in 20- or 60-count tablets 
per dose strength per bottle
1.3.1.3. Toxicology
General and Reproductive Adult Toxicology: 
Oral administration of TEV-50717 in rats 
reduced body weight gain, increased mammary
hyperplasia, and produced estrous cycle
changes, all of which occurred with 
tetrabenazine at doses that produced similar 
systemic exposures to test articles and 
metabolites. Mammary and estrus effects are 
likely consequences of reduced central 
dopamine and subsequently increased 
prolactin, consistent with information in the 
Xenazine® (tetrabenazine) label. Oral 
administration of TEV-50717 in pregnant rats 
did not produce test article-related embryofetal 
toxicities, even at doses that led to reduced 
body weight gain in dams. Oral administration 
of metabolite M1 to pregnant rats from 
gestational days 6 to 17 produced no test 
article-related maternal or fetal toxicities.
Genetic Toxicology: TEV-50717 and its α-
HTBZ and β-HTBZ metabolites were negative 
in in vitro studies for mutagenicity (bacterial 
reverse mutation, or the Ames test) and for 
chromosomal structural aberrations in human 
peripheral blood lymphocytes. Oral doses of 
TEV-50717 arewere negative for inducing 
micronuclei in the bone marrow of treated 
mice. 
Juvenile Toxicology: The effects of 
TEV-50717 on juvenile development was 
assessed in male and female rats with oral 
dosing from weaning (postnatal day [PND] 
21) to PND 71, similar to human dosing from 
Year 2 through early adolescence and 
overlapping with TEV-50717 oral dosing in a 
general adult toxicology study. The effects of 
M1 were assessed in male and female juvenile 
rats from PND 25 to PND 70 with a recovery 
phase and postdosing reproductive 
assessment.
TEV-50717 produced no test-article-related 
effects on learning and memory functions, on 
histopathology assessments, on reproductive 
capacity (male and female fertility, estrus 
cyclicity), or on intrauterine survival of 
embyros from matings during recovery from 
General and Reproductive Adult 
Toxicology: Oral administration 
of TEV-50717 in rats reduced
body weight gain, increased 
mammary hyperplasia, and 
produced estrous cycle changes, 
all of which occurred with 
tetrabenazine at doses that 
produced similar systemic 
exposures to test articles and 
metabolites. Mammary and estrus 
effects are likely consequences of 
reduced central dopamine and 
subsequently increased prolactin, 
consistent with information in the 
Xenazine® (tetrabenazine) label. 
Oral administration of TEV-
50717 in pregnant rats did not 
produce test article-related 
embryofetal toxicities, even at 
doses that led to reduced body 
weight gain in dams. Oral 
administration of metabolite M1 
to pregnant rats from gestational 
days 6 to 17 produced no test 
article-related maternal or fetal 
toxicities
Genetic Toxicology: TEV-50717 
and its α-HTBZ and β-HTBZ 
metabolites were negative in in 
vitro studies for mutagenicity 
(bacterial reverse mutation, or the 
Ames test) and for chromosomal 
structural aberrations in human 
peripheral blood lymphocytes. 
Oral doses of TEV-50717 were 
negative for inducing micronuclei 
in the bone marrow of treated 
mice. 
Juvenile Toxicology: The effects 
of TEV-50717 on juvenile 
development was assessed in male 
and female rats with oral dosing 
from weaning (postnatal day 
[PND] 21) to PND 71, similar to 
human dosing from Year 2 
This section was 
updated to include 
results from oral 
administration of 
metabolite M1 to 
pregnant rats


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Study TV50717-CNS-30047
131
test article administration. Adversely reduced 
body weight gain and adverse clinical 
observation of tremors and in-cage 
hyperactivity were all noted in previous 
studies with adult rats; these effects have not 
predicted adult clinical intolerance to 
TEV-50717. The highest dose level of M1 (50 
mg/kg/day) produced no test article-related 
toxicities (clinical observations, changes in 
body weight gain, clinical pathology, 
histopathology, ophthalmology, and 
performance in learning and memory tests).
through early adolescence and 
overlapping with TEV-50717 oral 
dosing in a general adult 
toxicology study. The effects of 
M1 were assessed in male and 
female juvenile rats from PND 25 
to PND 70 with a recovery phase 
and postdosing reproductive 
assessment.
TEV-50717 produced no 
test-article-related effects on 
learning and memory functions, 
on histopathology assessments, on 
reproductive capacity (male and 
female fertility, estrus cyclicity), 
or on intrauterine survival of 
embryos from matings during 
recovery from test article 
administration. Adversely reduced 
body weight gain and adverse 
clinical observation of tremors 
and in-cage hyperactivity were all 
noted in previous studies with 
adult rats; these effects have not 
predicted adult clinical intolerance 
to TEV-50717. The highest dose 
level of M1 (50 mg/kg/day) 
produced no test article-related 
toxicities (clinical observations, 
changes in body weight gain, 
clinical pathology, histopathology, 
ophthalmology, and performance 
in learning and memory tests)
1.3.2.
Clinical Studies
The clinical development plan for TEV-50717 
to date includes:

6 completed Phase 1 studies in healthy 
adult volunteers

1 completed Phase 3 pivotal study for the 
treatment of chorea associated with HD

1 ongoing Phase 3 long-term safety study 
in patients with HD

12 completed Phase 2/3 and 
Phase 3studies in patients with TD

31 ongoing Phase 3 long-term safety
studies in patients with TD

1 completed Phase 1b study in patients 
The clinical development plan for 
TEV-50717 to date includes:

6 completed Phase 1 studies 
in healthy adult volunteers

1 completed Phase 3 pivotal 
study for the treatment of 
chorea associated with HD

1 ongoing Phase 3 long-term 
safety study in patients with 
HD

2 completed Phase 2/3 and 
Phase 3 studies in patients 
with TD

1 ongoing Phase 3 long-term 
The status and 
details of clinical 
studies were
updated to the
current status of 
study information.


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
132
with TS

1 planned Phase 2/3 study in patients with 
TS
safety studies in patients with 
TD

1 completed Phase 1b study 
in patients with TS
1.3.2.1.
Clinical Pharmacology Studies
SixFive Phase 1 clinical pharmacology studies
were conducted in healthy adult volunteers. In 
addition, sparse pharmacokinetic sampling
was included in the Phase 3 studies with HD 
patients where population pharmacokinetic 
analyses were performed to extensively 
evaluate the pharmacological profile
pharmacokinetics and 
pharmacokinetics/pharmacodynamics 
relationship of TEV-50717. A summary of the 
clinical pharmacology findings is provided in 
the IB.
Five Phase 1 clinical 
pharmacology studies were 
conducted in healthy adult 
volunteers. In addition, sparse 
pharmacokinetic sampling was 
included in the Phase 3 studies 
with HD patients where 
population pharmacokinetic 
analyses were performed to 
extensively evaluate the 
pharmacokinetics and 
pharmacokinetics/pharmacodyna
mics relationship of TEV-50717. 
A summary of the clinical 
pharmacology findings is 
provided in the IB.
The details of 
clinical 
pharmacology 
studies was updated 
to reflect accuracy 
of clinical 
pharmacology 
study information.
1.4. 
Known and Potential Benefits and Risks to Patients (Other sections affected by this change: 
1.4.1., 1.4.1.2., 1.4.2.)
1.4.Known and Potential Benefits and 
Risks to Patients
Additional information regarding benefits and 
risks to patients may be found in the current 
IB and in the United States prescribing 
information for AUSTEDO™
(deutetrabenazine).
1.4.1.1.Benefits of TEV50717
Although the efficacy of TEV 50717 in 
patients with TS has not yet been definitively 
established, preliminary efficacy data from 
Study SD 809 C 17 indicates a clinically 
meaningful reduction in motor and phonic tics 
observed by patients, parents, and treating 
clinicians. Furthermore, TEV 50717 has the 
same mechanism of action and 
indistinguishable pharmacology as 
tetrabenazine, an agent that is generally 
accepted among movement disorder experts to 
provide clinical benefit in this patient 
population (Jankovic and Kurlan 2011). Based 
on the nonclinical data discussed above and 
similar efficacy observed for tetrabenazine 
and TEV 50717 in studies of other indications 
1.4.Known and Potential 
Benefits and Risks to Patients
Additional information regarding 
benefits and risks to patients may 
be found in the current IB and in 
the United States prescribing 
information for AUSTEDO™ 
(deutetrabenazine).
The section was 
modified to reflect 
accurate and 
consistent 
information 
regarding known 
and potential 
benefits and risks to 
patients.


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
133
(see IB), TEV 50717 has the potential to offer 
effective treatment in children and adolescents 
with TS. 
1.4.1.2. Potential Risks of TEV 50717
The following information is based on clinical 
trial experience with TEV 50717 and the 
United States prescribing information for 
Xenazine (tetrabenazine):

TEV 50717 is contraindicated in patients 
who are actively suicidal, or in patients 
with untreated or inadequately treated 
depression.

TEV 50717 is contraindicated in patients 
with impaired hepatic function.

TEV 50717 is contraindicated in patients 
taking monoamine oxidase inhibitors 
(MAOIs). TEV 50717 should not be used 
in combination with an MAOI, or within a 
minimum of 14 days of discontinuing 
therapy with an MAOI.

TEV 50717 is contraindicated in patients 
taking reserpine. At least 21 days should 
elapse after stopping reserpine before 
starting TEV 50717.
Additional information regarding each 
potential issue may be found in the current IB.
1.4.2. Overall Risk and Benefit Assessment 
for This Study
There is a significant need to identify new 
treatments for TS that do not antagonize 
dopamine receptors, as these latter agents pose 
serious risks such as metabolic syndrome and 
TD, a movement disorder that is often 
irreversible. The results from 
Study SD 809 C 17 demonstrated meaningful 
efficacy in the context of good tolerability and 
no signal on safety scales, vital signs, 
laboratory parameters, or 12 lead 
electrocardiograms (ECGs). These findings 
are consistent with results in other study 
populations, such as HD, where the rates for 
TEV 50717 and placebo were similar for 
overall adverse events, neurologic and 
psychiatric adverse events, as well as dose 
reduction or dose suspension for adverse 
events (see IB for details).
1.8. 
Location and Study Duration


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
134
This study is planned to be conducted in the 
USA, Canada, Denmark, Spain, Germany, and 
Russia North America and Europe at 
approximately 40100 centers. It is expected to 
start in June 2016 January 2018 and conclude 
in October 2018 June 2020 and have a 
duration of approximately 28 30 months.
This study is planned to be 
conducted in North America and 
Europe at approximately 100 
centers. It is expected to start in 
January 2018 and conclude in 
June 2020 and have a duration of 
approximately 30 months.
The study duration 
was updated to 
reflect accurate 
timing and duration 
of the planned 
study period. 
2.3.3. Exploratory Endpoints (Other sections affected by this change: 3.4.2., 9.5.2.)
 
 
 
 
 
 
 
 
.
3.1. General Design and Study Schematic Diagram (Other sections affected by this change: 9.1.)
This is a 56-week, open-label, single-arm 
study to evaluate the safety of TEV-50717 in 
children and adolescents with tics associated 
with TS after they have successfully 
completed eitherany of the parent study 
(Study studies (SD-809-C-17 [Phase 1b] or 
Study], TV50717-CNS-30046 [Phase 2/3], or 
TV50717-CNS-30060 [Phase 3]).
Informed consent/assent and/or co-consent for 
patients 14 years of age and older, as 
appropriate, will be obtained before any study 
procedures are performed. Patients may have 
informed consent/assent and/or co-consent for 
patients 14 years of age and older, as 
appropriate, obtained prior to the baseline 
visit, up to 4 weeks in advance of open-label 
participation.
Patients who have successfully completed
either parent study any of the parent studies 
may be eligible to enroll in the current study
after they complete a 1-week washout period 
and the final evaluation in the parent study. To 
reduce patient burden, after obtaining 
informed consent/assent and/or co-consent for 
patients 14 years of age and older, as 
appropriate, some data collected in 
Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 will be used to 
provide corresponding baseline data in the 
This is a 56-week, open-label, 
single-arm study to evaluate the 
safety of TEV-50717 in children 
and adolescents with tics 
associated with TS after they have 
successfully completed any of the 
parent studies (SD-809-C-17 
[Phase 1b], TV50717-CNS-30046 
[Phase 2/3], or TV50717-
CNS-30060 [Phase 3]).
Informed consent/assent and/or 
co-consent for patients 14 years 
of age and older, as appropriate, 
will be obtained before any study 
procedures are performed. 
Patients may have informed 
consent/assent and/or co-consent 
for patients 14 years of age and 
older, as appropriate, obtained 
prior to the baseline visit, up to 4 
weeks in advance of open-label 
participation.
Patients who have successfully 
completed any of the parent 
studies may be eligible to enroll 
in the current study after they 
complete a 1-week washout 
period and the final evaluation in 
the parent study. To reduce 
patient burden, after obtaining 
The general design, 
sample size, and 
power calculations 
were updated to 
include 
Study TV5017-
CNS-30060 
calculations. 
Study TV50717-
CNS-30060 was 
added globally 
throughout the 
document as a 
parent study for 
patients to enroll 
from into 
Study TV50717-
CNS-30047.


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
135
current open-label study (see Table 1).
Up to 110260 patients are planned to be 
enrolled (up to 10 patients are estimated to 
enroll from the Phase 1b Study SD-809-C-17, 
and up to 90100 patients are estimated to 
enroll from Phase 2/3 Study TV50717-
CNS-30046, and up to 150 patients are 
estimated to enroll from the Phase 3 
Study TV50717-CNS-30060).
informed consent/assent and/or 
co-consent for patients 14 years 
of age and older, as appropriate, 
some data collected in 
Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 will 
be used to provide corresponding 
baseline data in the current open-
label study (see Table 1).
Up to 260 patients are planned to 
be enrolled (up to 10 patients are 
estimated to enroll from the Phase 
1b Study SD-809-C-17, up to 100 
patients are estimated to enroll 
from Phase 2/3 Study TV50717-
CNS-30046, and up to 150 
patients are estimated to enroll 
from the Phase 3 Study TV50717-
CNS-30060).
3.1.1 Screening Period (up to 4 Weeks; Minimum of 3 Days) (Other sections affected by this 
change: 3.12, 3.12.1, 4.1, 12.1)
After informed consent (and written assent 
and/or co-consent for patients 14 years of age 
and older, as appropriate) is obtained, patients 
who are stable from a medical and psychiatric 
standpoint will undergo a screening 
evaluation, including medical history, physical 
and neurological examination, laboratory 
testing, and 12-lead ECG, along with rating 
scales to assess severity, frequency, and 
impairment of tics and comorbid TS 
symptoms and behavioral status. 
After informed consent (and 
written assent and/or co-consent 
for patients 14 years of age and 
older, as appropriate) is obtained, 
patients who are stable from a 
medical and psychiatric 
standpoint will undergo a 
screening evaluation, including 
medical history, physical and 
neurological examination, 
assessment of vital signs, 
laboratory testing, and 12-lead 
ECG, along with rating scales to 
assess comorbid TS symptoms 
and behavioral status.
An option was 
added for co-
consent for patients 
14 years of age and 
older, as 
appropriate.
3.1.1 Screening Period (up to 4 Weeks; Minimum of 3 Days)
For patients from Study TV50717 CNS-30046 
or Study TV50717-CNS-30060:
For patients from Study TV50717 
CNS-30046 or Study TV50717-
CNS-30060:
Study TV50717-
CNS-30060 was 
added globally as a 
parent study 
throughout the 
document for 
patients to enroll 
from into 
Study TV50717-
CNS-30047.


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
136
3.1.2.
Baseline Visit (All Patients) (Other section affected by this change: 3.12.2.)
Baseline visit (all patients): For patients 
enrolled inrolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060, 
the baseline visit of this study will occur 
simultaneously withthe week 13 visit 
(Study TV50717-CNS-30046) or week 9 visit 
(Study TV50717-CNS-30060) will be the 
baseline visit for Study TV50717-CNS-30047. 
Patients rolling over from Study SD-809-C-17
will need to undergo all baseline assessments. 
Baseline assessments for Study TV50717-
CNS-30047 that are also specified for the 
baseline visit ofthat are identical to 
Study TV50717-CNS-30046 week 13 or 
Study TV50717-CNS-30060 week 9 visit
assessments do not need to be repeated. In 
addition to assessmentsAdditionally, 
Study TV50717-CNS-30047 required 
evaluations will be completed at 
Study TV50717-CNS-30046 week 13 visit, 
evaluations required as part of the current 
study will be completed on the same day as 
the week13 or Study TV50717-CNS-30060 
week 9 visit (see Table 1). For all patients, the 
baseline visit will occur on the same day as 
the scheduled first dose of the study drugIMP
(day 1). If washout period is >7 days, the 
medical monitor must be consulted for which 
entry tests that require repeating.
For patients with clinically significant 
laboratory abnormalities at week 12 in 
Study TV50717-CNS-30046, the or at week 8 
in Study TV50717-CNS-30060, 
Study TV50717 CNS-30046 week 13 value(s)
or Study TV50717-CNS-30060 week 9 
value(s) will serve as baseline laboratory 
values in this study. Rollover for such patients 
must be approved by the medical monitor and 
may be delayed.
Baseline visit (all patients): For 
patients rolling over from 
Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, the 
week 13 visit (Study TV50717-
CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) 
will be the baseline visit for 
Study TV50717-CNS-30047. 
Patients rolling over from 
Study SD-809-C-17 will need to 
undergo all baseline assessments. 
Baseline assessments for 
Study TV50717-CNS-30047 that 
are identical to Study TV50717-
CNS-30046 week 13 or 
Study TV50717-CNS-30060 
week 9 assessments do not need 
to be repeated. Additionally, 
Study TV50717-CNS-30047 
required evaluations will be 
completed at Study TV50717-
CNS-30046 week 13 visit or 
Study TV50717-CNS-30060 
week 9 visit (see Table 1). For all 
patients, the baseline visit will 
occur on the same day as the 
scheduled first dose of the IMP 
(day 1). If washout period is >7 
days, the medical monitor must 
be consulted for which entry tests 
that require repeating.
For patients with clinically 
significant laboratory 
abnormalities at week 12 in 
Study TV50717 CNS-30046 or at 
week 8 in Study TV50717-
CNS-30060, Study TV50717 
CNS-30046 week 13 value(s) or 
Study TV50717-CNS-30060 
week 9 value(s) will serve as 
baseline laboratory values in this 
study. Rollover for such patients 
must be approved by the medical 
monitor and may be delayed.
The baseline visit 
assessment design 
has been updated to 
include handling 
and results from 
previous study 
assessment.
3.1.3. Titration Period (Other section affected by this change: 5.1.)
Patients will receive 6 mg of TEV-50717 with
food on the evening of day 1. Tablets should 
Patients will receive 6 mg of 
TEV-50717 with food on the 
A statement was 
added to further 


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
137
be taken with food (eg, a snack) and should 
not be taken on an empty stomach.
evening of day 1. Tablets should 
be taken with food (eg, a snack) 
and should not be taken on an 
empty stomach.
clarify that the IMP 
should be taken 
with a snack and 
not on an empty 
stomach.
3.1.3. Titration Period
In-person (in-clinic) study visits will be 
scheduled at weeks 2, 4, and 6, and telephone 
contacts will be scheduled for weeks 1, 3, 5, 
and 7 in order to assess tic severity and 
adverse events. 
The dose of the study drugIMP should be 
increased on a weekly basis until one of the 
following criteria is metoccurs:
there is optimal reduction of tics, as 
determined by the investigator, in consultation 
with the patient and caregiver/adult.The 
investigator determines there has been a 
clinically meaningful reduction in tics, as 
indicated by a sustained reduction in the TS-
CGI
The patient experiences a protocol-defined 
“clinically significant” adverse event (defined 
as an adverse event that is related to 
medication drugIMP and is either moderate or 
severe in intensity or meets the criteria for a 
serious adverse event)
The maximum allowable dose is reached, 
based on the patient’s weight and use of 
strong CYP2D6 inhibitors
In-person (in-clinic) study visits 
will be scheduled at weeks 2, 4, 
and 6, and telephone contacts will 
be scheduled for weeks 1, 3, 5, 
and 7 in order to assess tic 
severity and adverse events.
The dose of the IMP should be 
increased on a weekly basis until 
one of the following occurs:
The investigator determines there 
has been a clinically meaningful 
reduction in tics, as indicated by a 
sustained reduction in the TS-CGI
The patient experiences a 
protocol-defined “clinically 
significant” adverse event 
(defined as an adverse event that
is related to IMP and is either 
moderate or severe in intensity or 
meets the criteria for a serious 
adverse event)
The maximum allowable dose is 
reached, based on the patient’s 
weight and use of strong CYP2D6 
inhibitors
The titration 
instructions were 
modified to provide 
more objective 
guidance to 
investigators, who 
are now directed to 
increase the dose 
until there is a 
sustained reduction 
in the TS-CGI.
3.4.1. Efficacy Measures and Time Points (Other sections affected by this change: Sections 6.1., 
6.1.1., 6.1.2.)

YGTSS (to calculate TTS): Screening (only 
for patients who completed 
Study SD-809-C-17); baseline (ie, week 13 
data from Study TV50717-CNS-30046 or 
week 9 data from Study TV50717-
CNS-30060); and weeks 2, 4, 6, 8, 15, 28, 41, 
54, and 55

TS-CGI: Baseline (only for patients who 
completed Study SD 809 C 17) (ie, week 13 
data from Study TV50717-CNS-30046 or 
week 9 data from Study TV50717-
CNS-30060) and weeks 2, 4, 6, 8, 15, 28, 41, 

YGTSS (to calculate TTS): 
Screening (only for patients who 
completed Study SD-809-C-17);
baseline (ie, week 13 data from 
Study TV50717-CNS-30046 or 
week 9 data from 
Study TV50717-CNS-30060); 
and weeks 2, 4, 6, 8, 15, 28, 41, 
54, and 55

TS-CGI: Baseline (ie, week 13 
data from Study TV50717-
CNS-30046 or week 9 data from 
This section was 
updated to identify 
baseline data from 
parent studies,
which will be 
utilized in this 
open-label study. 


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
138
54, and 55

TS-PGIS: Baseline (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 
2, 4, 6, 8, 15, 28, 41, 54, and 55
Study TV50717-CNS-30060)
and weeks 2, 4, 6, 8, 15, 28, 41, 
54, and 55

TS-PGIS: Baseline (ie, week 13 
data from Study TV50717-
CNS-30046 or week 9 data from 
Study TV50717-CNS-30060) 
and weeks 2, 4, 6, 8, 15, 28, 41, 
54, and 55
3.7. Drugs Used in the Study
The IMP is a matrix formulation and is 
designed as a gastro-erosional tablet to be 
administered with food and should not be 
taken on an empty stomach.
The IMP is a matrix formulation 
and is designed as a gastro-
erosional tablet to be 
administered with food and 
should not be taken on an empty 
stomach.
A statement was 
added to further 
clarify that the IMP 
should not be taken 
on an empty 
stomach.
3.12. Study Procedures and Assessments
Study procedures and assessments with their 
timinge points are summarized presented in
Table 1. During a visit, study procedures and 
assessments should be performed in the order 
specified in the study manual.
Study procedures and assessments 
with their time points are 
presented in Table 1. During a 
visit, study procedures and 
assessments should be performed 
in the order specified in the study 
manual.
The section was 
modified to provide 
guidance that the 
order of procedures 
will be determined 
in a study manual. 
3.12.1 Procedures for Screening and Enrollment (Visit 1)
After informed consent is obtained, patients 
rolling over from Study SD 809 C 17 who are 
screened will be assigned an 8 digit 
permanent identification number such that all 
patients from each investigational center are 
given consecutive identification numbers in 
successive order of inclusion. The first 2 digits 
of the screening number will be the number 
assigned to the country where the 
investigational center is located, the next 
3 digits will be the assigned number of the 
investigational center, and the last 3 digits will 
be assigned at the investigational center (eg, if 
the number assigned to the country is 01, the 
third patient screened at fifth investigational 
center would be given the number of 
01005003).
This paragraph was 
deleted to remove 
the detailed 
specificity for 
patient ID 
assignment.
3.12.1 Procedures for Screening and Enrollment (Visit 1) 
administer the following questionnaires 
(Note: For MINI Kid and C-SSRS, 

administer the following 
questionnaires (Note: For 
Specific instruction 
was provided for 


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
139
children 13 years of age and under must 
be interviewed in conjunction with the 
caregiver/adult. For children over 13 years 
of age, caregiver/adult involvement is 
strongly encouraged. Questions should be 
directed to the child, but the 
caregiver/adult should be encouraged to 
add relevant information. The YGTSS 
questionnaire should be performed before 
any blood draws or ECG assessments.):
MINI Kid and C-SSRS, 
children 13 years of age and 
under must be interviewed in 
conjunction with the 
caregiver/adult. For children 
over 13 years of age, 
caregiver/adult involvement is 
strongly encouraged. 
Questions should be directed 
to the child, but the 
caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS 
questionnaire should be 
performed before any blood 
draws or ECG assessments.):
the YGTSS 
assessment to be 
performed before 
any blood draws or 
ECG. 
3.12.1.1. YGTSS Rater Certification
3.12.1.1. YGTSS Rater Certification
All investigators and sub-investigators who 
will be administering the YGTSS from 
screening through the end of study visit must 
undergo and pass a Rater Certification 
Program which will be provided separately 
from this protocol. Every effort must be made 
to ensure that the same certified rater 
administers the YGTSS to a specific patient at 
all visits, especially at the baseline and week 
54/early termination visits. However, if due to 
unforeseen circumstances the same rater is 
absolutely unavailable to complete a visit 
rating, the YGTSS can be administered only 
by another certified individual from that study 
site.
3.12.1.1. YGTSS Rater 
Certification
All investigators and sub-
investigators who will be 
administering the YGTSS from 
screening through the end of 
study visit must undergo and pass 
a Rater Certification Program 
which will be provided separately 
from this protocol. Every effort 
must be made to ensure that the 
same certified rater administers 
the YGTSS to a specific patient at 
all visits, especially at the 
baseline and week 54/early 
termination visits. However, if 
due to unforeseen circumstances 
the same rater is absolutely 
unavailable to complete a visit 
rating, the YGTSS can be 
administered only by another 
certified individual from that 
study site.
This section was 
added for 
instruction related 
to protocol specific 
YGTSS rater 
certification.
3.12.2. Procedures before Investigational Medicinal Product Treatment (Baseline) (Other sections 
affected by this change: 3.12.3.1.2., 3.12.3.2.1., 3.12.4.1)


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
140
administer the following questionnaires (Note: 
For C-SSRS, Tic-free Interval, CY-BOCS, and 
GTS-QOL, children 13 years of age and under 
must be interviewed in conjunction with the 
caregiver/adult. For children over 13 years of 
age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant information. The 
YGTSS, TS-CGI, and TS-PGIS questionnaires 
should be performed before any blood draws or 
ECG assessments.):
administer the following 
questionnaires (Note: For C-
SSRS, Tic-free Interval, 
CY-BOCS, and GTS-QOL, 
children 13 years of age and 
under must be interviewed in 
conjunction with the 
caregiver/adult. For children 
over 13 years of age, 
caregiver/adult involvement is 
strongly encouraged. Questions 
should be directed to the child, 
but the caregiver/adult should 
be encouraged to add relevant 
information. The YGTSS, TS-
CGI, and TS-PGIS 
questionnaires should be 
performed before any blood 
draws or ECG assessments.):
Specific instruction 
was provided for 
the YGTSS, TS-
CGI, and TS-PGIS 
assessments to be 
performed before 
any blood draws or 
ECG.
4.1.
Patient Inclusion Criteria
h.
Women/girls of childbearing potential 
(not surgically sterile [at least 3 months] or 
congenitally sterile) whose male partners are 
of childbearing potential must use 
contraception for the duration of the study and 
for 30 days after discontinuation of study 
drug. Acceptable methods of contraception are 
those with a failure rate of less than 1% per 
year (eg, intrauterine device inert, copper or 
levonorgestrel; combined [estrogen and 
progestogen] hormonal contraceptive [oral, 
implanted, transdermal]; progesterone only 
[implanted, oral and injected]; and intrauterine 
hormone releasing system); and sole partner 
vasectomy (medically assessed for surgical 
success). Examples of surgical sterility are 
documented: Bi tubal ligation, hysterectomy, 
bilateral salpingo oophorectomy, bilateral 
oophorectomy, and hysterectomy with 
bilateral salpingo oophorectomy. These 
methods need to be initiated at least 3 months 
prior to study drug administration.Females 
may be included only if they have a negative 
β-human chorionic gonadotropin test at 
baseline or are sterile. Definitions of sterile 
are given in Appendix L.
i.
Females of childbearing potential whose 
male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth 
h.
Females may be included 
only if they have a negative β-
human chorionic gonadotropin 
test at baseline or are sterile. 
Definitions of sterile are given in 
Appendix L.
i.
Females of childbearing 
potential whose male partners are 
potentially fertile (ie, no 
vasectomy) must use highly 
effective birth control methods 
for the duration of the study (ie, 
starting at screening) and for 30 
days or 5 drug half lives, 
whichever is longer after last dose 
of IMP. Further details are 
included in Appendix L.
The inclusion 
criteria for females 
was updated to 
include additional 
inclusion criteria 
related to β HCG 
test and the 
requirement to use 
highly effective 
birth control 
methods.


Uncontrolled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 04
Study TV50717-CNS-30047
141
control methods for the duration of the study 
(ie, starting at screening) and for 30 days or 5 
drug half lives, whichever is longer after last 
dose of IMP. Further details are included in 
Appendix L.
4.2. Patient Exclusion Criteria
m. Patient requires treatment with drugs 
known to prolong the QT interval (see 
Appendix A, Table 7) for a complete list of 
prohibited QT prolonging drugs).has a QT 
interval corrected for heart rate using 
Fridericia’s formula (QTcF) interval value 
>450 msec (males) or >460 msec (females) or 
>480 msec (with right bundle branch block) 
on 12-lead ECG at screening.
m.n.
Patient has a QTcF interval value 
>440 msec on 12 lead ECG at 
screening.Patients with a history of torsade de 
pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart 
failure.
m. Patient has a QT interval 
corrected for heart rate using 
Frederica’s formula (QTcF) 
interval value >450 msec (males) 
or >460 msec (females) or 
>480 msec (with right bundle 
branch block) on 12-lead ECG at 
screening. 
n.
Patients with a history of 
torsade de pointes, congenital 
long QT syndrome, 
bradyarrhythmias, or 
uncompensated heart failure.
The exclusion 
criteria was 
modified to further 
define criteria for 
QTc and add
additional exclusion 
criteria related to 
specific cardiac 
conditions.
4.2 Patient Exclusion Criteria
t.
Patient is a pregnant or breastfeeding or 
lactating female, or plans to become pregnant 
during the study
t.
The patient is a pregnant or 
lactating female, or plans to 
become pregnant during the 
study.
The exclusion 
criteria for females 
was updated to 
include additional 
exclusion criteria.
4.4. Withdrawal Criteria and Procedures (Other sections affected by this change: 7.1.7., 7.7.)
In accordance with the Declaration of Helsinki 
(in accordance with the applicable country’s 
acceptance), each patient is free to withdraw 
from the study drugIMP at any time. The 
investigator also has the right to withdraw a 
patient from the study drugIMP in the event of 
intercurrent illness, adverse events, pregnancy 
(see Section 7.3), or other reasons concerning 
the health or well-being of the patient, or in 
the event of lack of cooperation. If a post-
baseline QTcF value >500 msec or change 
from baseline >60 msec is found, the 
investigator should repeat the ECG 
assessment twice and compare the average of 
the 2 pre-treatment QTcF values (baseline and 
screening) to the average of the 3 post-
baseline QTcF values. The IMP must be 
stopped for any confirmed post-baseline QTcF 
value >500 msec or increase from baseline 
In accordance with the 
Declaration of Helsinki (in 
accordance with the applicable 
country’s acceptance), each 
patient is free to withdraw from 
the IMP at any time. The 
investigator also has the right to 
withdraw a patient from the IMP 
in the event of intercurrent illness, 
adverse events, pregnancy (see 
Section 7.3), or other reasons 
concerning the health or 
well-being of the patient, or in the 
event of lack of cooperation. If a 
post-baseline QTcF value >500 
msec or change from baseline 
>60 msec is found, the 
investigator should repeat the 
ECG assessment twice and 
The additional text 
regarding ECG 
assessments and 
QTc limit was 
included to identify 
QTc changes that 
will require IMP 
suspension.


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>60 msec. In addition, a patient may be 
withdrawn from the study drugIMP as 
described in Sections 3.10, 3.12.3.2.2, 5.4, and 
7.1.7.
compare the average of the 2 pre-
treatment QTcF values (baseline 
and screening) to the average of 
the 3 post-baseline QTcF values. 
The IMP must be stopped for any 
confirmed post-baseline QTcF 
value >500 msec or increase from 
baseline >60 msec. In addition, a 
patient may be withdrawn from 
the IMP as described in 
Sections 3.10, 3.12.3.2.2, 5.4, 
and7.1.7.
5.1. Drugs Administered During the Study
Not applicable
Added header “Daily dose (mg) at 
the start of visit/week”
The table header 
was updated in the 
synopsis to clarify 
table contents.
5.1. Drugs Administered During the Study


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Weight category Daily dose 
(mg) at the start of visit/week
Study we
eka
20 to 
<30 kg
(44 to 
<66 lbs)
30 to 
<40 kg
66 to 
<88 lbs
)
≥40 kg
(≥88 lbs)
Week 1 
Baseline
mg
6 mg
6 mg 
(Days 
1 and 
2)
12 mgb
Week 2 1
12 mg
12 mg
18 mg
Week 3 2
18 mg
18 mg
24 mg
Week 43
18 mgc
24 mgc
30 mg
Week 54
24 mgc
30 mgc
36 mgc
Week 6 5
24 mgc
36 mgc
42 mgc
Week 7 6
30 mgc
42 mgc
48 mgc
Daily dose (mg) at 
the start of 
visit/week
Study
weeka
20 to 
<30 kg
(44 to 
<66 lbs
)
30 
to 
<40 
kg
(66
to 
<88
lbs)
≥40 
kg
(≥88
lbs)
Baseline
6 mg
6 
mg
6 mg 
(Days 
1 and 
2)
12 
mgb
Week 1 
12 mg
12 
mg
18 
mg
Week 2 
18 mg
18 
mg
24 
mg
Week 3 
18 mgc
24 
mgc
30 
mg
Week 4
24 mgc
30 
mgc
36 
mgc
Week 5 
24 mgc
36 
mgc
42 
mgc
Week 6 
30 mgc
42 
mgc
48 
mgc
The table was 
updated with 
weight details and 
clarifications 
regarding how 
study weeks are 
defined with the 
visit occurring at 
the beginning of the 
week.
5.3. Prior and Concomitant Medication or Treatment (Other sections affected by this change: 7.10.)
Any prior or concomitant therapy, medication, 
or procedure a patient has had within 3 
months before study drugIMP administration 
and up to the end of the study period, 
including follow-up, will be recorded on the 
CRF. Generic or trade name, indication, and 
dosage will be recorded. The sponsor will 
encode all therapy and medication according 
to the World Health Organization drug 
dictionary.
At each clinic visit after the screening visit, 
the investigator will ask patients whether they 
Any prior or concomitant therapy, 
medication, or procedure a patient 
has had within 3 months before 
IMP administration and up to the 
end of the study period, including 
follow-up, will be recorded on the 
CRF. Generic or trade name, 
indication, and dosage will be 
recorded. The sponsor will 
encode all therapy and medication 
according to the World Health 
Organization drug dictionary.
This additional 
instruction will 
allow the 
investigator to 
monitor new 
concomitant 
medications, thus 
enhancing patient 
safety.


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have taken any medications (other than study 
drugIMP), including over-the-counter 
medications, vitamins, or herbal or nutritional 
supplements, since the previous visit. 
Parents/patients will be instructed during the 
course of the study to notify the investigator if 
any new medication is prescribed, including 
over-the-counter medications. Any prescribed 
medication should be reviewed with the 
investigator. Indication, dosage, and start and 
end dates should be entered on the CRF. 
At each clinic visit after the 
screening visit, the investigator 
will ask patients whether they 
have taken any medications (other 
than IMP), including 
over-the-counter medications, 
vitamins, or herbal or nutritional 
supplements, since the previous 
visit. Parents/patients will be 
instructed during the course of the 
study to notify the investigator if 
any new medication is prescribed, 
including over-the-counter 
medications. Any prescribed 
medication should be reviewed 
with the investigator. Indication, 
dosage, and start and end dates 
should be entered on the CRF. 
6.1. Efficacy and Exploratory Measures

 
 

 
 
 
 
 
 
 
 
 
.
7.5. Clinical Laboratory Tests
The clinical significance of the lab values will 
be evaluated by the criteria described in the 
study lab manual and by the judgment of the 
investigator.
The clinical significance of the 
lab values will be evaluated by 
the criteria described in the study 
lab manual and by the judgment 
of the investigator.
This sentence was 
included to provide 
further guidance 
regarding clinical 
significance of 
laboratory values 
and investigator 
judgement. 
7.7. Electrocardiography
A 12-lead ECG will be recorded at the time 
points detailed in Table 1. All ECGs will be 
performed after at least 5 minutes rest in a 
supine or semi-supine position. A qualified 
physician at a central diagnostic center will be 
interpreting the ECG.
All ECG results outside of the reference 
ranges will be judged by the investigator as 
A 12-lead ECG will be recorded 
at the time points detailed in
Table 1. All ECGs will be 
performed after at least 5 minutes 
rest in a supine or semi-supine 
position. A qualified physician at 
a central diagnostic center will be 
interpreting the ECG.
This section was 
updated to specify 
ECG clinical 
significance 
correlating with 
adverse event 
determination. 


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belonging to one of the following categories:
abnormal and not clinically significant 
abnormal and clinically significant
Any ECG finding that is judged by the 
investigator as clinically significant (except at 
the screening visit) will be considered an 
adverse event, recorded on the source 
documentation and in the CRF 12 Lead ECGs 
will be interpreted by a cardiologist at a 
central diagnostic center. Heart rate and ECG 
intervals (PR, QRS, QT, and QTcF) and 
clinical interpretation will be assessed by the 
central cardiologist, recorded, and monitored 
as described in Section 7.1.2.
All ECG results outside of the 
reference ranges will be judged 
by the investigator as belonging 
to one of the following categories:
abnormal and not clinically 
significant 
abnormal and clinically 
significant
Any ECG finding that is judged 
by the investigator as clinically 
significant (except at the 
screening visit) will be considered 
an adverse event, recorded on the 
source documentation and in the 
CRF, and monitored as described 
in Section 7.1.2.
9.4.2. Demographic and Baseline Characteristics 
Patient demographic and baseline 
characteristics, including medical history, 
prior medications and treatments, and ECG 
findings, will be summarized using descriptive 
statistics and will be analyzed by age group.
Patient demographic and baseline 
characteristics, including medical 
history, prior medications and 
treatments, and ECG findings, 
will be summarized using 
descriptive statistics and will be 
analyzed by age group.
This section was 
updated to add that 
data will be 
analyzed by age 
group.
11.1.2. Protocol Violations
Protocol violations will be identified and 
recorded by investigational center personnel 
in a log or as part of the CRF.
Protocol violations will be 
identified and recorded by 
investigational center personnel in 
a log or as part of the CRF.
The documentation 
mechanism for 
recording protocol 
violations was 
updated to include a 
log.
APPRENDIX A ALLOWED AND DISALLOWED MEDICATIONS
Prohibited QTc Prolonging Drugs
Generic
Class/clinical use
Note
Azithromy
cin
Antibiotic/bacterial 
infection
Chloroquin
e / 
Mefloquine
Anti malarial/malaria 
infection
Clarithrom
ycina
Antibiotic/bacterial 
infection
Domperido
ne
Anti nausea/nausea
Not 
availabl
e in 
Not applicable
The restriction on 
the use of 
concomitant 
medications that are 
commonly used 
within the pediatric 
population and that 
prolong the QT 
interval (eg, 
antibiotics) was 
removed. 
Antipsychotic 
medications remain 
prohibited owing to 
their ability to 


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USA
Droperidol Sedative; anti
nausea/anesthesia 
adjunct, nausea
Erythromy
cin
Antibiotic; 
gastrointestinal (GI) 
stimulant; GI motility
Moxifloxac
in
Antibiotic/bacterial 
infection
Sevofluran
e
Anesthetic, 
general/anesthesia
Probucol
Antilipemic/hyperchol
esterolemia
Not 
availabl
e in 
USA
Sparfloxaci
n
Antibiotic/bacterial 
infection
Not 
availabl
e in 
USA
a
Systemic use only. Topical use is allowed.
USA=United States of America.
confound the 
efficacy and safety 
of TEV-50717. 
These changes were 
made based on the 
cardiodynamic data 
from the thorough 
QT study, the PK-
PD modeling of 
maximal steady 
exposure in studies 
with HD and TD, 
and with observed 
data from the TD 
program in which 
QT interval 
prolonging drugs 
were safely 
administered in 
conjunction with 
TEV-50717.
APPENDIX I TOURETTE SYNDROME-PATIENT GLOBAL IMPRESSION OF SEVERITY
Choose the statement that best describes 
your tics over the past week:
1
None. I have had no tics at all.
2
Mild. My tics are rarely noticed by 
others, they are not distressing, and 
they do not interfere with my daily 
life.
3
Moderate. My tics are sometimes 
noticed by others and occasionally 
bring me unwanted attention. They 
can be distressing or interfere with my 
daily life.
4
Marked. My tics are frequently 
noticed by others. They cause me 
substantial distress and interfere with 
my daily life.
5
Severe. My tics are almost always 
noticed by others and can cause pain, 
injury, or severe distress. They 
prevent me from doing most of my 
daily activities.
Not applicable
The “first table” in 
the appendix was 
deleted. The PGIS 
questionnaire 
remains in 
Appendix I.


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APPENDIX L BIRTH CONTROL METHODS AND PREGNANCY TESTING
Not applicable
Highly effective birth control 
methods:
Highly effective birth control 
methods are methods that can 
achieve a failure rate of less than 
1% per year when used 
consistently and correctly are 
considered. Such methods 
include:
•
Combined estrogen and 
progestogen hormonal 
contraception (oral, intravaginal, 
transdermal) associated with 
inhibition of ovulation; these 
should be initiated at least 7 days 
(for IMPs without suspected 
teratogenicity/genotoxicity) and 1 
month (for IMPs potentially 
teratogenic/genotoxic) before the 
first dose of IMP.
•
Progestogen-only hormonal 
contraception (oral, injectable, 
implantable) associated with 
inhibition of ovulation; these 
should be initiated at least 7 days 
(for IMPs without suspected 
teratogenicity/genotoxicity) and 
1 month (for IMPs potentially 
teratogenic/genotoxic) before the 
first dose of IMP.
•
Intrauterine device (IUD) and 
intrauterine hormone-releasing 
system (IUS) need to be in place 
at least 2 months before 
screening.
•
Bilateral tubal occlusion
•
Vasectomized partner 
provided he is the sole sexual 
partner and has received medical 
assessment of the surgical 
process.
•
Sexual abstinence is only 
considered a highly effective 
method if defined as refraining 
from heterosexual intercourse in 
the defined period. The reliability 
of sexual abstinence needs to be 
The Appendix for 
acceptable 
contraceptive 
methods for 
females was 
included and has 
been altered to 
include abstinence 
in the definition of 
highly effective 
birth control.


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evaluated in relation to the 
duration of the clinical study and 
the preferred and usual lifestyle of 
the patient.
•
Periodic abstinence (eg, 
calendar, ovulation, 
symptothermal, post-ovulation 
methods), declaration of 
abstinence for the duration of a 
study, and withdrawal are not 
acceptable methods of 
contraception (according to 
Medicines and Healthcare 
Products Regulatory Agency, 
MHRA).


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17.2.
Amendment 02 Dated 15 November 2017
The primary reason for this amendment is to incorporate a randomized drug withdrawal period, include and define CYP2D6 
impairment status, reorder the statistical testing methodology (ie, the inclusion of the TS-PGII assessment after TS-CGI and before the 
C&A-GTS-QOL ADL subscale), and include prohibited medications that are associated with QTc prolongation.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.
Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
Global
An Open-Label, Long-Term Safety Study Including a 
Double-Blind, Placebo-Controlled, Randomized 
Withdrawal Period of TEV-50717 (deutetrabenazine) 
for the Treatment of Tourette Syndrome in Children 
and Adolescents
An Open-Label, Long-Term Safety Study Including a Double-
Blind, Placebo-Controlled, Randomized Withdrawal Period of 
TEV-50717 (deutetrabenazine) for the Treatment of Tourette 
Syndrome in Children and Adolescents
Updated to reflect 
randomized drug 
withdrawal period
Reference Treatment: Not applicable
Placebo IMP: Placebo tablets and packaging match TEV-50717 
tablets
Added placebo to 
IMP
Child and Adolescent Gilles de la Tourette Syndrome -
Quality of Life (C&A-GTS-QOL)
Child and Adolescent Gilles de la Tourette Syndrome - Quality of 
Life (C&A-GTS-QOL)
Updated Gilles de 
la Tourette 
Syndrome -
Quality of Life 
(GTS-QOL) to 
Child and 
Adolescent Gilles 
de la Tourette 
Syndrome -
Quality of Life 
(C&A-GTS-QOL)
Site-administered scales include the YGTSS, CY-
Site-administered scales include the YGTSS, CY-BOCS, Mini 
Added TS-PGII


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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
BOCS, Mini International Neuropsychiatric Interview 
For Children and Adolescents (MINI Kid), and the C-
SSRS and self-administered scales include the TS-
PGIS, TS-PGII, Tic-free Interval, CDI-2, and C&A-
GTS-QOL.
International Neuropsychiatric Interview For Children and 
Adolescents (MINI Kid), and the C-SSRS and self-administered 
scales include the TS-PGIS, TS-PGII, Tic-free Interval, CDI-2, 
and C&A-GTS-QOL.
baseline day 1
day 1
To provide greater 
protocol clarity
and timing of 
assessments and 
procedures, 
references to 
“baseline” of study 
30047 were 
removed and 
replaced by 
“day 1”.
Not applicable
Created Part A (screening, titration, maintenance) and Part B
(randomized drug withdrawal, re-titration, maintenance)
Added Part B 
Double-blind 
placebo controlled 
randomized drug 
withdrawal
TS-PGII (Note: Input from the caregiver/adult is
required permitted.)
TS-PGIS (Note: Input from the caregiver/adult is 
required permitted.)
TS-PGII (Note: Input from the caregiver/adult is permitted.)
TS-PGIS (Note: Input from the caregiver/adult is permitted.)
Changed to 
indicate that TS-
PGII and TS-PGIS 
input from 
caregiver/adult is 
permitted
females of childbearing potential who are 
postmenarchal or ≥12 years of age
females who are postmenarchal or ≥12 years of age
The definition of 
women of 
childbearing 
potential has been 
updated 


Uncontrolled Study–Tourette Syndrome
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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
throughout the 
protocol
TITLE PAGE
Teva’s Development Partner
Nuvelution TS Pharma, Inc.
601 Gateway Boulevard
Suite 1270
South San Francisco, California 94080
United States of America
Teva’s Development Partner
Nuvelution TS Pharma, Inc.
601 Gateway Boulevard
Suite 1270
South San Francisco, California 94080
United States of America
Title page was 
changed to update 
Teva’s 
Development 
Partner to 
Nuvelution TS 
Pharma, Inc.
Clinical Laboratory and Other Departments and Institutions
Central Institutional Review Board
Quorum Review IRB
1501 Fourth Avenue, Suite 800
Seattle, WA 98101 Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Central Electrocardiogram Evaluation
Biomedical Systems
77 Progress Parkway
St. Louis, MO 63043 
USA
ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Central Institutional Review Board 
Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Central Electrocardiogram Evaluation
ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Integrated Response Technology
Endpoint
55 Francisco Street, Suite 200
San Francisco, CA 94133
Update 
Institutional 
Review Board to 
Copernicus Group 
IRB. Change in 
client vendors


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
Integrated Response Technology
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA
Endpoint
55 Francisco Street, Suite 200
San Francisco, CA 94133
USA
USA
Clinical Study Personnel Contact Information
For operational issues, contact the operational lead 
listed below: 
Nuvelution TS Pharma, INC
Tel: 
Email: 
For protocol issues, contact the study leader listed 
below:
 Nuvelution TS Pharma, INC.
Tel: 
Email:
Nuvelution Pharma
Tel: + 
For operational issues, contact the operational lead listed 
below:
 Nuvelution TS Pharma, INC.
Tel: 
Email: 
For protocol issues, contact the study leader listed below:
 Nuvelution TS Pharma, INC.
Tel: 
Email: 
 Nuvelution TS Pharma, INC
Tel: + 
Email: 
Change in 
Nuvelution study 
personnel


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
153
Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
Email: 
 Nuvelution TS Pharma, INC
Tel: 
Email: 
1.2 Name and Description of Investigational Medicinal Product
During the randomized drug withdrawal, TEV-50717 
tablets are available in the following dose strengths: 6, 
9, 12, 15, and 18 mg, all of which are identical in size, 
shape, and color (white). The IMP will be supplied in 
20-count bottles.
During the randomized drug withdrawal, TEV-50717 tablets are 
available in the following dose strengths: 6, 9, 12, 15, and 18 mg, 
all of which are identical in size, shape, and color (white). The 
IMP will be supplied in 20-count bottles.
Added last 
paragraph to 
describe IMP at 
randomized drug 
withdrawal
1.5.1 Justification for Dose of Active Drug
The dose ranges to be evaluated in this study, based on 
body weight and the use of strong CYP2D6 inhibitors 
at baseline, impairment status on day 1, were selected 
on the basis of the safety, preliminary efficacy, and 
population pharmacokinetics data generated from 
Study SD-809-C-17 (Table 2).
The dose ranges to be evaluated in this study, based on body
weight and CYP2D6 impairment status on day 1, were selected on 
the basis of the safety, preliminary efficacy, and population 
pharmacokinetics data generated from Study SD-809-C-17 (Table 
2).
Updated dose 
ranges to be based 
on “body weight 
and CYP2D6 
impairment status”
1.8 Location and Study Duration
This study is planned to be conducted in North
America, Latin America, Russia, Ukraine, South Korea, 
Turkey, and Europe at approximately 100 centers.
This study is planned to be conducted in North America, Latin 
America, Russia, Ukraine, South Korea, Turkey, and Europe at 
approximately 100 centers.
Added Latin 
America, Russia, 
Ukraine, South 
Korea, and Turkey 
to study location 
list
2.1 Purpose of the Study
This is an open-label, Phase 3 study with a 2-week, 
double-blind, placebo-controlled, randomized drug 
withdrawal period to evaluate the safety and efficacy of 
This is an open-label, Phase 3 study with a 2-week, double-blind, 
placebo-controlled, randomized drug withdrawal period to 
evaluate the safety and efficacy of TEV 50717 tablets in patients 
Updated to more 
clearly specify the 
inclusion of the 2-


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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
TEV 50717 tablets in patients who have previously
completed participation in Study SD-809 C-17, 
Study TV50717 CNS-30046, or Study TV50717-
CNS-30060.
who have previously completed participation in Study SD-809 C-
17, Study TV50717 CNS-30046, or Study TV50717-CNS-30060.
week, double-
blind, placebo-
controlled, 
randomized drug 
withdrawal period
2.2.2 Secondary Objectives
The secondary objectives of thethis study is are as 
follows:
to evaluate the efficacy of long-term therapy of with
TEV-50717 in reducing the severity of TS tics
to confirm long-term maintenance of effect by means 
of a double-blind, placebo-controlled, randomized drug 
withdrawal period after 28 weeks of open-label 
treatment
The secondary objectives of this study are as follows:
to evaluate the efficacy of long-term therapy with TEV-50717 in 
reducing the severity of TS tics
to confirm long-term maintenance of effect by means of a double-
blind, placebo-controlled randomized withdrawal period after 28 
weeks of open-label treatment
Added objective 
for randomized 
drug withdrawal
2.3.1 Safety Endpoints
The following safety endpoints will be assessed in Part 
A:
The following safety endpoints will be assessed in Part A:
The following safety endpoints will be assessed in Part B: 
incidence of adverse events
Added endpoints 
for Part B
2.3.2 Efficacy Endpoints
The following efficacy endpoints will be assessed in 
Part A:
Change in the YGTSS TTS from baseline day 1 to each 
visit in which the scale is administered
Change in the TS-CGI score from baseline day 1 to 
each visit in which the scale is administered
Change in the Tourette Syndrome-Patient Global 
Impression of Severity Impact (TS PGISPGII) score 
from baseline day 1 to each visit in which the scale is 
The following efficacy endpoints will be assessed in Part A:
change in the YGTSS TTS from day 1 to each visit in which the 
scale is administered
change in the TS-CGI score from day 1 to each visit in which the 
scale is administered
change in the Tourette Syndrome-Patient Global Impression of 
Impact (TS-PGII) score from day 1 to each visit in which the scale 
is administered
change in the Child and Adolescent Gilles de la Tourette 
Added Part B 
endpoints
Added TS-PGII to 
efficacy endpoints;


Uncontrolled Study–Tourette Syndrome
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Study TV50717-CNS-30047
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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
administered
Change in the Child and Adolescent Gilles de la 
Tourette Syndrome – Quality of Life (C&A-GTS QOL) 
physical/activities of daily living (ADL) subscale score 
from baseline day 1 to each visit in which the scale is 
administered
The following efficacy endpoints will be assessed in 
Part B: 
change in the TTS of the YGTSS from week 28 to 
week 30
Syndrome – Quality of Life (C&A-GTS-QOL) activities of daily 
living (ADL) subscale score from day 1 to each visit in which the 
scale is administered
The following efficacy endpoints will be assessed in Part B: 
change in the TTS of the YGTSS from week 28 to week 30
2.3.3 Exploratory Endpoints
The following exploratory endpoints will be assessed in 
Part A:
•
 
•
•
 
 
•
 
 
•
 
 
•
 
•
 
•
 
•
 
•
 
•
 
•
 
•
 
 
•
 
 
 
 
 
 


Uncontrolled Study–Tourette Syndrome
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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
 
•
 
 
•
•
 
•
 
•
 
•
 
3.1 General Design and Study Schematic Diagram
This is a 56-week, open-label, single-arm study that 
included a 2-week, double-blind, placebo-controlled, 
randomized drug withdrawal period to evaluate the 
safety of TEV-50717 in children and adolescents with 
tics associated with TS after they have successfully 
completed any of the parent studies (SD-809-C-17 
[Phase 1b], TV50717-CNS-30046 [Phase 2/3], or 
TV50717-CNS-30060 [Phase 3]). Patients rolling over 
from Study SD-809-C-17 will need to undergo all day 1
assessments. For patients rolling over from 
Study TV50717-CNS-30046 or Study TV50717 CNS-
30060, the week 13 visit (Study TV50717-CNS-30046) 
or the week 9 visit (Study TV50717-CNS-30060) will 
be the day 1 visit for Study TV50717-CNS-30047. If 
the patient does not wish to enroll in Study TV50717-
CNS-30047 at that visit, they can enroll up to 1 week 
This is a 56-week, open-label, single-arm study that included a 2-
week, double-blind, placebo-controlled, randomized drug 
withdrawal period to evaluate the safety of TEV-50717 in children 
and adolescents with tics associated with TS after they have 
successfully completed any of the parent studies (SD-809-C-17 
[Phase 1b], TV50717-CNS-30046 [Phase 2/3], or TV50717-
CNS-30060 [Phase 3]). Patients rolling over from 
Study SD-809-C-17 will need to undergo all day 1 assessments. 
For patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717 CNS-30060, the week 13 visit (Study TV50717-
CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) 
will be the day 1 visit for Study TV50717-CNS-30047. If the 
patient does not wish to enroll in Study TV50717-CNS-30047 at 
that visit, they can enroll up to 1 week following the week 13 or 
week 9 visits, respectively.
For patients rolling over from Study SD-809-C-17, this study will
Update study 
design; include 
time allowed for 
patients to enroll 
in study; include 
re-consent text.
Updated 
assessment scale 
instructions. 
Added text to 
cross-reference 
Figure 2; the 
additional diagram 
that details the 
blinded, 
randomized drug 


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Protocol Amendment 01 text with changes shown
New wording
Reason/Justificati
on for change
following the week 13 or week 9 visits, respectively.
For patients rolling over from Study SD-809-C-17, this 
study will consist of up to a 4-week screening period, a 
54 week, open label treatment period (including 7 (up 
to 31 days) and up to 52 weeks of titration and 47 
weeks of maintenance), and a 1 week washout period
treatment. Patients will have a follow-up telephone 
contact to evaluate safety 1 week after the end of the 
washout period (2 weeks after their last dose of IMP). 
Patients are expected to participate in this study for its 
entire duration, which is a minimum of 56 weeks. The 
end of study is defined as the date of the week 56 visit 
of the last participant.
Informed consent/assent and/or co-consent for patients 
14 years of age and older, as appropriate, will be 
obtained before any study procedures are performed. 
Patients may have informed consent/assent and/or co-
consent for patients 14 years of age and older, as 
appropriate, obtained prior to the baseline day 1 visit, 
up to 4 weeks in advance of open-label participation.
Any patient that turns 18 years of age during the course 
of Study TV50717-CNS-30047 will need to be re-
consented as an adult.
Patients who have successfully completed any of the 
parent studies may be eligible to enroll in the current 
study after they complete a 1-week washout period and 
the final evaluation (week 13 in TV50818-CNS-30046 
or week 9 in TV50717-CNS-30060) in the parent study. 
To reduce patient burden, after obtaining informed 
consent/assent and/or co-consent for patients 14 years 
of age and older, as appropriate, some data collected in 
Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 will be used to provide corresponding 
consist of up to a 4-week screening period (up to 31 days) and up 
to 52 weeks of treatment. Patients will have a follow-up telephone 
contact to evaluate safety 1 week after the end of the washout 
period (2 weeks after their last dose of IMP). Patients are expected 
to participate in this study for its entire duration, which is a 
minimum of 56 weeks. The end of study is defined as the date of 
the week 56 visit of the last participant.
Informed consent/assent and/or co-consent for patients 14 years of 
age and older, as appropriate, will be obtained before any study 
procedures are performed. Patients may have informed 
consent/assent and/or co-consent for patients 14 years of age and 
older, as appropriate, obtained prior to the day 1 visit, up to 4 
weeks in advance of open-label participation. Any patient that 
turns 18 years of age during the course of Study TV50717-
CNS-30047 will need to be re-consented as an adult.
Patients who have successfully completed any of the parent 
studies may be eligible to enroll in the current study after they 
complete a 1-week washout period and the final evaluation (week 
13 in TV50818-CNS-30046 or week 9 in TV50717-CNS-30060) 
in the parent study. To reduce patient burden, after obtaining 
informed consent/assent and/or co-consent for patients 14 years of 
age and older, as appropriate, some data collected in 
Study TV50717-CNS-30046 or Study TV50717-CNS-30060 will 
be used to provide corresponding day 1 data in the current open-
label study (see Table 1).
All screening procedures will be performed for patients rolling 
over from Study SD 809 C 17, as they will have been off IMP for 
several months at the time of enrollment into the current study. 
Site-administered scales include the YGTSS, CY-BOCS, Mini 
International Neuropsychiatric Interview for Children and 
Adolescents (MINI Kid), and the C-SSRS and self-administered 
scales include the TS-PGII, TS-PGIS, Tic-free Interval, CDI-2, 
and C&A-GTS- QOL. For the YGTSS, input from the 
withdrawal/titratio
n period (Part B of 
the study) 


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baseline day 1 data in the current open-label study (see 
Table 1).
All screening procedures will be performed for patients 
rolling over from Study SD 809 C 17, as they will have 
been off IMP for several months at the time of 
enrollment into the current study. Site-administered 
scales include the YGTSS, CY-BOCS, Mini 
International Neuropsychiatric Interview for Children 
and Adolescents (MINI Kid), and the C-SSRS and self-
administered scales include the TS-PGII, TS-PGIS, 
Tic-free Interval, CDI-2, and C&A-GTS- QOL. For the 
YGTSS, input from the caregiver/adult is required. For 
both the TS-PGII and TS -PGIS, input from the 
caregiver/adult is required. For the Tic free Interval, C 
SSRS, and CY BOCS permitted. For all other scales, 
children 13 years of age and under must, interviews 
may be interviewed in conjunction performed 
separately or jointly with the caregiver/adult as 
appropriate or as defined by the scale.
The study schematic diagram is presented in Figure 1. 
An additional diagram that details the blinded, 
randomized drug withdrawal/titration period (Part B of 
the study) is presented in Figure 2.
caregiver/adult is required. For both the TS-PGII and TS -PGIS, 
input from the caregiver/adult is permitted. For all other scales, 
children 13 years of age and under, interviews may be performed 
separately or jointly with the caregiver/adult as appropriate or as 
defined by the scale.
The study schematic diagram is presented in Figure 1. An 
additional diagram that details the blinded, randomized drug 
withdrawal/titration period (Part B of the study) is presented in 
Figure 2.
Figure 1 and Figure 2
Not applicable
[Figure 1 was updated for consistency with changes made to the 
table of procedures]
[Figure 2 was created and inserted to more clearly indicate the 
processes for Part B]
Updated study 
schematic Figure 1 
and Figure 2 for 
consistency with 
protocol edits and
to include drug 
withdrawal re-
randomization 


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period, 
respectively
Section 3.1.1 Screening Period (up to 31 Days)
Screening period (up to 4 weeks; minimum of 331 
days): All screening procedures will be performed for 
patients rolling over from Study SD 809 C 17, as they 
will have been off IMP for several months at the time 
of enrollment into this study (TV50717 CNS-30047).
At the discretion of the investigator, the screening visit 
may be divided into 2 visits if the visit length is deemed 
to be too burdensome for the patient. Patients may be 
rescreened at1 time if there is a change in the discretion 
of the patient’s medical monitor background, a 
modification of study entry criteria, or other relevant 
change (Note: Details of a patient’s rescreening must 
be approved).
Screening period (up to 31 days): All screening procedures will be 
performed for patients rolling over from Study SD 809 C 17, as 
they will have been off IMP for several months at the time of 
enrollment into this study (TV50717 CNS-30047).
At the discretion of the investigator, the screening visit may be 
divided into 2 visits if the visit length is deemed to be too 
burdensome for the patient. Patients may be rescreened 1 time if 
there is a change in the patient’s medical background, a 
modification of study entry criteria, or other relevant change 
(Note: Details of a patient’s rescreening must be approved).
Change screening 
period from up to 
4 weeks to up to 
31 days.
Updated screening 
visit details
3.1.2 Day 1 Visit (All Patients)
For patients rolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060, the week 
13 visit (Study TV50717-CNS-30046) or the week 9 
visit (Study TV50717-CNS-30060) will be the baseline 
day 1 visit for Study TV50717-CNS-30047. Patients 
rolling over from Study SD-809-C-17 will need to 
undergo all baseline day 1 assessments.Baseline Day 1
assessments for Study TV50717-CNS-30047 that are 
identical to Study TV50717-CNS-30046 week 13 or 
Study TV50717-CNS-30060 week 9 assessments do 
not need to be repeated. Additionally, Study TV50717-
CNS-30047 required evaluations will be completed at 
Study TV50717-CNS-30046 week 13 visit or 
Study TV50717-CNS-30060 week 9 visit (see Table 1). 
For patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, the week 13 visit (Study TV50717-
CNS-30046) or the week 9 visit (Study TV50717-CNS-30060) 
will be the day 1 visit for Study TV50717-CNS-30047. Patients 
rolling over from Study SD-809-C-17 will need to undergo all day 
1 assessments. Day 1 assessments for Study TV50717-CNS-30047 
that are identical to Study TV50717-CNS-30046 week 13 or 
Study TV50717-CNS-30060 week 9 assessments do not need to 
be repeated. Additionally, Study TV50717-CNS-30047 required 
evaluations will be completed at Study TV50717-CNS-30046 
week 13 visit or Study TV50717-CNS-30060 week 9 visit (see 
Table 1). For all patients, the day 1 visit will occur on or as close 
as possible to the week 13 or week 9 visit from Study TV50717-
CNS-30046 and Study TV50717-CNS-30060, respectively, but 
Updated day 1 
visits


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For all patients, the baseline day 1 visit will occur on or 
as close as possible to the same day as the scheduled 
first dose of the IMP (day 1). If washout period is week 
13 or week 9 visit from Study TV50717-CNS-30046 
and Study TV50717-CNS-30060, respectively, but not
>7 days, the medical monitor must be consulted for 
which entry tests that require repeating beyond those 
respective visits.
not >7 days, beyond those respective visits.
3.1.3 Titration Period
As patients from Study SD-809-C-17 will have been 
off study drug for several months at the time of 
enrollment, and since patients from Study TV50717-
CNS-30046 will have discontinued study drug (TEV-
50717 or placebo) for at least 1 week at completion of 
the parent study, all patients will undergo TEV-50717 
dose titration in this study. Patients will receive 6 mg of 
TEV-50717 with food on the evening of day 1. The 
titration scheme and maximum dose will be determined 
by body weight and use of strong cytochrome P450 
2D6 (CYP2D6) inhibitors, as shown in CYP2D6 
impairment status from the parent study. Patients will 
be classified as CYP2D6 impaired if they are receiving 
a strong CYP2D6 inhibitor or are a CYP2D6 poor 
metabolizer based on blinded assessment of CYP2D6 
genotype at baseline of the parent study. Patients who 
are CYP2D6 impaired will have a dose cap in the open 
label study, as shown in Table 2 and Table 3, 
respectively.
As patients from Study SD-809-C-17 will have been off IMP for 
several months at the time of enrollment, and since patients from 
Study TV50717-CNS-30046 or Study TV50717-CNS-30060 will 
have discontinued IMP (TEV-50717 or placebo) for at least 1 
week at completion of the parent study, all patients will undergo 
TEV-50717 dose titration in this study. Patients will receive 6 mg 
of TEV-50717 with food on the evening of day 1. Tablets should 
be taken with food (eg, a snack) and should not be taken on an 
empty stomach. The titration scheme and maximum dose will be 
determined by body weight and CYP2D6 impairment status from 
the parent study. Patients will be classified as CYP2D6 impaired if 
they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 
poor metabolizer based on blinded assessment of CYP2D6 
genotype at baseline of the parent study. Investigators will be 
unblinded to CYP2D6 metabolizer by a dose cap for CYP2D6 
impairment status, as shown in Table 2.
Update titration 
period to include 
and define 
CYP2D6 
impairment status 
in titration scheme 
and dosing
3.1.4 Maintenance Period
At the end of the titration period, the patient’s initial 
dose for the maintenance period will be established. 
Dose adjustments of TEV 50717 (upward or 
At the end of the titration period, the patient’s initial dose for the 
maintenance period will be established. Dose adjustments of TEV 
50717 (upward or downward) may be made during the 
Updated the 
maintenance 


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downward) may be made during the maintenance 
period, if necessary, but not more often than every 5 
days and only in increments of 6 mg. Dose As during 
titration, dose adjustments should be made based on all 
available information, including the patient and 
caregiver/adult reports of adverse events and tic 
reduction, the clinical assessment of safety and efficacy 
by the investigator, the patient’s weight, and 
information from the rating scales.
During the maintenance period, in-person (in-clinic) 
study visits will be scheduled at weeks 8, 15, 28 34, 41, 
and 54 for assessments of safety and efficacy and 
telephone contacts will be scheduled for weeks 21, 34,
and 47 in order to assess adverse events and tic 
severity. At week 54, patients will undergo a complete 
evaluation, including physical and neurological 
examination, safety laboratory testing, 12-lead ECG, 
CDI-2, and C SSRS assessments, as well as the 
YGTSS, TS-CGI, TS-PGIS, TS-PGII, Tic free Interval, 
CY-BOCS, and C&A-GTS- QOL.
maintenance period, if necessary, but not more often than every 5 
days and only in increments of 6 mg. As during titration, dose 
adjustments should be made based on all available information.
During the maintenance period, in-person (in-clinic) study visits 
will be scheduled at weeks 8, 15, 34, 41, and 54 for assessments of 
safety and efficacy and telephone contacts will be scheduled for 
weeks 21 and 47 in order to assess adverse events and tic severity. 
At week 54, patients will undergo a complete evaluation, 
including physical and neurological examination, safety laboratory 
testing, 12-lead ECG, CDI-2, and C SSRS assessments, as well as 
the YGTSS, TS-CGI, TS-PGIS, TS-PGII, Tic free Interval, CY-
BOCS, and C&A-GTS- QOL
period statement
3.1.5 Washout Period and Follow-up
See Figure 1 and Figure 2 for study schema
See Figure 1 and Figure 2 for study schema
Added Figure 2 as 
reference
3.1.6.
Part B: Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal Period
Not applicable
At week 28, the patients will be randomized 2:1 to their current 
dose of TEV-50717 or placebo in order to check for return of 
symptoms. Patients will have a follow-up telephone contact for 
safety evaluation 1 week after the start of the randomized drug 
withdrawal period. At week 30, safety and efficacy will be 
assessed. At the week 30 visit, patients who receive TEV-50717 
during the randomized drug withdrawal period will continue at the 
Added section and 
statements for 
randomized drug 
withdrawal period 
and re-titration


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same dose. Any patient who was randomized to placebo during 
this 2-week period will begin re titration. Patients will have a 
follow-up telephone contact for safety evaluation at weeks 31 and 
33. All patients should be back at their maintenance dose on or 
before week 34 and return to open-label treatment for the 
remainder of the study.
3.1.7.
Titration Post-Drug Withdrawal (Weeks 31, 32, and 33)
Not applicable
Any patient who was randomized to placebo during weeks 28 to 
30 will undergo re-titration to their target dose over the 3 weeks of 
treatment following the randomized drug withdrawal period. The 
titration scheme and maximum dose will be determined by body 
weight and CYP2D6 impairment status. The dose of IMP for each 
patient who underwent 2 weeks of placebo will be titrated back to 
the maintenance dose that was used by the patient up to week 28 
followed by continued maintenance therapy at that dose.
Added section and 
statements for the 
titration post-
withdrawal 
(Weeks 31 to 33)
3.2. Justification for Study Design
This is an open-label, single-arm study that includes a 
2-week, double-blind, placebo-controlled, randomized 
drug withdrawal period in which patients with TS may 
be eligible to participate after successful completion of 
any of the parent studies (SD-809-C-17 [Phase 1b], 
TV50717-CNS-30046 [Phase 2/3], or TV50717-
CNS-30060 [Phase 3]). Patients who have successfully 
completed a parent study may be eligible to enroll in 
this study after they complete a 1-week washout period 
and the final evaluation in the parent study. For patients 
rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, the week 13 visit 
(Study TV50717-CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) will be the day 1 visit 
for Study TV50717-CNS-30047. If the patient does not 
wish to enroll in Study TV50717-CNS-30047 at that 
This is an open-label, single-arm study that includes a 2-week, 
double-blind, placebo-controlled, randomized drug withdrawal 
period in which patients with TS may be eligible to participate 
after successful completion of any of the parent studies (SD-809-
C-17 [Phase 1b], TV50717-CNS-30046 [Phase 2/3], or TV50717-
CNS-30060 [Phase 3]). Patients who have successfully completed 
a parent study may be eligible to enroll in this study after they 
complete a 1-week washout period and the final evaluation in the 
parent study. For patients rolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060, the week 13 visit 
(Study TV50717-CNS-30046) or the week 9 visit 
(Study TV50717-CNS-30060) will be the day 1 visit for 
Study TV50717-CNS-30047. If the patient does not wish to enroll 
in Study TV50717-CNS-30047 at that visit, they can enroll up to 1 
week following the week 13 or week 9 visits, respectively. The 
end of study is defined as the date of the week 56 visit of the last 
Updates made to 
clarify study 
design and 
guidance to the 
investigators


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visit, they can enroll up to 1 week following the week 
13 or week 9 visits, respectively. The end of study is 
defined as the date of the week 56 visit of the last 
participant.
The open-label study design (ie, no placebo or 
comparator) was selected to allow further evaluation 
and review long-term safety of TEV-50717 in this 
patient population. Patients will receive twice daily 
dosing for up to 54 weeks, with an initial 7-week 
titration period to allow for optimal dose selection. At 
week 28, patients will begin a blinded, randomized 
drug withdrawal period. The randomized drug 
withdrawal period will rigorously assess the long-term 
maintenance of effect. Patients will be randomized to 
their current dose of TEV-50717 or placebo for 2 
weeks. After completing the 2 weeks, patients will 
continue their same dose of TEV-50717 or be re titrated 
(patients receiving placebo only) for 3 weeks. At week 
34, patients will resume their maintenance dose. This is 
a classic ABA study design (ie, drug, placebo, drug) 
that allows for a more rigorous test of the intervention. 
In the traditional AB design, changes in symptoms 
(particularly in a long trial) could be attributed to other 
factors (eg, life changes, societal issues, and regression 
to the mean); however, an acute change demonstrated 
only in a placebo group among subjects that have been 
maintained for several months would reduce the 
likelihood of any other explanations for changes in 
symptoms.
participant.
The open-label study design (ie, no placebo or comparator) was 
selected to allow further evaluation and review long-term safety of 
TEV-50717 in this patient population. Patients will receive twice 
daily dosing for up to 54 weeks, with an initial 7-week titration 
period to allow for optimal dose selection. At week 28, patients 
will begin a blinded, randomized drug withdrawal period. The 
randomized drug withdrawal period will rigorously assess the 
long-term maintenance of effect. Patients will be randomized to 
their current dose of TEV-50717 or placebo for 2 weeks. After 
completing the 2 weeks, patients will continue their same dose of 
TEV-50717 or be re titrated (patients receiving placebo only) for 3 
weeks. At week 34, patients will resume their maintenance dose. 
This is a classic ABA study design (ie, drug, placebo, drug) that 
allows for a more rigorous test of the intervention. In the 
traditional AB design, changes in symptoms (particularly in a long 
trial) could be attributed to other factors (eg, life changes, societal 
issues, and regression to the mean); however, an acute change 
demonstrated only in a placebo group among subjects that have 
been maintained for several months would reduce the likelihood of 
any other explanations for changes in symptoms.
3.3 Safety Measures and Time Points
Part A:
Physical examination: Screening (only for patients who 
Part A:
Physical examination: Screening (only for patients who completed 
Updates to Part A 
assessments 


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completed Study SD-809 C-17; data from 
Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients) 
and weeks 28 and week 54
Vital signs and weight: Screening (only for patients 
who completed Study SD-809-C 17; data from 
Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients); 
baseline day 1; and weeks 2, 4, 6, 8, 15, 28 34, 41, 54, 
and 55
   -Note: Orthostatic blood pressure (BP) and pulse at 
baseline; on day 1 and weeks 4, 28 8, and 54
Children’s C-SSRS
Since Last Visit (SLV) scale: Baseline Day 1 (only 
for patients who completed Study SD 809-C-17) and 
weeks 2, 4, 6, 8, 15, 28 34, 41, 54, and 55
•
CDI-2 (Parent and Self-report versions): Screening 
and baselineday 1 (ie, only for patients who completed 
Study SD 809 C 17) and weeks 2, 4, 6, 8, 15, 2834, 41, 
54, and 55
•
12-Lead ECG: Screening (ie, only for patients who 
completed Study SD 809 C 17); baselineday 1; and 
weeks 4, 6, 288, and 54
•
Clinical laboratory tests (serum chemistry, 
hematology, and urinalysis): Screening (ie, only for 
patients who completed Study SD 809 C 17; data from 
Study TV50717-CNS-30046 or Study TV50717-
CNS-30060 should be used for the remaining patients); 
baselineday 1; and weeks 6, 28,8 and 54
•
Pregnancy testing: Screening (ie, only for patients 
who completed Study SD 809 C 17); baseline;day 1 
and weeks 284, 8, 15, 34, and 54
Study SD-809 C-17; data from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 should be used for the remaining 
patients) and week 54
Vital signs and weight: Screening (only for patients who 
completed Study SD-809-C 17; data from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 should be used for the 
remaining patients); day 1; and weeks 2, 4, 6, 8, 15, 34, 41, 54, 
and 55
   -Note: Orthostatic blood pressure (BP) and pulse on day 1 and 
weeks 4, 8, and 54
Children’s C-SSRS
Since Last Visit (SLV) scale: Day 1 (only for patients who 
completed Study SD 809-C-17) and weeks 2, 4, 8, 15, 34, 41, 54, 
and 55
•
CDI-2 (Parent and Self-report versions): Screening and day 1 
(ie, only for patients who completed Study SD 809 C 17) and 
weeks 2, 4, 6, 8, 15, 34, 41, 54, and 55
•
12-Lead ECG: Screening (ie, only for patients who completed 
Study SD 809 C 17); day 1; and weeks 4, 6, 8, and 54
•
Clinical laboratory tests (serum chemistry, hematology, and 
urinalysis): Screening (ie, only for patients who completed 
Study SD 809 C 17; data from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 should be used for the remaining 
patients); day 1; and weeks 8 and 54
•
Pregnancy testing: Screening (ie, only for patients who 
completed Study SD 809 C 17); day 1 and weeks 4, 8, 15, 34, and 
54
timing


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Not applicable
Part B: 
Adverse events and concomitant medications: From the signing of 
the informed consent form through follow-up, inclusive of all 
visits and telephone contacts
Physical examination: Weeks 28 and 30
Vital signs and weight: Weeks 28, 30, and 32
Note: Orthostatic BP and pulse at week 28
Children’s C-SSRS:
SLV scale: Weeks 28 and 30
CDI-2 (parent and self-report versions): Weeks 28 and 30
Pregnancy testing: Week 28
Added safety 
measures/assessme
nts to be 
conducted for Part 
B
3.4.1 Efficacy Measures and Time Points
Part A and Part B:
•
YGTSS (to calculate TTS): Screening (only for 
patients who completed Study SD 809 C 17); baseline
day 1 (ie, week 13 data from Study TV50717-
CNS-30046 or week 9 data from Study TV50717-
CNS-30060); and weeks 2, 4, 6, 8, 15, 28, 30, 34, 41, 
54, and 55
•
TS PGIS: Baseline TS-CGI: Day 1 (ie, week 13 
data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060) and weeks 2, 4, 6, 
8, 15, 28, 34, 41, 54, and 55
•
TS-PGII: Day 1 (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data from
Study TV50717-CNS-30060) and weeks 4, 8, 15, 28, 
34, 41, 54, and 55
•
C&A-GTS- QOL (physical/ADL subscale): 
Baseline Day 1 and weeks 6, 28, 34, and 54
Part A and Part B:

YGTSS (to calculate TTS): Screening (only for patients 
who completed Study SD 809 C 17); day 1 (ie, week 13 
data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717-CNS-30060); and weeks 2, 4, 8, 15, 
28, 30, 34, 41, 54, and 55

TS-CGI: Day 1 (ie, week 13 data from Study TV50717-
CNS-30046 or week 9 data from Study TV50717-
CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

TS-PGII: Day 1 (ie, week 13 data from Study TV50717-
CNS-30046 or week 9 data from Study TV50717-
CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55

C&A-GTS- QOL (ADL subscale): Day 1 and weeks 6, 28, 
34, and 54
Added efficacy 
measures and time 
points for Part A 
and B


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3.4.2 Exploratory Measures and Time Points
Part A and Part B:
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Part A and Part B:
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6 Randomization and Blinding
This is a nonrandomized, open label study with no 
blinding and only 1 treatment group.
This is an open-label study that includes a 2-week, 
double-blind, placebo-controlled, randomized drug 
withdrawal period. At the randomized drug withdrawal 
This is an open-label study that includes a 2-week double-blind, 
placebo-controlled, randomized drug withdrawal period. At the 
randomized drug withdrawal period (Week 28), the patients will 
be randomized 2:1 to the current dose or placebo in order to check 
for return of symptoms. At the end of this period, patients who 
receive TEV-50717 during the randomized drug withdrawal 
Update to 
randomization and 
blinding for 
randomized drug 
withdrawal period


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period (week 28), the patients will be randomized 2:1 
to the current dose or placebo in order to check for 
return of symptoms. At the end of this period, patients 
who receive TEV-50717 during the randomized drug 
withdrawal period will return to the most recent dose of 
TEV-50717 and patients who received placebo during 
the randomized drug withdrawal period will begin 
titration post-drug withdrawal. All patients will return 
to open-label dosing at week 34.
period will return to the most recent dose of TEV-50717 and 
patients who received placebo during the randomized drug 
withdrawal period will begin re-titration. All patients will return to 
open-label dosing at week 34.
3.7 Drugs Used in the Study
This is an uncontrolled study with no other IMP.
Patients who receive TEV-50717 during the 
randomized drug withdrawal period will remain on 
blinded active IMP from week 30 to week 34; those 
assigned to placebo during the randomized drug 
withdrawal period will undergo blinded re-titration
from week 30 to week 34 back to their maintenance 
dose from week 28. TEV-50717 tablets are available in 
the following dose strengths: 6, 9, 12, 15, and 18 mg, 
all of which are identical in size, shape, and color 
(white). The IMP will be supplied in 20-count bottles.
Patients who receive TEV-50717 during the randomized drug 
withdrawal period will remain on blinded active IMP from week 
30 to week 34; those assigned to placebo during the randomized 
drug withdrawal period will undergo blinded re-titration from 
week 30 to week 34 back to their maintenance dose from week 28. 
TEV-50717 tablets are available in the following dose strengths: 6, 
9, 12, 15, and 18 mg, all of which are identical in size, shape, and 
color (white). The IMP will be supplied in 20-count bottles.
Added statement
into the section to 
account for the 
randomized drug 
withdrawal period
3.8.2 Drug Accountability
A record of IMP accountability (ie, IMP and other 
materials received, used, retained, returned, or 
destroyed) must be prepared and signed by the 
principal investigator or designee, with an account 
given for any discrepancies. Empty, partially used, and 
unused IMP will be disposed of per site policy, or 
returned to the sponsor or its designee, as agreed with 
the sponsor.
A record of IMP accountability (ie, IMP and other 
A record of IMP accountability (ie, IMP and other materials 
received, used, retained, returned, or destroyed) must be prepared 
and signed by the principal investigator or designee, with an 
account given for any discrepancies. Empty, partially used, and 
unused IMP will be returned to the sponsor or its designee, as 
agreed with the sponsor.
Study drug to be 
returned to 
sponsor or 
designee


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materials received, used, retained, returned, or 
destroyed) must be prepared and signed by the 
principal investigator or designee, with an account 
given for any discrepancies. Empty, partially used, and 
unused bottles of IMP will be returned to the sponsor or 
designee.
3.9 Duration of Patient Participation and Justification
This For patients rolling over from 
Study SD-809-C-17, this study will consist of up to a 4-
week screening period, a 54 week, open label (up to 31 
days) and up to 52 weeks of treatment period, and a 1
week washout period. Patients will have a follow-up 
telephone contact to evaluate safety 1 week after the 
end of the washout period (2 weeks after their last dose 
of IMP).
For patients rolling over from Study SD-809-C-17, this study will 
consist of up to a 4-week screening period (up to 31 days), and up 
to 52 weeks of treatment. Patients will have a follow-up telephone 
contact to evaluate safety 1 week after the end of the washout 
period (2 weeks after their last dose of IMP).
Updated to more 
clearly indicate 
duration of patient 
participation in the 
study 
3.11 Source Data Recorded on the Case Report Form
If patient data are processed from other vendors (eg, 
clinical laboratory, central ECG, electronic diary data), 
the results will be sent to the investigational center, 
where they will be retained but not entered into the 
CRF. These data may also be sent electronically to the 
sponsor (or organization performing data management) 
for direct use with the clinical database (see Section 
13.1). All clinical patient data from other vendors will 
be available to the investigator.
If patient data are processed from other vendors (eg, clinical 
laboratory, central ECG, diary data), the results will be sent to the 
investigational center, where they will be retained but not entered 
into the CRF. These data may also be sent electronically to the 
sponsor (or organization performing data management) for direct 
use with the clinical database (see Section 13.1). All clinical 
patient data from other vendors will be available to the 
investigator.
Removed
“electronic”
3.12 Table 1 Study Procedures and Assessments
Not applicable
[Table 1 was updated to add/remove assessments and to make a 
few adjustments as to the timing of some of the assessments. 
Changes were made in alignment with the changes made 
throughout the protocol.
Table 1 was 
updated to 
add/remove 
assessments and to 


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A “second part” of the table was added to include more clear 
direction on the expectations of Part B and resuming of Part A 
thereafter. Footnotes were also adjusted as necessary]
make a few 
adjustments as to 
the timing of some 
of the assessments. 
Changes were 
made in alignment 
with the changes 
made throughout 
the protocol. The
Randomized drug 
withdrawal period 
(and continuation 
of Part A 
thereafter) and
respective
assessments were 
added to the 
second part of the 
table
3.12.1 Procedures for Screening and Enrollment (Visit 1)
•
administer the following questionnaires (Note: For 
MINI Kid and C-SSRS, children 13 years of age and 
under mustmay be interviewed in conjunctionseparately 
or jointly with the caregiver/adult as appropriate or 
defined by the scale. For children over 13 years of age, 
caregiver/adult involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant 
information. The YGTSS questionnaire should be 
performed before any blood draws or ECG 
assessments.):
•
administer the following questionnaires (Note: For MINI Kid 
and C-SSRS, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as 
appropriate or defined by the scale. For children over 13 years of 
age, caregiver/adult involvement is strongly encouraged. 
Questions should be directed to the child, but the caregiver/adult 
should be encouraged to add relevant information. The YGTSS 
questionnaire should be performed before any blood draws or 
ECG assessments.):
Updated guidance 
on appropriate 
delivery of 
assessments/scales
3.12.1.1 YGTSS Rater Certification


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All investigators and subinvestigators who will be 
administering the YGTSS from screening through the 
end of study visit must undergo and pass a Rater 
Certification Program which will be provided 
separately from this protocol. Every effort must be 
made to ensure that the same certified rater administers 
the YGTSS to a specific patient at all visits where this 
scale is administered, especially at day 1 and at weeks 
28, 30, and 54/early termination visits. However, if due 
to unforeseen circumstances the same rater is 
absolutely unavailable to complete a visit rating, the 
YGTSS can be administered only by another certified 
individual from that study site.
All investigators and subinvestigators who will be administering 
the YGTSS from screening through the end of study visit must 
undergo and pass a Rater Certification Program which will be 
provided separately from this protocol. Every effort must be made 
to ensure that the same certified rater administers the YGTSS to a 
specific patient at all visits where this scale is administered, 
especially at day 1 and at weeks 28, 30, and 54/early termination 
visits. However, if due to unforeseen circumstances the same rater 
is absolutely unavailable to complete a visit rating, the YGTSS 
can be administered only by another certified individual from that 
study site.
Updated to clarify 
best guidance on 
YGTSS rater 
certification 
3.12.2 Procedures Before Investigational Medicinal Product Treatment (Day 1)
The following procedures will be performed at the 
baseline day 1 visit, as they:

perform a serum pregnancy (β-HCG) test (required 
for all females of childbearing potential who are 
postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: 
For C-SSRS, Tic-free Interval, CY BOCS, and 
C&A-GTS- QOL, children 13 years of age and 
under must may be interviewed in conjunction
separately or jointly with the caregiver/adult. as 
appropriate or defined by the scale. For 
children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions 
should be directed to the child, but the 
caregiver/adult should be encouraged to add 
relevant information. The YGTSS, TS-CGI, 
TS-PGIS, and TS PGIS PGII questionnaires 
should be performed before any blood draws or 
The following procedures will be performed at the day 1 visit, as 
they:

perform a serum pregnancy (β-HCG) test (required for all 
females who are postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: For C-
SSRS, Tic-free Interval, CY BOCS, and C&A-GTS-
QOL, children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult. 
as appropriate or defined by the scale. For children over 
13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but 
the caregiver/adult should be encouraged to add relevant 
information. The YGTSS, TS-CGI, TS-PGIS, and PGII 
questionnaires should be performed before any blood 
draws or ECG assessments.):
----TS-PGII (Note: Input from the caregiver/adult is 
permitted)
----TS-PGIS (Note: Input from the caregiver/adult is 
Updated guidance 
on appropriate 
delivery of 
assessments/scales
Updated planned 
assessments in 
alignment with 
protocol changes


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ECG assessments.):
--TS-PGII (Note: Input from the 
caregiver/adult is permitted.)
--TS-PGIS (Note: Input from the 
caregiver/adult is required permitted)
--C&A-GTS- QOL (including VAS) (required 
for all patients)
permitted)
---C&A-GTS- QOL (including VAS) (required for all 
patients)
3.12.3.1.2 In-Clinic Visits (Weeks 2, 4, and 6)
•
at weeks 4 and 6 only, perform 12-lead ECG (Note: 
ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position)
•
perform a urine pregnancy (β-HCG) test (only in 
females who are postmenarchal or ≥12 years of age) at 
week 4
•
administer the following questionnaires (Note: For 
C-SSRS, Tic-free Interval, CY BOCS, and C&A-GTS-
QOL, children 13 years of age and under must may be 
interviewed in conjunction separately or jointly with 
the caregiver/adult. as appropriate or defined by the 
scale. For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should 
be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information. The 
YGTSS, TS-CGI, TS-PGIS, and TS-PGISPGII
questionnaires should be performed before any blood 
draws or ECG assessments.):
---CDI-2, Parent and Self-report at weeks 2 and 4 only
(Note: Children 6 years of age at baseline on day 1 will 
not complete the self-report version; the caregiver/adult 
will complete the Parent version)
--- C-SSRS (children’s SLV) at weeks 2 and 4 only
•
at week 4 only, perform 12-lead ECG (Note: ECG will be 
performed after at least 5 minutes rest in a supine or semi-supine 
position)
•
perform a urine pregnancy (β-HCG) test (only in females who 
are postmenarchal or ≥12 years of age) at week 4
•
administer the following questionnaires (Note: For C-SSRS, 
Tic-free Interval, CY BOCS, and C&A-GTS- QOL, children 13 
years of age and under may be interviewed separately or jointly 
with the caregiver/adult. as appropriate or defined by the scale. For 
children over 13 years of age, caregiver/adult involvement is 
strongly encouraged. Questions should be directed to the child, but 
the caregiver/adult should be encouraged to add relevant 
information. The YGTSS, TS-CGI, TS-PGIS, and TS-PGII 
questionnaires should be performed before any blood draws or 
ECG assessments.):
---CDI-2, Parent and Self-report at weeks 2 and 4 only (Note: 
Children 6 years of age at on day 1 will not complete the self-
report version; the caregiver/adult will complete the Parent 
version.)
--- C-SSRS (children’s SLV) at weeks 2 and 4 only
--- YGTSS at weeks 2 and 4 only (Note: at week 2, only perform 
assessment of “Severity Ratings” of the questionnaire only. 
Inventory portions [ie, “Motor Tic Symptom Checklist” and 
Updated guidance 
on appropriate 
delivery of 
assessments/scales
Updated planned 
assessments in 
alignment with 
protocol changes


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---YGTSS at weeks 2 and 4 only (Note: at weeks 2 and 
6, only perform assessment of “Severity Ratings” of the 
questionnaire only. Inventory portions [ie, “Motor Tic 
Symptom Checklist” and “Phonic Tic Symptom 
Checklist”] do not need to be performed. Input from the 
caregiver/adult is required.)
---TS-CGI at week 4
---TS-PGII at week 4 (Note: Input from the 
caregiver/adult is permitted)
---TS-PGIS at week 4 (Note: Input from the 
caregiver/adult is required permitted)
---Tic-free Interval at week 4
---C&A-GTS- QOL (including VAS); week 6 only
“Phonic Tic Symptom Checklist”] do not need to be performed. 
Input from the caregiver/adult is required.)
---TS-CGI at week 4
---TS-PGII at week 4 (Note: Input from the caregiver/adult is 
permitted)
---TS-PGIS at week 4 (Note: Input from the caregiver/adult is 
permitted)
---Tic-free Interval at week 4
---C&A-GTS- QOL (including VAS); week 6 only
3.12.3.2.1 In-Clinic Visits (Weeks 8, 15, 30, 32, 34, 41, and 54)
The following procedures/assessments will be 
performed at weeks 8, 15, 2830, 32, 34, 41, and 54:
•
measure vital signs (pulse, BP, body temperature, 
and respiratory rate); at weeks 28 andweek 54, 
orthostatic BP and pulse should be measured after the 
patient is in a standing position for at least 3 minutes
•
measure weight (Note: weight must be measured 
with shoes and outerwear off)
•
perform full physical examination (including 
height) at weeks 2830 and 54 
•
perform neurological examination at week 54 
•
perform 12-lead ECG (Note: ECG will be 
performed after at least 5 minutes rest in a supine or 
semi-supine position.) at weeks 288 and 54
•
perform clinical laboratory tests, including serum 
chemistry, hematology, and urine analyses at weeks 8, 
The following procedures/assessments will be performed at weeks 
8, 15, 30, 32, 34, 41, and 54:
•
measure vital signs (pulse, BP, body temperature, and 
respiratory rate); at week 54, orthostatic BP and pulse should be 
measured after the patient is in a standing position for at least 3 
minutes
•
measure weight (Note: weight must be measured with shoes 
and outerwear off)
•
perform full physical examination (including height) at weeks 
30 and 54 
•
perform neurological examination at week 54 
•
perform 12-lead ECG (Note: ECG will be performed after at 
least 5 minutes rest in a supine or semi-supine position.) at weeks 
8 and 54
•
perform clinical laboratory tests, including serum chemistry, 
hematology, and urine analyses at weeks 8 and 54
Updated planned 
assessments in 
alignment with 
protocol changes
Timing of study 
assessments and 
timing of 
procedures in Part 
B were added


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28, and 54
•
perform UDS at weeks 28 andweek 54
•
perform a serum pregnancy (β-HCG) test (only in 
females of childbearing potentialwho are 
postmenarchal or ≥12 years of age) at weeks 288, 15, 
34, and 54
•
administer the following questionnaires (Note: For 
C-SSRS, Tic-free Interval, CY BOCS, and C&A-GTS-
QOL, children 13 years of age and under mustmay be 
interviewed in conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale. 
For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should 
be directed to. For children over 13 years of age, 
caregiver/adult involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant 
information. child, but the caregiver/adult should be 
encouraged to add relevant information. The YGTSS, 
TS-CGI, TS-PGIS, and TS-PGII questionnaires should 
be performed before any blood draws or ECG 
assessments.):
-
CDI-2, Parent and Self-report at weeks 8, 15, 30, 
34, 41, and 54 (Note: Children 6 years of age at 
baselineon day 1 will not complete the self-report 
version; the caregiver/adult will complete the Parent 
version.)
-
C-SSRS (children’s SLV) at weeks 8, 15, 2830, 34, 
41, and 54
-
YGTSS at weeks 8, 15, 30, 34, 41, and 54 (at 
weeks 8, 15, and 41, only perform assessment of 
“Severity Ratings” of the questionnaire; inventory 
•
perform UDS at week 54
•
perform a serum pregnancy (β-HCG) test (only in females 
who are postmenarchal or ≥12 years of age) at weeks 8, 15, 34, 
and 54
•
administer the following questionnaires (Note: For C-SSRS, 
Tic-free Interval, CY BOCS, and C&A-GTS- QOL, children 13 
years of age and under may be interviewed separately or jointly 
with the caregiver/adult as appropriate or defined by the scale. For 
children over 13 years of age, caregiver/adult involvement is 
strongly encouraged. Questions should be directed to. For children 
over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information. 
The YGTSS, TS-CGI, TS-PGIS, and TS-PGII questionnaires 
should be performed before any blood draws or ECG 
assessments.):
-
CDI-2, Parent and Self-report at weeks 8, 15, 30, 34, 41, and 
54 (Note: Children 6 years of age on day 1 will not complete the 
self-report version; the caregiver/adult will complete the Parent 
version.)
-
C-SSRS (children’s SLV) at weeks 8, 15, 30, 34, 41, and 54
-
YGTSS at weeks 8, 15, 30, 34, 41, and 54 (at weeks 8, 15, and 
41, only perform assessment of “Severity Ratings” of the 
questionnaire; inventory portions [ie, “Motor Tic Symptom 
Checklist” and “Phonic Tic Symptom Checklist”] do not need to 
be performed. Input from the caregiver/adult is required.)
-
TS-CGI at weeks 8, 15, 34, 41, and 54
-
TS-PGIS at weeks 8, 15, 34, 41, and 54 (Note: Input from the 
caregiver/adult is permitted.)
-
TS-PGII at weeks 8, 15, 34, 41, and 54 (Note: Input from the 
caregiver/adult is permitted.)


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portions [ie, “Motor Tic Symptom Checklist” and 
“Phonic Tic Symptom Checklist”] do not need to be 
performed. Input from the caregiver/adult is required.)
-
TS-CGI at weeks 8, 15, 34, 41, and 54
-
TS-PGIS at weeks 8, 15, 34, 41, and 54 (Note: 
Input from the caregiver/adult is permitted.)
-
TS-PGII at weeks 8, 15, 34, 41, and 54 (Note: Input 
from the caregiver/adult is requiredpermitted.)
-
Tic-free Interval assessment at weeks 8, 15, 34, 41, 
and 54
-
CY-BOCS at weeks 34 and 54 
-
C&A-GTS- QOL (including VAS) at weeks 2834
and 54
•
dispense IMP (sufficient doses to cover treatment 
until the following in-clinic visit) at weeks 8, 15, 2830, 
32, 34, and 41
-
Tic-free Interval assessment at weeks 8, 15, 34, 41, and 54
-
CY-BOCS at weeks 34 and 54 
-
C&A-GTS- QOL (including VAS) at weeks 34 and 54
•
dispense IMP (sufficient doses to cover treatment until the 
following in-clinic visit) at weeks 8, 15, 30, 32, 34, and 41
3.12.3.3 Blinded, Randomized Drug Withdrawal Period/Titration Post-Drug Withdrawal Period (Weeks 28 to 33)
Not applicable
[Section 3.12.3.3 was added]
Section was added 
to specify Part B 
of the study
3.12.3.3.1 In-Clinic Visit (Week 28)
Not applicable
The following procedures/assessments will be performed at 
week 28:

measure vital signs (pulse, BP, body temperature, and 
respiratory rate)); orthostatic BP and pulse should be measured 
after the patient is in a standing position for at least 3 minutes

measure weight (Note: weight must be measured with 
shoes and outerwear off)

perform full physical examination (including height) 

perform 12-lead ECG (Note: ECG will be performed after at 
Addition of the
section to specify 
assessments at 
week 28 during 
part B of the study


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least 5 minutes rest in a supine or semi-supine position.)

perform clinical laboratory tests, including serum chemistry, 
hematology, and urine analyses

up to 2 blood samples separated by 2 hours or more should be 
collected, if possible, for patients discontinuing for insufficient 
efficacy (early termination)

perform a serum pregnancy (β-HCG) test (only in females who 
are postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: For C-SSRS, 
Tic-free Interval, CY-BOCS, and C&A-GTS QOL, children 13 
years of age and under may be interviewed separately or jointly 
with the caregiver/adult as appropriate or defined by the scale. 
For children over 13 years of age, caregiver/adult involvement 
is strongly encouraged. Questions should be directed to the 
child, but the caregiver/adult should be encouraged to add 
relevant information. The YGTSS, TS-CGI, TS-PGIS, and 
TS-PGII questionnaires should be performed before any blood 
draws or ECG assessments.):
-CDI-2, Parent and Self-report versions (Note: 
Children 6 years of age on day 1 will not complete the 
self-report version; the caregiver/adult will complete 
the Parent version.)
-C-SSRS (children’s SLV)
-YGTSS (only perform assessment of “Severity 
Ratings” of the questionnaire; inventory portions [ie, 
“Motor Tic Symptom Checklist” and “Phonic Tic 
Symptom Checklist”] do not need to be performed. 
Input from the caregiver/adult is required.)
-TS-CGI
-TS-PGII (Note: Input from the caregiver/adult is 


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permitted.)
-TS-PGIS (Note: Input from the caregiver/adult is 
permitted.)
-Tic-free Interval assessment
-CY-BOCS
-C&A-GTS QOL (including VAS)

dispense IMP (sufficient doses to cover treatment until the 
following in-clinic visit)

assess drug accountability/compliance/supply 

collect used and unused IMP bottles

inquire about adverse events

review concomitant medications
3.12.3.3.2 In-clinic Visit (Weeks 30 and 32)
Not applicable
•
evaluate IMP
•
measure vital signs (pulse, BP, body temperature, and 
respiratory rate)
•
physical examination (week 30)
•
CDI-2, Parent and Self-report versions at week 30 (Note: 
Children 6 years of age on day 1 will not complete the self-report 
version; the caregiver/adult will complete the Parent version.)
•
C-SSRS (children’s SLV) at week 30
•
YGTSS at week 30
•
collect IMP/dispense IMP (sufficient doses to cover treatment 
until the following in-clinic visit)
•
assess IMP accountability/compliance/supply status to ensure 
that the patient has adequate tablets and remind them to bring used 
and unused IMP bottles to the next in clinic visit
•
inquire about adverse events
Addition of the 
section to specify 
assessments at 
week 30 and 32 
during part B of 
the study


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•
review concomitant medications
3.12.3.3.3 Telephone Contacts (Weeks 29, 31, and 33)
Not applicable
Patients will be contacted by telephone to evaluate tic reduction 
and adverse events. Dose adjustment will be made by the 
investigator after telephone contact with the patient and 
caregiver/adult. The following procedures/assessments will be 
performed via telephone contact at weeks 29, 31, and 33:
•
assess IMP accountability/compliance/supply status to 
ensure the patient has adequate tablets, inform the patient if 
they should titrate, and remind them to bring used and unused 
IMP bottles to the next in-clinic visit
•
inquire about adverse events
•
review concomitant medications
Addition of the 
section to specify 
expectations at 
weeks 29, 31, and 
33 during part B of 
the study
3.12.4.1 In-Clinic Visit (Week 55)
The following procedures/assessments will be 
performed at week 55:
•
measure vital signs (pulse, BP, body temperature, 
and respiratory rate)
•
measure weight (Note: weight must be measured 
with shoes and outerwear off)
•
administer the following questionnaires (Note: For 
C-SSRS, Tic-free Interval, and CY-BOCS, children 13 
years of age and under may be interviewed separately 
or jointly with the caregiver/adult as appropriate or 
defined by the scale. For children over 13 years of age, 
caregiver/adult involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant 
information. The YGTSS, TS CGI, TS-PGIS, and TS-
PGII questionnaires should be performed before any 
The following procedures/assessments will be performed at week 
55:
•
measure vital signs (pulse, BP, body temperature, and 
respiratory rate)
•
measure weight (Note: weight must be measured with shoes 
and outerwear off)
•
administer the following questionnaires (Note: For C-SSRS, 
Tic-free Interval, and CY-BOCS, children 13 years of age and 
under may be interviewed separately or jointly with the 
caregiver/adult as appropriate or defined by the scale. For children 
over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information. 
The YGTSS, TS CGI, TS-PGIS, and TS-PGII questionnaires 
should be performed before any blood draws or ECG 
assessments.):
Updates to the 
procedures after 
IMP treatment 
(Follow-up) at 
week 55


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blood draws or ECG assessments.):
-CDI-2, Parent and Self-report (Note: Children 6 years 
of age on day 1 will not complete the self-report 
version; the caregiver/adult will complete the Parent 
version.)
-TS-PGII (Note: Input from the caregiver/adult is 
permitted.)
-TS-PGIS (Note: Input from the caregiver/adult is
requiredpermitted.)
- CDI-2, Parent and Self-report (Note: Children 6 years of age 
on day 1 will not complete the self-report version; the 
caregiver/adult will complete the Parent version.)
-TS-PGII (Note: Input from the caregiver/adult is permitted.)
-TS-PGIS (Note: Input from the caregiver/adult is permitted.)
3.12.5. Unscheduled Visits
-
CDI 2, Parent and Self-report (Note: Children 6 
years of age at baselineon day 1 will not complete the 
Self-report version; the caregiver/adult will complete 
the Parent version.)
-
C-SSRS (children’s SLV; Note: Children 13 years 
of age and under mustmay be interviewed in 
conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale. 
For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should 
be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information.)
-
CDI 2, Parent and Self-report (Note: Children 6 years of age 
on day 1 will not complete the Self-report version; the 
caregiver/adult will complete the Parent version.)
-
C-SSRS (children’s SLV; Note: Children 13 years of age and 
under may be interviewed separately or jointly with the 
caregiver/adult as appropriate or defined by the scale. For children 
over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information.)
Updated the 
guidance on 
administration of 
scales during 
unscheduled visits
4.1 Patient Inclusion Criteria
Patients who have completed Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 may be 
enrolled in this study only if they meet have already 
met all of the following criteria below.
In addition, patients who have completed 
Study SD-809-C-17 may be included in the study if, 
during screening, they meet all of the following criteria:
Patients who have completed Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 have already met the criteria below.
In addition, patients who have completed Study SD-809-C-17 may 
be included in the study if, during screening, they meet all of the 
following criteria:
a.
Patient is younger than 18 years of age on day 1 
b.
Patient weighs at least 44 pounds (20 kg) on day 1. 
Updated age
criteria at time of 
study and updated 
criteria to specify 
expectations that 
were met in parent 
studies during 
screening 


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a.
Patient has completed Study SD 809 C 17, 
Study TV50717 CNS 30046, or Study TV50717
CNS 30060 Patient is younger than 18 years of age on 
day 1.
b.
Patient weighs at least 44 pounds (20 kg) at 
baseline day 1. 
h.
Females who are postmenarchal or ≥12 years of 
age may be included only if they have a negative β-
human chorionic gonadotropin test at day 1baseline or 
are sterile. Definitions of sterile are given in Appendix 
L.
i.
Females who are postmenarchal or ≥12 years of 
age of childbearing potential whose male partners are 
potentially fertile (ie, no vasectomy) must use highly 
effective birth control methods for the duration of the 
study (ie, starting at screening) and for 30 days or 5 
drug half-lives, whichever is longer after last dose of 
IMP. Further details are included in Appendix L.
h.
Females who are postmenarchal or ≥12 years of age may be 
included only if they have a negative β human chorionic 
gonadotropin test on day 1 or are sterile. Definitions of sterile are 
given in Appendix L.
i.
Females who are postmenarchal or ≥12 years of age whose 
male partners are potentially fertile (ie, no vasectomy) must use 
highly effective birth control methods for the duration of the study 
(ie, starting at screening) and for 30 days or 5 drug half-lives, 
whichever is longer after last dose of IMP. Further details are 
included in Appendix L.
processes.
4.2 Patient Exclusion Criteria
Patients who have completed Study TV50717-
CNS-30046 or Study TV50717-CNS-30060 have 
already been confirmed to not will not be enrolled in 
this study if they meet any of the below following
criteria.
In addition, patients who have completed 
Study SD-809-C-17 will not be enrolled if, during 
screening, they meet any of the following criteria:
a.
Patient is 18 years of age or older
de. Patient has clinically significant depression at 
screening or day 1baseline. 
hi. Patient has clinically significant OCD at 
Patients who have completed Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 have already been confirmed to not 
meet any of the below criteria.
In addition, patients who have completed Study SD-809-C-17 will 
not be enrolled if, during screening, they meet any of the 
following criteria:
a.
Patient is 18 years of age or older
e.
Patient has clinically significant depression at screening or day 
1.
i.
Patient has clinically significant OCD on day 1 that, in the 
opinion of the investigator, is the primary cause of impairment.
m. Patient has an unstable or serious medical illness at screening 
Exclusion criteria 
updated to account 
for recent safety 
updates/pregnancy 
language and to 
specify 
expectations that 
were met in parent 
studies during 
screening 
processes.


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day 1baseline that, in the opinion of the investigator, is 
the primary cause of impairment.
lm. Patient has an unstable or serious medical illness at 
screening or day 1baseline
mn.Patient has a QT interval corrected for heart rate 
using Frederica’s formula (QTcF) interval value >450 
msec (males) or >460 msec (females) or >480 msec 
(with right bundle branch block) on 12-lead ECG at 
screening. Patient requires treatment with drugs known 
to prolong the QT interval (see Appendix A Table 8 for 
a complete list of prohibited QT-prolonging drugs).
qr. Patient has received a MAOI within 14 days of the 
day 1baseline visit.
st. Patient has participated in an investigational drug 
or device study (with the exception of Study SD 809 C 
17 or Study TV50717-CNS-30046 or Study TV50717-
CNS-30060) and received IMP/intervention within 30 
days or 5 drug half-lives of day 1baseline, whichever is 
longer.
uv. Patient has a history of, or acknowledges, alcohol-
related disorder or substance abuse in the previous 12 
months, as defined in the Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-V5).
or day 1.
n.
Patient has a QT interval corrected for heart rate using 
Frederica’s formula (QTcF) interval value >450 msec (males) or 
>460 msec (females) or >480 msec (with right bundle branch 
block) on 12-lead ECG at screening. Patient requires treatment 
with drugs known to prolong the QT interval (see Appendix A 
Table 8 for a complete list of prohibited QT-prolonging drugs).
r.
Patient has received a MAOI within 14 days of the day 1 visit.
t.
Patient has participated in an investigational drug or device 
study (with the exception of Study SD 809 C 17 or 
Study TV50717-CNS-30046 or Study TV50717-CNS-30060) and 
received IMP/intervention within 30 days or 5 drug half-lives of 
day 1, whichever is longer.
v.
Patient has a history of or acknowledges alcohol-related 
disorder in the previous 12 months, as defined in the Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5™).
5.1 Drugs Administered During the Study
During the open-label period, TEV-50717 tablets are 
available in the following dose strengths: 6, 9, and 12 
mg. Patients will receive twice daily dosing for up to 54 
weeks, with an initial 7-week titration period to allow 
for optimal dose selection. 
Patients who receive TEV-50717 during the randomized 
drug withdrawal period will remain on blinded active IMP 
from week 30 to week 34; those assigned to placebo during 
During the open-label period, TEV-50717 tablets are available in 
the following dose strengths: 6, 9, and 12 mg. Patients will receive 
twice daily dosing for up to 54 weeks, with an initial 7-week 
titration period to allow for optimal dose selection. 
Patients who receive TEV-50717 during the randomized drug withdrawal 
period will remain on blinded active IMP from week 30 to week 34; 
those assigned to placebo during the randomized drug withdrawal period 
will undergo blinded re-titration from week 30 to week 34 back to their 
Updated to include 
randomized drug 
withdrawal period


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the randomized drug withdrawal period will undergo blinded 
re-titration from week 30 to week 34 back to their 
maintenance dose from week 28. TEV-50717 tablets are 
available in the following dose strengths: 6, 9, 12, 15, and 18 
mg, all of which are identical in size, shape, and color 
(white). The IMP will be supplied in 20-count bottles. The 
placebo tablets and packaging will match those for TEV-
50717. 
maintenance dose from week 28. TEV-50717 tablets are available in the 
following dose strengths: 6, 9, 12, 15, and 18 mg, all of which are 
identical in size, shape, and color (white). The IMP will be supplied in 
20-count bottles. The placebo tablets and packaging will match those for 
TEV-50717.

Dosing will be based on body weight and strong
CYP2D6 inhibitor useimpairment status, as shown 
in Table 2 and Table 3.

During the titration period, the dose of the IMP 
should be adjusted according to Table 2 to identify 
a dose level that optimally reduces tics (as 
determined by the investigator, in consultation 
with the patient and caregiver/adult) and is well 
tolerated. A dose cap for poor metabolizers will 
be prespecified by the Table 2.

After week 24, patient dose should be kept stable, if 
possible, until beginning Part B (week 28).

During the randomized drug withdrawal 
period, the patient will continue to receive their 
current dose of TEV-50717 or receive 
matching placebo until returning to their dose 
of TEV-50717 at week 30 (patients who 
receive TEV-50717 during the randomized 
drug withdrawal period will remain on blinded 
active IMP from week 30 to week 34; those 
assigned to placebo during the randomized 
drug withdrawal period will undergo re-
titration from week 30 to week 34 back to their 
maintenance dose from week 28). During the 
re-titration period, the dose of the IMP should 
be adjusted according to Table 3.

Dosing will be based on body weight and strong CYP2D6 
impairment status, as shown in Table 2.

During the titration period, the dose of the IMP should be 
adjusted according to Table 2 to identify a dose level that 
optimally reduces tics (as determined by the investigator, in 
consultation with the patient and caregiver/adult) and is 
well tolerated. A dose cap for poor metabolizers will be 
prespecified by the Table 2.

After week 24, patient dose should be kept stable, if possible, 
until beginning Part B (week 28).

During the randomized drug withdrawal period, the 
patient will continue to receive their current dose of TEV-
50717 or receive matching placebo until returning to their 
dose of TEV-50717 at week 30 (patients who receive 
TEV-50717 during the randomized drug withdrawal 
period will remain on blinded active IMP from week 30 to 
week 34; those assigned to placebo during the randomized 
drug withdrawal period will undergo re-titration from 
week 30 to week 34 back to their maintenance dose from 
week 28). During the re-titration period, the dose of the 
IMP should be adjusted according to Table 3.
Table 2:
Maximum Daily Dose of IMP by Study Day and 
Weight Category on Day 1 for Titration at 
Study Initiation
Updated Tables 
and included 
additional dosing 
instructions


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Table 2:
Maximum Daily Dose of IMP by 
Study WeekDay and Weight Category 
on Day 1 for Titration at 
BaselineStudy Initiation
Weight categoryDaily dose (mg) at the 
start of visit/week
Study week
daya
20 to <30 
kg
(44 to 
<66 lbs)
30 to <40 
kg
(66 to 
<88 lbs)
≥40 kg
(≥88 lbs)
CYP 
impairmen
t status
Not 
impai
red
Imp
aire
d
Not 
impai
red
Imp
aire
d
Not 
impair
ed
Impai
red
BaselineDa
y 1-7
6 mg
6 
mg
6 mg
6 
mg
6 mg 
(Days 1 
and 2)
12 mgb
6 mg 
(Days 
1 and 
2)
12 mg
b
Week 1
Day 8-14
12 mg 12 
mg
12 mg 12 
mg
18 mg
18 mg
Week 2
Day 15-21
18 mg 18 
mg
18 mg 18 
mg
24 mg
24 mg
Week 3
Day 22-28
18 mgc 18 
mg
24 mgc 24 
mg
30 mg
30 mg
Week 4Day 
29-35
24 mgc 18 
mg
30 mgc 24 
mg
36 mgc 36 mg
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP 
impairment 
status
Not 
impaire
d
Impa
ired
Not 
impaire
d
Impa
ired
Not 
impaire
d
Impair
ed
Day 1-7
6 mg
6 mg 6 mg
6 mg 6 mg 
(Days 1 
and 2)
12 mgb
6 mg 
(Days 1 
and 2)
12 mgb
Day 8-14
12 mg
12 
mg
12 mg
12 
mg
18 mg
18 mg
Day 15-21
18 mg
18 
mg
18 mg
18 
mg
24 mg
24 mg
Day 22-28
18 mg
18 
mg
24 mg
24 
mg
30 mg
30 mg
Day 29-35
24 mg
18 
mg
30 mg
24 
mg
36 mg
36 mg
Day 36-42
24 mg
18 
mg
36 mg
24 
mg
42 mg
36 mg
Day 43-49
30 mg
18 
mg
42 mg
24 
mg
48 mg
36 mg
a Administration of a given dose will take place throughout the days 
indicated. The new dose starts the morning after the telephone contact 
or the morning after the clinic visit as applicable.
b Patients will receive 6 mg on days 1 and 2, and 12 mg starting on day 
3.
CYP=cytochrome P450; IMP=investigational medicinal product.
Note: CYP impaired=patients who are receiving a strong CYP2D6 
inhibitor or who are a CYP2D6 poor metabolizer. The investigator, in 


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Week 5 
Day 36-42
24 mgc 18 
mg
36 mgc 24 
mg
42 mgc 36 mg
Week 6 
Day 43-49
30 mgc 18 
mg
42 mgc 24 
mg
48 mgc 36 mg
a Administration of a given dose will take place throughout 
the weekdays indicated, with the . The new dose starts the 
morning after the telephone contact or the morning after 
the clinic visit occurring at the beginning of the weekas 
applicable.
b Patients will receive 6 mg once daily dose on days 1 and 2, 
and 6 12 mg twice daily dose starting on day 3.
c For those taking strong CYP2D6 inhibitors such as 
paroxetine, fluoxetine, and bupropion, maximum daily 
dose for patients ≥40 kg is 36 mg/day, 30 to <40 kg is 
CYP24 mg/day, and 20 to <30 kg is 18 mg/day (see table 
below).
CYP2D6=cytochrome P450 2D6; IMP=investigational 
medicinal product.
Note: CYP impaired=patients who are receiving a strong 
CYP2D6 inhibitor or who are a CYP2D6 poor metabolizer.
The investigator, in consultation with the patient and 
caregiver/adult, will determine if a dose increase is 
warranted to achieve optimal tic reduction.
Table 3:
Maximum Daily Dose of IMP by Day 1 
Body Weight Category, CYP2D6 
Impairment, and Study Week (re-
titration) for Patients Receiving and Not 
Receiving CYP2D6 
InhibitorsRandomized to Placebo 
During the Blinded, Randomized Drug 
Withdrawal Period
consultation with the patient and caregiver/adult, will determine if a 
dose increase is warranted to achieve optimal tic reduction.
Table 3:
Daily Dose of IMP by Day 1 Body Weight Category, 
CYP2D6 Impairment, and Study Week (Re-
titration) for Patients Randomized to Placebo 
During the Blinded, Randomized Drug Withdrawal 
Period
Dose 
group
Day 1 
weight 
(kg)
Daily dose (mg) at the 
start of visit/week
We
ek 
31
We
ek 
32
We
ek 
33
Week 
34 
maint
enanc
e 
dose 
≥40
12
24
36
48
≥40, CYP impaired
12
18
24
30
30 to <40
12
24
30
36
30 to <40, CYP impaired
12
12
18
18
20 to <30
12
18
24
30
20 to <30, CYP impaired
12
12
12
12
CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or 
who are a CYP2D6 poor metabolizer.
CYP=cytochrome P450; CYP2D6=cytochrome P450 2D6; 


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Reason/Justificati
on for change
Dose 
group
Day 1 
weight 
(kg)
Maximum daily 
dose
Maximum daily dose 
if receiving a strong 
CYP2D6 
inhibitorDaily dose 
(mg) at the start of 
visit/week
W
ee
k 
31
W
ee
k 
32
W
ee
k 
33
Wee
k 34 
mai
nten
ance 
dose 
≥40
12
24
36
48
≥40, CYP impaired
12
18
24
30
2030 to <30 kg40
12
24
30
mg
361
8 
mg
30 to <40, CYP impaired
12
12
18
18
3020 to <40 kg30
42 
mg
12
18
24
mg
30
≥40 kg20 to <30, CYP 
impaired
48 
mg
12
36 
mg
12
12
12
CYP impaired=patients who are receiving a strong CYP2D6 
inhibitor or who are a CYP2D6 poor metabolizer.
CYP=cytochrome P450; CYP2D6=cytochrome P450 2D6; 
IMP=investigational medicinal product.
Note: Strong CYP2D6 inhibitors include paroxetine, 
fluoxetine, and bupropion.
IMP=investigational medicinal product.


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5.2 Restrictions
While patients receiving strong CYP2D6 inhibitors 
(paroxetine, fluoxetine, and bupropion) at baselineon 
day 1 may be enrolled into this study, the addition or 
removal of strong CYP2D6 inhibitors during treatment 
is discouraged as this would have an effect on exposure 
to active circulating drug. If the addition or removal of 
a strong CYP2D6 inhibitor is required from a clinical 
perspective, the medical monitor should be contacted 
so an appropriate change in IMP can be made. The 
addition of a strong CYP2D6 inhibitor is prohibited.
While patients receiving strong CYP2D6 inhibitors (paroxetine, 
fluoxetine, and bupropion) on day 1 may be enrolled into this 
study, the removal of strong CYP2D6 inhibitors during treatment 
is discouraged as this would have an effect on exposure to active 
circulating drug. If the removal of a strong CYP2D6 inhibitor is 
required from a clinical perspective, the medical monitor should 
be contacted so an appropriate change in IMP can be made. The 
addition of a strong CYP2D6 inhibitor is prohibited.
Updated to 
indicate that 
addition of 
CYP2D6 
inhibitors is 
prohibited 
5.3 Prior and Concomitant Medication or Treatment
The medical monitor must be contacted if a patient is 
receiving (or has to begin or stop receiving during the 
study) a medication that is associated with QTc 
prolongation or that is a known strong CYP inhibitor. 
Addition of a strong CYP inhibitor is prohibited.
Prohibited antipsychotic drugs medications are listed in 
Appendix A, Table 7, while prohibited medications that 
are associated with QTc prolongation are listed in 
Appendix A, Table 8.
The medical monitor must be contacted if a patient is receiving (or 
has to begin or stop receiving during the study) a medication that 
is associated with QTc prolongation or that is a known strong 
CYP inhibitor. Addition of a strong CYP inhibitor is prohibited.
Prohibited antipsychotic drugs medications are listed in Appendix 
A, Table 7, while prohibited medications that are associated with 
QTc prolongation are listed in Appendix A, Table 8.
Updated to 
indicate that 
addition of 
CYP2D6 
inhibitors is 
prohibited. I 
addition, included 
a reference to the 
table with the 
specific prohibited 
medications
6.
ASSESSMENT OF EFFICACY
Site-administered efficacy scales include the YGTSS and 
CY-BOCS, and self-administered efficacy scales include the 
TS-PGIS, TS-PGII, Tic-free Interval, and C&A-GTS-QOL.
Site-administered efficacy scales include the YGTSS and CY-BOCS, and 
self-administered efficacy scales include the TS-PGIS, TS-PGII, Tic-free 
Interval, and C&A-GTS-QOL.
Inclusion of TS-
PGII as a self-
administered 
efficacy scale
6.1 Efficacy and Exploratory Measures
 
 
 


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6.1.1 Tourette Syndrome–Clinical Global Impression
TS-CGI is administered at baselineon day 1 (ie, week 
13 data from Study TV50717-CNS-30046 or week 9 
data from Study TV50717-CNS-30060) and weeks 2, 4,
6, 8, 15, 28, 34, 41, 54, and 55.
TS-CGI is administered on day 1 (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data from Study TV50717-
CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55.
Timepoints added 
and removed for 
the TS-CGI 
assessment.
6.1.2. Tourette Syndrome-Patient Global Impression of Impact
The TS-PGISPGII is administered at baselineon day 1 
(ie, week 13 data from Study TV50717-CNS-30046 or 
week 9 data from Study TV50717 CNS-30060) and 
weeks 2, 4, 6, 8, 15, 28, 34, 41, 54, and 55. Input from 
the parent/legal guardian is required.
The TS-PGII is a single-item questionnaire that asks 
the patient to assess the degree of impact due to current 
tics. The TS-PGII uses a 5-point scale, ranging from 
not at all (1) to very much (5), to assess overall 
response to therapy. In general, patient-rated global 
measures of change have face validity and have been 
shown to correlate with disability for a number of 
chronic conditions.
The TS-PGII is administered on day 1 (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data from Study TV50717 
CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55. Input from 
the parent/legal guardian is required.
The TS-PGII is a single-item questionnaire that asks the patient to 
assess the degree of impact due to current tics. The TS-PGII uses a 
5-point scale, ranging from not at all (1) to very much (5), to 
assess overall response to therapy. In general, patient-rated global 
measures of change have face validity and have been shown to 
correlate with disability for a number of chronic conditions.
Description of TS-
PGII included 
along with 
timepoints for the 
assessment


Uncontrolled Study–Tourette Syndrome
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Reason/Justificati
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6.1.3. Tourette Syndrome Patient Global Impression of Severity
The TS-PGIS is administered on day 1 (ie, week 13 
data from Study TV50717-CNS-30046 or week 9 data 
from Study TV50717 CNS-30060) and weeks 4, 8, 15, 
28, 34, 41, 54, and 55. Input from the caregiver/adult is 
requiredpermitted.
The TS-PGIS is a single-item questionnaire that asks 
the patient to assess their current ticsover the preceding 
week.
The TS-PGIS is administered on day 1 (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data from Study TV50717 
CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 55. Input from 
the caregiver/adult is permitted.
The TS-PGIS is a single-item questionnaire that asks the patient to 
assess their current tics.
Updated TS-PGIS 
assessment 
timepoints and 
details 
6.1.4. Tic-Free Interval Assessment
Tic-free Interval is assessed at baselineon day 1 (only 
for patients who completed Study SD-809-C-17) and at 
weeks 2, 4, 6, 8, 15, 28, 34, 41, 54, and 55. Children 
13 years of age and under mustmay be interviewed in 
conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale.
Tic-free Interval is assessed on day 1 (only for patients who 
completed Study SD-809-C-17) and at weeks 4, 8, 15, 28, 34, 41, 
54, and 55. Children 13 years of age and under may be 
interviewed separately or jointly with the caregiver/adult as 
appropriate or defined by the scale.
Updated the 
guidance on 
administration of 
assessment and 
timepoints
6.1.5 Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Scale
The C&A-GTS-QOL is administered at baselineon
day 1 and weeks 6, 28, 34, and 54. Children 13 years of 
age and under must be interviewed in conjunction with 
the caregiver/adult. For children overChildren 13 years 
of age and under may be interviewed separately or 
jointly with the caregiver/adult involvement is strongly 
encouraged.as appropriate or defined by the scale.
Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant 
information.
The C&A-GTS-QOL is administered on day 1 and weeks 6, 28, 
34, and 54. Children 13 years of age and under must be 
interviewed in conjunction with the caregiver/adult. Children 
13 years of age and under may be interviewed separately or jointly 
with the caregiver/adult as appropriate or defined by the scale. 
Questions should be directed to the child, but the caregiver/adult 
should be encouraged to add relevant information.
Updated the 
guidance on 
administration of 
assessment and 
timepoints
6.1.6. Children’s Yale-Brown Obsessive-Compulsive Scale
Complete CY-BOCS (Checklist and Severity Ratings) 
is administered at baselineon day 1 (only for patients 
Complete CY-BOCS (Checklist and Severity Ratings) is 
administered on day 1 (only for patients who completed 
Updated the 
guidance on 


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Protocol Amendment 01 text with changes shown
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Reason/Justificati
on for change
who completed Study SD-809-C-17) and weeks 6, 28,
34, 54, and 55. 

Complete assessment (Checklist and Severity 
Ratings) at baselineon day 1 (only for patients 
who completed Study SD-809-C-17) and week 
54

Severity Ratings of OCD symptoms (questions 
1 through 10 only) at baselineon day 1 (only 
for patients who completed Study TV50717-
CNS-30046 or Study TV50717-CNS-30060) 
and weeks 6 and 55
Children 13 years of age and under mustmay be 
interviewed in conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale.
Study SD-809-C-17) and weeks 6, 28, 34, 54, and 55. 
Complete assessment (Checklist and Severity Ratings) on day 1 
(only for patients who completed Study SD-809-C-17) 
Severity Ratings of OCD symptoms (questions 1 through 10 only) 
on day 1 (only for patients who completed Study TV50717-
CNS-30046 or Study TV50717-CNS-30060) and weeks 6 and 55
Children 13 years of age and under may be interviewed separately 
or jointly with the caregiver/adult as appropriate or defined by the 
scale.
administration of 
assessment and 
timepoints
(Previous version Am01) Section 6.1.8 Overdose of IMP
Any dose of IMP, whether taken intentionally or 
unintentionally, in excess of that prescribed during the 
given time period must be immediately reported to the 
sponsor.
Not applicable
This section was 
removed from the 
latest version 
protocol
7.1.1 Definition of an Adverse Event
An adverse event is anyAny untoward medical 
occurrence in a patient or clinical investigation subject
administered a pharmaceutical product, regardless of 
whether it hasand which does not necessarily have to 
have a causal relationship with this treatment.
In this study, any adverse event occurring after the 
clinical study patient has signed the informed consent 
form should be recorded and reported as an adverse 
event.
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with 
this treatment.
Updates to adverse 
event definition
7.1.2 Recording and Reporting of Adverse Events


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Further details are given in the Safety Monitoring Plan.
Additional 
reference to the 
Safety Monitoring 
Plan added.
7.1.5 Serious Adverse Event
For recording of serious adverse events, the study period is 
defined for each patient as the time period from signing of the 
informed consent form to the end of the follow-up period as 
defined in Section 7.1.2. Serious adverse events occurring in a 
patient after the end of the follow-up period should be reported to 
the sponsor if the investigator becomes aware of them, following 
the procedures described in Section 7.1.5.3.1.
Additional 
description about 
recording adverse 
events was added 
to the section
7.1.5.2. Expectedness
A serious adverse event that is not included in the 
Adverse Reaction section of the relevant reference 
safety information (RSI) by its specificity, severity, 
outcome, or frequency is considered an unexpected 
adverse event. The Reference Safety Information for 
expedited reporting purposesRSI for this study is
provided in Appendix A of the IB.
A serious adverse event that is not included in the 
reference safety informationListing of Adverse 
Reactions in the IBRSI by its specificity, severity, 
outcome, or frequency is considered an unexpected 
adverse event.
A serious adverse event that is not included in the Adverse 
Reaction section of the relevant reference safety information (RSI) 
by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The RSI for this study is the IB.
A serious adverse event that is not included in the Listing of 
Adverse Reactions in the RSI by its specificity, severity, outcome, 
or frequency is considered an unexpected adverse event.
The RSI for this 
protocol was 
specified
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse 
events (as described in Section 7.1.5.1) that occur 
during the study period (including the protocol defined 
follow up period, described in Section 7.1.2), regardless 
To satisfy regulatory requirements, all serious adverse events that 
occur during the study, regardless of judged relationship to 
administration of the IMP, must be reported to the sponsor by the 
investigator. The event must be reported within 24 hours of when 
IEC/IRB reporting 
requirement was 
removed
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of judged relationship to treatment withadministration 
of the IMP, must be reported to the sponsor by the 
investigator. The event must be reported within 24 
hours of when the investigator learns about it. 
Completing the serious adverse event form and 
reporting the event must not be delayed, even if not all 
the information is available. The investigator does not 
need to actively monitor patients for adverse events 
once this study has ended.
Serious adverse events occurring to a patient after the 
treatmentlast administration of that patient has 
endedIMP should be reported to the sponsor if the 
investigator becomes aware of them.
The investigator must ensure that the IEC/IRB is also 
informed of the event, in accordance with national and 
local regulations.
Additional information (follow-up) about any serious 
adverse event unavailable at the initial reporting should 
be forwarded by the investigational centerinvestigator
within 24 hours of when it becomes known to the same 
address as the initial report.
the investigator learns about it. Completing the serious adverse 
event form and reporting the event must not be delayed, even if 
not all the information is available. The investigator does not need 
to actively monitor patients for adverse events once this study has 
ended.
Serious adverse events occurring to a patient after the last 
administration of IMP should be reported to the sponsor if the 
investigator becomes aware of them.
Additional information (follow-up) about any serious adverse 
event unavailable at the initial reporting should be forwarded by 
the investigator within 24 hours of when it becomes known to the 
same address as the initial report.
event reporting 
should be 
completed by the 
investigator
7.1.6. Protocol Defined Adverse Events of Special Interest
7.1.6. Protocol Defined Adverse Events for Expedited 
Reportingof Special Interest
No protocol-defined adverse events for expedited 
reportingof special interest were identified for this 
study.
7.1.6. Protocol Defined Adverse Events of Special Interest 
No protocol-defined adverse events of special interest were 
identified for this study.
Term updated 
from adverse 
events for 
expedited 
reporting to 
adverse events of 
special interest
7.2.1 Mini International Neuropsychiatric Interview for Children and Adolescents
Select MINI Kid modules are administered at screening 
Select MINI Kid modules are administered at screening (only for 
Updated the 


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(only for patients who completed Study SD-809-C-17). 
Children 13 years of age and under mustmay be 
interviewed in conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale. 
For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should 
be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information.
The MINI Kid is a short questionnaire to be 
administered by a trained clinician. The MINI Kid 
assesses symptoms of psychiatric disorders as outlined 
in the International Classification of Diseases-10 and 
the DSM V in children 6 to 17 years of age by self-
report. For children under 13 years old, the patient 
ismay be interviewed separately or jointly with the 
parent presentcaregiver/adult as appropriate or defined 
by the scale, and the parentcaregiver/adult is 
encouraged to participate when needed.
patients who completed Study SD-809-C-17). Children 13 years of 
age and under may be interviewed separately or jointly with the 
caregiver/adult as appropriate or defined by the scale. For children 
over 13 years of age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to the child, but the 
caregiver/adult should be encouraged to add relevant information.
The MINI Kid is a short questionnaire to be administered by a 
trained clinician. The MINI Kid assesses symptoms of psychiatric 
disorders as outlined in the International Classification of 
Diseases-10 and the DSM in children 6 to 17 years of age by self-
report. For children under 13 years old, the patient may be 
interviewed separately or jointly with the caregiver/adult as 
appropriate or defined by the scale, and the caregiver/adult is 
encouraged to participate when needed.
guidance on 
administration of 
assessment 
Parent was 
changed to 
caregiver/adult.


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7.2.2 Columbia-Suicide Severity Rating Scale
The C-SSRS children’s baseline screening scale 
collects the history assesses past and current suicidal 
ideations and behaviors to determine suicide risk and is 
administered at screening. C-SSRS children’s SLV 
scale is administered at baselineon day 1 (only for 
patients who completed Study SD-809-C-17) and 
weeks 2, 4, 6, 8, 15, 28, 30, 34, 41, 54, and 55. 
Children 13 years of age and under mustmay be 
interviewed in conjunctionseparately or jointly with the 
caregiver/adult as appropriate or defined by the scale.
For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should 
be directed to the child, but the caregiver/adult should 
be encouraged to add relevant information.
The C SSRS (Posner et al 2009) is a Food and Drug 
Administration (FDA) endorsed questionnaire to screen 
for suicidality in studies of central nervous system
active compounds (in September 2010). The C SSRS is 
an interview by trained study personnel. 
The C-SSRS children’s baseline screening scale assesses past and 
current suicidal ideations and behaviors to determine suicide risk 
and is administered at screening. C-SSRS children’s SLV scale is 
administered on day 1 (only for patients who completed 
Study SD-809-C-17) and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 
55. Children 13 years of age and under may be interviewed 
separately or jointly with the caregiver/adult as appropriate or 
defined by the scale. For children over 13 years of age, 
caregiver/adult involvement is strongly encouraged. Questions 
should be directed to the child, but the caregiver/adult should be 
encouraged to add relevant information.
Updated the 
guidance on 
administration of 
assessment 
Timepoints added 
and removed
7.2.3 Children’s Depression Inventory, Second Edition
7.2.3 Children’s Depression Inventory2, Second 
Edition
CDI-2 (Parent and Self-report versions) is administered 
at screening and baselineday 1 (only for patients who 
completed Study SD-809-C-17) and weeks 2, 4, 6, 8, 
15, 28, 30, 34, 41, 54, and 55. As the CDI-2 is designed 
for children 7 to 17 years of age, children 6 years of age 
at baselineon day 1 will not complete the Self-report 
version; the caregiver/adult will complete the Parent 
version.
7.2.3 Children’s Depression Inventory, Second Edition
CDI-2 (Parent and Self-report versions) is administered at 
screening and day 1 (only for patients who completed 
Study SD-809-C-17) and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, and 
55. As the CDI-2 is designed for children 7 to 17 years of age, 
children 6 years of age on day 1 will not complete the Self-report 
version; the caregiver/adult will complete the Parent version.
Assessment 
Timepoints were
added and 
removed


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7.3 Pregnancy
Any female patient becoming pregnant during the study 
will discontinue IMP.
All pregnancies of femalesfemale patients participating 
in the study that occur during the study, or within 
14 days of completionafter the end of the study, are to 
be reported immediately to the physician identified in 
the Clinical Study Personnel Contact Information 
section of this protocol, and the investigator must 
provide the sponsor (LSO/INC Research) with the 
completed pregnancy form. The process for reporting a 
pregnancy is the same as that for reporting a serious 
adverse event but using the pregnancy form (see 
Section 7.1.5.3).
Any female patient becoming The investigator is not 
required to report patients who are found to be pregnant 
duringbetween screening and day 1, provided no IMP 
was given. All female patients participating in the study 
will discontinue treatment. All patients who who 
become pregnant will be monitored for the outcome of 
the pregnancy (including spontaneous, elective, or 
voluntary terminationabortion). If the pregnancy 
continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and 
presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, 
will be reported to the sponsor. Any complication of 
pregnancy during the study and any complication of 
pregnancy that the investigator becomes aware of after 
withdrawal from the study will be reported as an 
adverse event or serious adverse event, as appropriate.
If the pregnancy in the female patient participating in 
Any female patient becoming pregnant during the study will 
discontinue IMP.
All pregnancies of female patients participating in the study that 
occur during the study, or within 14 days after the end of the 
study, are to be reported immediately to the physician identified in 
the Clinical Study Personnel Contact Information section of this 
protocol, and the investigator must provide the sponsor (LSO/INC 
Research) with the completed pregnancy form. The process for 
reporting a pregnancy is the same as that for reporting a serious 
adverse event but using the pregnancy form (see Section 7.1.5.3).
The investigator is not required to report patients who are found to 
be pregnant between screening and day 1, provided no IMP was 
given. All female patients participating in the study who become 
pregnant will be monitored for the outcome of the pregnancy 
(including spontaneous, elective, or voluntary abortion). If the 
pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and presence or 
absence of any birth defect, congenital abnormalities, or maternal 
and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy during the study and any complication 
of pregnancy that the investigator becomes aware of after 
withdrawal from the study will be reported as an adverse event or 
serious adverse event, as appropriate.
If the pregnancy in the female patient participating in the study 
does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse 
event.

For an elective abortion due to developmental anomalies, 
report as a serious adverse event.

For an elective abortion not due to developmental 
Update to 
pregnancy 
section/requiremen
ts


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the study does not continue to term, 1 of the following 
actions will be taken:

For a spontaneous abortion, report as a serious 
adverse event.

For an elective abortion due to developmental 
anomalies, report as a serious adverse event.

For an elective abortion not due to 
developmental anomalies, report on the 
pregnancy form; do not report as an adverse 
event.
anomalies, report on the pregnancy form; do not report as 
an adverse event.
7.4.Medication Error and Special Situations Related to the Investigational Medicinal Product
2.
Overdose: Administration of a quantity of a 
medicinal product given per administration or 
cumulatively which is above the maximum 
recommended dose according to the authorized product 
information. Clinical judgment should always be 
applied. Any dose of IMP (whether the test IMP or 
placebo IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be 
immediately reported to the sponsor.
3.
Misuse: Situations where the medicinal 
productIMP is intentionally and inappropriately used 
not in accordance with the authorized product 
information.
4.
Abuse: Persistent or sporadic, intentional excessive 
use of medicinal productsIMP which is accompanied 
by harmful physical or psychological effects.
5.
Off-label use: Situations where a medicinal 
productan IMP is intentionally used for a medical 
purpose not in accordance with the authorized product 
information.
2.
Overdose: Administration of a quantity of a medicinal product 
given per administration or cumulatively which is above the 
maximum recommended dose according to the authorized product 
information. Clinical judgment should always be applied. Any 
dose of IMP (whether the test IMP or placebo IMP), whether taken 
intentionally or unintentionally, in excess of that prescribed must 
be immediately reported to the sponsor.
3.
Misuse: Situations where the IMP is intentionally and 
inappropriately used not in accordance with the authorized product 
information.
4.
Abuse: Persistent or sporadic, intentional excessive use of 
IMP which is accompanied by harmful physical or psychological 
effects.
5.
Off-label use: Situations where an IMP is intentionally used 
for a medical purpose not in accordance with the authorized 
product information.
6.
Occupational exposure: Exposure to an IMP, as a result of 
one’s professional or non-professional occupation.
7.
Breastfeeding: Suspected adverse reactions that occur in 
infants following exposure to a medicinal product from breast 
Added
breastfeeding text 
as well as 
reporting info for 
overdose


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6.
Occupational exposure: Exposure to a medicinal 
productan IMP, as a result of one’s professional or non-
professional occupation.
7.
Breastfeeding: Suspected adverse reactions that 
occur in infants following exposure to a medicinal 
product from breast milk.
milk.
7.5 Clinical Laboratory Tests
The clinical significance of the lablaboratory values 
will be evaluated by the criteria described in the study 
lablaboratory manual and by the judgment of the 
investigator. A laboratory test result that is judged by 
the investigator as clinically significant will be 
recorded both on the source documentation transcribed 
to and the CRF as an adverse event, and monitored as 
described in Section 7.1.2. An event may include a 
laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that results in the 
withdrawal of the patient from the study, the temporary 
or permanent cessation of treatment withadministration 
of IMP or medical treatment, or further diagnostic 
work-up. Abnormal laboratory tests can be repeated 
without approval from the medical monitor. (Note: 
Abnormal laboratory or diagnostic test results at the 
screening visit that preclude a patient from entering the 
study or receiving IMP are not considered adverse 
events).
The clinical significance of the laboratory values will be evaluated 
by the criteria described in the study laboratory manual and by the 
judgment of the investigator. A laboratory test result that is judged 
by the investigator as clinically significant will be recorded both 
on the source documentation and the CRF as an adverse event, and 
monitored as described in Section 7.1.2. An event may include a 
laboratory or diagnostic test abnormality (once confirmed by 
repeated testing) that results in the withdrawal of the patient from 
the study, the temporary or permanent cessation of administration 
of IMP or medical treatment, or further diagnostic work-up. 
Abnormal laboratory tests can be repeated without approval from 
the medical monitor. (Note: Abnormal laboratory or diagnostic 
test results at the screening visit that preclude a patient from 
entering the study or receiving IMP are not considered adverse 
events).
Added note 
regarding 
abnormal 
laboratory or 
diagnostic test 
results at the 
screening visit
7.6 Vital Signs
Before BP and pulse are measured, the patient must 
berest in a supine or semi erect/seated position and 
resting for at least 35 minutes. (The same position and 
arm should be used each time vital signs are measured 
Before BP and pulse are measured, the patient must rest in a 
supine or semi erect/seated position and resting for at least 5 
minutes. (The same position and arm should be used each time 
vital signs are measured for a given patient.)
Updated directions 
on measuring BP 
and pulse
Timepoints of the 


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for a given patient.)
At baselineOn day 1 and weeks 4, 8, 28, and 54, 
orthostatic BP and pulse will be measured after the 
patient is in a standing position for at least 3 minutes.
On day 1 and weeks 4, 8, 28, and 54, orthostatic BP and pulse will 
be measured after the patient is in a standing position for at least 3 
minutes.
assessments were 
adjusted
7.8 Physical Examinations
Any physical examination finding that is judged by the 
investigator as clinically significant (except at the 
screening visit) will be considered an adverse event, 
recorded on the CRF, and monitored as described in 
Section 7.1.2.
Any physical examination finding that is judged by the 
investigator as clinically significant (except at the screening visit) 
will be considered an adverse event, recorded on the CRF, and 
monitored as described in Section 7.1.2.
Exception for the 
screening visit
added
7.9. Assessment of Suicidality
Not applicable
TEV-50717 is considered to be central nervous system (CNS)-
active. In addition, there have been some reports of suicidal 
ideation or behavior as reported in the product label when it has 
been given to some patients with certain conditions. The sponsor 
considers it important to monitor for such events before and during 
this clinical study.
Some CNS-active IMPs may be associated with an increased risk 
of suicidal ideation or behavior when given to some patients with 
certain conditions. Although this IMP or other similar medicinal 
products in this class have not been shown to be associated with an 
increased risk of suicidal thinking or behavior when given to this 
study population, the sponsor considers it important to monitor for 
such events before or during this clinical study.
The study population being administered TEV-50717 should be 
monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing TEV-50717 in 
participants who experience signs of suicidal ideation or behavior.
Families and caregivers of participants being treated with TEV-
50717 should be instructed to monitor participants for the 
Section added


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emergence of unusual changes in behavior, as well as the 
emergence of suicidal ideation and behavior, and to report such 
symptoms immediately to the study investigator.
The day 1 assessment of suicidal ideation and behavior and 
treatment-emergent suicidal ideation and behavior will be assessed 
during the study using the C-SSRS described in Section 7.2.2.
A reference sample is provided in Appendix E.
7.12 Methods and Time Points of Assessing, Recording, and Analyzing Safety Data
All adverse events will be reviewed on a periodic basis 
by the CPP/medical monitor according to the safety 
monitoring plan (eg, scheduled safety reviews for TEV 
50717) as preliminary safety databases become 
available. Safety data will additionally be evaluated 
periodically and ad hoc (if necessary) in the Product 
Safety Group.
All adverse events will be reviewed on a periodic basis by the 
CPP/medical monitor according to the safety monitoring plan (eg, 
scheduled safety reviews for TEV 50717) as preliminary safety 
databases become available. 
Periodic 
evaluation 
removed.
9.1. Sample Size and Power Considerations
Not applicable
For the randomized drug withdrawal period, enrolling at least 190 
patients will provide at least 90% power to detect a difference 
between SD-809 and placebo-treated patients assuming a 
difference in YGTSS TTS of 4.5 with a standard deviation of 9 
assuming a type 1 error rate of 5%.
Text added
9.2.3. Randomized Withdrawal ITT Population
Not applicable
The Randomized Withdrawal ITT (RWITT) Population will 
include all subjects enrolled in the randomized drug withdrawal 
period of the study.
Section added
9.2.4. Randomized Withdrawal Safety Population
Not applicable
The Randomized Withdrawal Safety (RWSAF) Population will 
include all subjects enrolled in the randomized drug withdrawal 
period who are administered any study drug. All summaries of 
Section added


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safety measures in the randomized withdrawal period will be 
summarized descriptively in the RWSAF Population.
9.2.5. Randomized Withdrawal Modified Intent-to-Treat Population
Not applicable
The Randomized Withdrawal mITT (RWmITT) Population will 
include all subjects enrolled in the randomized drug withdrawal 
period who receive study drug and have a centrally read AIMS 
score at both the randomized drug withdrawal period initial visit 
and the week 30 visit. All efficacy measures in the randomized 
drug withdrawal period will be analyzed using the (RWmITT) 
Population.
Section added
9.4 Study Population
The ITT analysis set (see Section 9.29.2.1) will be used 
for all open-label efficacy summaries and analyses 
unless otherwise noted. The safety analyses set will be 
used for all safety summaries. Summaries will be 
presented for all patients.
The RWmITT analysis set (see Section 9.2.5) will be 
used for all randomized withdrawal efficacy summaries 
and analyses unless otherwise noted. The RWSAF 
analysis set will be used for all randomized-withdrawal 
safety summaries.
The ITT analysis set (see Section 9.2.1) will be used for all open-
label efficacy summaries and analyses unless otherwise noted. The 
safety analyses set will be used for all safety summaries. 
Summaries will be presented for all patients.
The RWmITT analysis set (see Section 9.2.5) will be used for all 
randomized withdrawal efficacy summaries and analyses unless 
otherwise noted. The RWSAF analysis set will be used for all 
randomized-withdrawal safety summaries.
Two analysis sets, 
the RWmITT and 
the RWSAF were 
added
9.4.1 Patient Disposition
Data from patients who are enrolled, patients enrolled 
but not treated (and the reason), patients in the ITT, 
safety, and other analysis sets, patients who enter the 
randomized drug withdrawal period, patients who 
complete the randomized drug withdrawal period, 
patients who complete the study, and patients who 
withdraw from the study will be summarized using 
descriptive statistics. Data from patients who withdraw 
Data from patients who are enrolled, patients enrolled but not 
treated (and the reason), patients in the ITT, safety, and other 
analysis sets, patients who enter the randomized drug withdrawal 
period, patients who complete the randomized drug withdrawal 
period, patients who complete the study, and patients who 
withdraw from the study will be summarized using descriptive 
statistics. Data from patients who withdraw from the study will 
also be summarized by reason for withdrawal using descriptive 
Additional 
populations that 
will be 
summarized by 
descriptive 
statistics were 
added


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from the study will also be summarized by reason for 
withdrawal using descriptive statistics.
statistics.
9.5. Efficacy Analysis
No formal inferential statistics will be applied to the 
efficacy endpoints. Descriptive statistics will be 
presented. in Part A; however, inferential statistics will 
be applied to the efficacy endpoints in Part B (see 
Section 9.5.1).
No formal inferential statistics will be applied to the efficacy 
endpoints in Part A; however, inferential statistics will be applied 
to the efficacy endpoints in Part B (see Section 9.5.1).
Updated the 
analysis methods 
to present strategy 
in both Part A and 
Part B
9.5.1 Efficacy Endpoints
The following efficacy endpoints are:Changewill be 
assessed in Part A: 

Change in the TTS of the YGTSS TTS from 
baselineday 1 to each visit in which the scale is 
administered

Change in the TS-CGI score from 
baselineday 1 to each visit in which the scale is 
administered

Change in the TS-PGISPGII score from 
baselineday 1 to each visit in which the scale is 
administered

Change in the C&A-GTS-QOL physical/ADL 
subscale score from baselineday 1 to each visit 
in which the scale is administered
The following efficacy endpoint will be assessed in 
Part B: 

Change in the TTS of the YGTSS from week 
28 to week 30 
(This change also applies to Section 9.5.)
The following efficacy endpoints will be assessed in Part A: 

Change in the TTS of the YGTSS from day 1 to each visit
in which the scale is administered

Change in the TS-CGI score from day 1 to each visit in 
which the scale is administered

Change in the TS-PGII score from day 1 to each visit in 
which the scale is administered

Change in the C&A-GTS-QOL ADL subscale score from 
day 1 to each visit in which the scale is administered
The following efficacy endpoint will be assessed in Part B: 

Change in the TTS of the YGTSS from week 28 to week 
30 
Efficacy endpoints 
were changed to 
be grouped by Part 
A or B
9.5.2 Exploratory Endpoints


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The following exploratory endpoints arewill be 
assessed in Part A:
 
 
 
 
 
 
 
 
 
 
The following exploratory endpoints will be assessed in Part A:
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5.3.1 Efficacy Analysis for the Blinded, Randomized, Drug Withdrawal Study
Not applicable
For the randomized drug withdrawal portion of the study, an 
analysis of covariance model will be used as the primary analysis 
model with the change from randomized-withdrawal week 28 to 
week 30 in YGTSS TTS as the dependent variable, and treatment 
group, randomized withdrawal week 28 TTS and age group as 
covariates. The least squares mean of the change in TTS from 
week 28 at week 30 will be compared (the active treatment arm 
and placebo arm) using a 2-sided test at the alpha=0.05 level of 
significance.
Section added
9.6 Multiple Comparisons and Multiplicity
No adjustments will be made for multiplicity.
This does not apply to this study.
This does not apply to this study.
Adjusted text for 
clarity
9.7 Safety Endpoints and Analysis
Safety analyses will be performed on the safety 
analysis set (Section 9.2.2) for the open-label study and 
the RWSAF set for the randomized drug withdrawal 
portion.
Safety analyses will be performed on the safety analysis set 
(Section 9.2.2) for the open-label study and the RWSAF set for the 
randomized drug withdrawal portion.
Text was added 
for clarity on what 
would be analyzed
9.7.1 Safety Endpoints
The following safety endpoints are:will be assessed in 
Part A (Day 1, Titration, and Maintenance):
The following safety endpoint will be assessed in Part 
B (Blinded, Randomized Drug Withdrawal Period and 
Titration Post-Drug Withdrawal Period): 

incidence of adverse events
The following safety endpoints will be assessed in Part A (Day 1, 
Titration, and Maintenance):
The following safety endpoint will be assessed in Part B (Blinded, 
Randomized Drug Withdrawal Period and Titration Post-Drug 
Withdrawal Period): 

incidence of adverse events 
Safety endpoints 
were revised to 
classify Part A 
versus Part B 
assessments
9.9 Planned Interim Analysis


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Due to the open label nature of the study, there will be 
no formalNo interim statistical analysis is planned for 
this study.
No interim analysis is planned for this study.
Text revised for 
clarity
12.1 Informed Consent/Assent and/or Co-Consent
A personally signed and dated informed consent form 
will be obtained from parent/legally acceptable 
representative, and a signed and dated assent and/or co-
consent form for patients 14 years of age and older, as 
appropriate, will be obtained from each patient (if the 
patient is able) before any study specific procedures or 
assessments are done and after the aims, methods, 
anticipated benefits, and potential hazards are 
explained; according to national and local IEC/IRB 
requirements. The forms will be signed and dated also 
by the person who conducted the informed consent 
discussion. The investigator will keep the original 
informed consent/assent and/or co-consent forms for 
patients 14 years of age and older, as appropriate, and 
copies will be given to the patients. It will also be 
explained to the patients (and parent/legally acceptable 
representative) that they are free to refuse participation 
in the study and free to withdraw from the study at any 
time without prejudice to future treatment. Any patient 
that turns 18 years of age during the course of 
Study TV50717-CNS-30047 will need to be re-
consented as an adult.
A personally signed and dated informed consent form will be 
obtained from parent/legally acceptable representative, and a 
signed and dated assent and/or co-consent form for patients 14 
years of age and older, as appropriate, will be obtained from each 
patient (if the patient is able) before any study specific procedures 
or assessments are done and after the aims, methods, anticipated 
benefits, and potential hazards are explained; according to national 
and local IEC/IRB requirements. The forms will be signed and 
dated also by the person who conducted the informed consent 
discussion. The investigator will keep the original informed 
consent/assent and/or co-consent forms for patients 14 years of 
age and older, as appropriate, and copies will be given to the 
patients. It will also be explained to the patients (and 
parent/legally acceptable representative) that they are free to 
refuse participation in the study and free to withdraw from the 
study at any time without prejudice to future treatment. Any 
patient that turns 18 years of age during the course of 
Study TV50717-CNS-30047 will need to be re-consented as an 
adult.
Additional 
language regarding
patients who turn 
18 during the 
study was added
Appendix A Allowed and Disallowed Medications
The medical monitor must be contacted if a patient is 
receiving (or has to begin or stop receiving during the 
study) a medication that is associated with QTc 
prolongation or that is a known strong cytochrome 
The medical monitor must be contacted if a patient is receiving (or 
has to begin or stop receiving during the study) a medication that 
is associated with QTc prolongation or that is a known strong 
cytochrome P450 inhibitor. The addition of a strong CYP inhibitor 
Add Prohibited 
QTc Prolonging 
Drugs back with 
comment that up 


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P450 inhibitor. The addition of a strong CYP inhibitor 
is prohibited.
Prohibited antipsychotic drugs are listed in Table 7. 
Prohibited medications that are associated with QTc 
prolongation are listed in Table 8.
is prohibited.
Prohibited antipsychotic drugs are listed in Table 7. Prohibited 
medications that are associated with QTc prolongation are listed in 
Table 8.
Table 8:
Prohibited QTc Prolonging Drugs
Generic
Class/clinical use
Note
Azithromycina
Antibiotic/bacterial infection
Chloroquine/Mef
loquine
Anti-malarial/malaria infection
Clarithromycinb
Antibiotic/bacterial infection
Domperidone
Anti-nausea/nausea
Not 
available in 
USA
Droperidol
Sedative; anti-nausea/anesthesia 
adjunct, nausea
Erythromycinb
Antibiotic; gastrointestinal (GI) 
stimulant; GI motility
Moxifloxacin
Antibiotic/bacterial infection
Sevoflurane
Anesthetic, general/anesthesia
Probucol
Antilipemic/hypercholesterolemi
a
Not 
available in 
USA
Sparfloxacin
Antibiotic/bacterial infection
Not 
available in 
USA
to 500 mg/day of 
Azithromycin is 
allowed
Table of 
prohibited QTc 
prolonging drugs 
added


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a Allowed dose of Azithromycin is up to 500 mg/day 
b Systemic use only. Topical use is allowed.
GI=gastrointestinal; USA=United States of America.
APPENDIX I. TOURETTE SYNDROME PATIENT GLOBAL IMPRESSION OF IMPACT AND SEVERITY
Not applicable
[Appendix I was updated to include impact and severity 
assessments]
Updated Appendix 
I to present only 
the specific 
assessments that 
will be conducted 
to assess impact 
and severity
Appendix K Child and Adolescent Gilles De La Tourette Syndrome – Quality Of Life Scale for Patients Aged 6 to 12 Years (C&A-GTS-
QOL 6-12) and 13 to 18 Years (C&A-GTS QOL 13-18)
Not applicable
[The previous appendix K was form for children 13 to 18 years of 
age was updated. An additional form was added to the appendix to 
account for and be used by children aged 6 to 12]
This appendix was 
added to show the 
distinct 
forms/assessments
to be used for each 
of these two age 
categories of 
patients
Appendix L Females of Childbearing Potential and Birth Control Methods AND PREGNANCY TESTING
Contraception recommendations and pregnancy testing 
should encompass all IMPs as well as non
investigational medicinal products, eg, background 
therapy, and the measures to be followed should be 
based on the medicinal product with highest risk.
Assessment of likelihood of possible interaction 
between IMP or concomitant medications and 
hormonal contraception should be conducted.
Females of childbearing potential are defined as:
•
not surgically (documented hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or congenitally sterile
•
postmenarchal or ≥12 years of age
Highly effective birth control methods:
Highly effective birth control methods are methods that can 
achieve a failure rate of less than 1% per year when used 
Updated Appendix 
to align with edits 
to pregnancy 
language made to 
the body of the 
protocol and the 
observed 
“possible” risks


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Hormonal contraception may be susceptible to 
interaction with the IMP, which may reduce the 
efficacy of the contraception method, eg, CYP 4A 
inducers. In case of suspected interaction, hormonal 
contraceptive alone may not be sufficient. In the 
absence of clinical pharmacokinetic interaction study 
data in IMPs with demonstrated or suspected human 
teratogenicity/fetotoxicity, recommendation for use of 
hormonal contraceptives should be thoroughly justified 
by the sponsor. Additional contraceptive methods, 
including supplementary barrier methods, may be 
considered.
Females of childbearing potential are defined as:
•
not surgically (documented hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or 
congenitally sterile
•
not postmenopausal postmenarchal or ≥12 years of 
age
Description of different birth control methods
Highly effective birth control methods:
Highly effective birth control methods are methods that 
can achieve a failure rate of less than 1% per year when 
used consistently and correctly are considered. Such 
methods include:
•
Combined estrogen and progestogen hormonal 
contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation; these should be 
initiated at least 7 days (for IMPs without suspected 
teratogenicity/genotoxicity) and 1 month (for IMPs 
potentially teratogenic/genotoxic) before the first dose 
of IMP.
•
Progestogen-only hormonal contraception (oral, 
consistently and correctly are considered. Such methods include:
•
Combined estrogen and progestogen hormonal contraception 
(oral, intravaginal, transdermal) associated with inhibition of 
ovulation; these should be initiated at least 1 month before the first 
dose of IMP.
•
Progestogen-only hormonal contraception (oral, injectable, 
implantable) associated with inhibition of ovulation; these should 
be initiated at least 1 month before the first dose of IMP.
•
Intrauterine device (IUD) and intrauterine hormone-releasing 
system (IUS) need to be in place at least 2 months before 
screening.
•
Bilateral tubal occlusion
•
Vasectomized partner provided he is the sole sexual partner 
and has received medical assessment of the surgical process.
•
Sexual abstinence is only considered a highly effective 
method if defined as refraining from heterosexual intercourse in 
the defined period. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient.
•
Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration 
of a study, and withdrawal are not acceptable methods of 
contraception (according to Medicines and Healthcare Products 
Regulatory Agency, MHRA).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom 
should not be used together.


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injectable, implantable) associated with inhibition of 
ovulation; these should be initiated at least 7 days (for 
IMPs without suspected teratogenicity/genotoxicity) 
and 1 month (for IMPs potentially 
teratogenic/genotoxic) before the first dose of IMP.
•
Intrauterine device (IUD) and intrauterine 
hormone-releasing system (IUS) need to be in place at 
least 2 months before screening.
•
Bilateral tubal occlusion
•
Vasectomized partner provided he is the sole 
sexual partner and has received medical assessment of 
the surgical process.
•
Sexual abstinence is only considered a highly 
effective method if defined as refraining from 
heterosexual intercourse in the defined period. The 
reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient.
•
Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a study, and withdrawal 
are not acceptable methods of contraception (according 
to Medicines and Healthcare Products Regulatory 
Agency, MHRA).
Acceptable birth control methods:
Acceptable birth control methods that result in a failure 
rate of more than 1% per year include: progestogen
only oral hormonal contraception for which the 
inhibition of ovulation is not the primary mode of 
action; male or female condom with or without 
spermicide; cap, diaphragm, or sponge with spermicide. 
The combination of male condom with either cap, 


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diaphragm, or sponge with spermicide (double barrier
methods) are also considered acceptable but not highly 
effective methods of birth control.
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-
ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method 
(LAM) are not acceptable methods of contraception. 
Female condom and male condom should not be used 
together.
Male contraception:
Male patients must always use a condom, except in 
cases of no genotoxicity; or no demonstrated or 
suspected human teratogenicity/fetotoxicity.
Vasectomy:
Use of contraceptive methods applies also to 
vasectomized men, because of the risk associated with 
transfer of a drug via seminal fluid.
Contraception for female partners of male study 
participants:
Female partners (who are not pregnant) of male study 
participants must use contraception for non pregnant 
WOCBP until the end of relevant systemic exposure in 
case of IMPs with genotoxicity or IMPs with no 
genotoxicity but demonstrated or suspected human
teratogenicity/fetotoxicity.
Pregnancy tests in females of childbearing potential:
1.
Conduct monthly pregnancy testing from first dose 
of IMP until last dose of IMP and additional 30 days in 
case the IMP does not have a marketing authorization 
and has suspected human 


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teratogenicity/genotoxicity/fetotoxicity. Conduct 
monthly pregnancy testing and in case the IMP has a 
marketing authorization, if the IMP has a demonstrated 
or suspected human 
teratogenicity/genotoxicity/fetotoxicity according to 
Risk Safety Information. Shorter testing intervals are to 
be considered depending on drug dosing schedule.
2.
Consider additional pregnancy testing, but at least 
at the end of relevant systemic exposure, in case of 
possible human teratogenicity/fetotoxicity. This refers 
to IMPs, for which human data on pregnancies is 
limited or not available, there is no suspicion of human 
teratogenicity based on class effects or genotoxic 
potential, and nonclinical reproductive toxicity studies 
of relevance for early human pregnancy show positive 
findings that do not generate a strong suspicion of 
human teratogenicity/ fetotoxicity.
3.
For IMPs with unlikely risk of human 
teratogenicity/fetotoxicity, additional pregnancy testing 
is generally not necessary. This refers to IMPs for 
which assessment of the completed necessary 
nonclinical studies does not indicate teratogenicity/ 
fetotoxicity in early pregnancy and human data are not 
available or do not contradict these findings or there is 
already sufficient evidence for lack of risk based on 
human data.
Pregnant female partners of male study participants:
Male study participants must use condoms during 
intercourse if their female partners are pregnant.


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17.3.
Amendment 03 Dated 01 February 2018
The primary reason for this amendment is to correct and clarify the re-titration regimen in Part B.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.
Note: In addition to the specific changes to the protocol that are listed in the table below, some minor typographical and grammatical 
changes were made for clarity and are not individually listed. Text that was moved but not otherwise changed is also not listed.
Original text with changes shown
New wording
Reason/Justification for 
change
Global
Mini International Neuropsychiatric Interview For Children 
and Adolescents (MINI Kid, version 6.0)
Mini International Neuropsychiatric Interview 
For Children and Adolescents (MINI Kid, 
version 6.0)
Included MINI Kid version 
each time the full name (not 
abbreviation) was used.
DSM-5™
DSM-5™
Corrected the name of 
DSM-5™.
INVESTIGATOR AGREEMENT
Updated to reflect a change 
in the Sponsor’s Authorized 
Representative.
COORDINATING INVESTIGATOR AGREEMENT
 
Title: 
 
 
 
Updated to provide contact 
information for coordinating 
investigator.


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change
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS
Central Clinical Laboratory
Q2 Solutions
1201 S. Collegeville Road 27027 Tourney Road, Suite 2E 
Collegeville, PA 19426 Valencia, CA 91355
USA
Central Clinical Laboratory
Q2 Solutions
27027 Tourney Road, Suite 2E 
Valencia, CA 91355
USA
Updated to reflect a change 
in the address of the central 
clinical laboratory.
Bioanalytical Pharmacokinetics Evaluation Data Analysis
Information will be included in the Trial Master File.
Not applicable
Pharmacokinetic 
assessments will no longer 
be conducted in this study.
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
Sponsor’s Authorized Representative:
VP, Therapy Area Head, Specialty R&D, Teva Branded 
Pharmaceutical Products R&D, Inc.
Email: 
Sponsor’s Authorized Representative:
VP, Therapy Area Head, Specialty R&D, Teva 
Branded Pharmaceutical Products R&D, Inc.
Tel: 
Email: 
Added information for the 
Sponsor’s Authorized 
Representative.
Section 1.1 Introduction
To address the limitations of commercial tetrabenazine
(Xenazine®), Auspex, a wholly owned subsidiary of Teva 
Pharmaceutical Products R&D, Inc, has developed a deuterated 
form of tetrabenazine (referred to as TEV-50717, previously 
SD-809) that is eliminated more slowly than tetrabenazine.
To address the limitations of commercial 
tetrabenazine (Xenazine®), Auspex, a wholly 
owned subsidiary of Teva Pharmaceutical 
Products R&D, Inc, has developed a deuterated 
tetrabenazine (referred to as TEV-50717, 
previously SD-809) that is eliminated more 
slowly than tetrabenazine.
Clarification of drug 
terminology.


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Reason/Justification for 
change
Synopsis
Section 1.5.1 Justification for Dose of Active Drug (also affects the Synopsis)
Similar to one of the parent studies (SD 809 C 17, TV50717-
CNS-30046, and TV50717 CNS 30060), IMP will be titrated 
based on investigator, patient, and parent/guardian assessments 
of tic reduction and adverse events.
Similar to one of the parent studies (TV50717-
CNS-30046), IMP will be titrated based on 
investigator, patient, and parent/guardian 
assessments of tic reduction and adverse events.
Clarified which parent study
used this approach.
Section 1.8 Location and Study Duration (also affects Synopsis)
This study is planned to be conducted globally (per Study SD-
809-C-17, Study TV50717-CNS-30046 in North America, Latin 
America, Russia, Ukraine, South Korea, Turkey, and Study 
TV50717-CNS-30060Europeat approximately 120100 centers.
This study is planned to be conducted globally 
(per Study SD-809-C-17, Study TV50717-
CNS-30046, and Study TV50717-CNS-30060) 
at approximately 120 centers.
Updated the number of 
sites. Updated the location 
of sites for flexibility to 
include all countries that 
had sites in the parent 
studies.
It is expected to start in January May 2018 and conclude in June 
2020 October 2020, withand have a duration of approximately 
30 months.
It is expected to start in May 2018 and conclude 
in October 2020, with a duration of 
approximately 30 months.
Updated the start and end 
dates.
Section 2.3.1 Safety Endpoints (also affects Sections 7.2.3, 9.7.1, and Synopsis)
•
observed values and changes from day 1 in the Children’s 
Depression Inventory, Second Edition (CDI 2;, Parent and Self-
rReport Profilesversions(CDI-2)
[…]
•
observed values in electrocardiogram (ECG) parameters and 
shifts from day 1 parent study baseline (for patients rolling over 
from Study TV50717-CNS-30046 or Study TV50717-CNS-
30060) or from day 1 (for patient[s] rolling over from Study SD-
809-C-17)for clinically significant abnormal findings
[…]
In addition to routine monitoring of adverse events, clinical 
•
observed values and changes from day 1 in 
the Children’s Depression Inventory, Second 
Edition, Parent and Self-Report Profiles 
(CDI-2)
[…]
•
observed values in electrocardiogram 
(ECG) parameters and shifts from parent study 
baseline (for patients rolling over from Study 
TV50717-CNS-30046 or Study TV50717-
CNS-30060) or from day 1 (for patient[s] 
rolling over from Study SD-809-C-17) for 
clinically significant abnormal findings
Updated the definition of 
CDI-2 to include profile 
types.
Clarified baseline for ECG 
shift analysis depending on 
parent study (see also 
changes listed for 
Section 4.4 below).
Added IDMC (see also 


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change
laboratory parameters, 12-lead ECGs, and safety scales, an 
Independent Data Monitoring Committee (IDMC) will monitor 
safety during the conduct of the study.
[…]
In addition to routine monitoring of adverse 
events, clinical laboratory parameters, 12-lead 
ECGs, and safety scales, an Independent Data 
Monitoring Committee (IDMC) will monitor 
safety during the conduct of the study.
changes listed for 
Section 3.7 below).
Section 2.3.2 Efficacy Endpoints (also affects Section 9.5.1 and Synopsis)
•
change in the TTS of the YGTSS from week 28 to week 30, 
with the primary analyses and sensitivity testing done as 
described in Section 9.5.3.1
•
change in the TTS of the YGTSS from 
week 28 to week 30, with the primary analyses 
and sensitivity testing done as described in 
Section 9.5.3.1
Clarification on where to 
find further information.
Section 2.3.3 Exploratory Endpoints (also affects Section 9.5.2. and Synopsis)
•
 
•
 
 
 
Section 3.1 General Design and Study Schematic Diagram (also affects Section 9.1, Figure 1, and Synopsis)
This is a 56-week, open-label, single-arm study that includes a 
2-week, double-blind, placebo-controlled, randomized drug 
withdrawal period followed by a 3-week blinded re-titration
period to evaluate the safety of TEV-50717 in children and 
adolescents with tics associated with TS after they have 
successfully completed any of the parent studies (SD-809-C-17 
[Phase 1b], TV50717-CNS-30046 [Phase 2/3], or 
TV50717-CNS-30060 [Phase 3]).
[...]
This is a 56-week, open-label, single-arm study 
that includes a 2-week, double-blind, 
placebo-controlled, randomized drug 
withdrawal period followed by a 3-week 
blinded re-titration period to evaluate the safety 
of TEV-50717 in children and adolescents with 
tics associated with TS after they have 
successfully completed any of the parent 
studies (SD-809-C-17 [Phase 1b], TV50717-
CNS-30046 [Phase 2/3], or TV50717-
CNS-30060 [Phase 3]).
[...]
Clarified terminology and 
timing related to Part B.


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For patients rolling over from Study SD-809-C-17, this study 
will consist of up to a 4-week screening period (up to 31 days) 
and up to 54 weeks of treatment.
[...]
Patients who have successfully completed any of the parent 
studies may be eligible to enroll in the current study after they 
complete a 1-week washout period and the final evaluation 
(week 13 in TV50717818-CNS 30046 or week 9 in TV50717-
CNS-30060) in the parent study.
[...]
Up to approximately 212260 patients are planned to be enrolled 
(up to 10 patients are approximately 1 patient is estimated to 
enroll from the Phase 1b Study SD-809-C-17, up to 
approximately 85100 patients are estimated to enroll from the 
Phase 2/3 Study TV50717-CNS-30046, and up to approximately 
126150 patients are estimated to enroll from the Phase 3 Study 
TV50717-CNS-30060).
Patients who complete all scheduled visits will have procedures 
and assessments performed at the final visit (week 54).
[...]
The study schematic diagram is presented in Figure 1. An 
additional diagram that details the blinded, randomized drug 
withdrawal/titration post-drug withdrawal period (Part B of the 
study) is presented in Figure 2.
[Figures 1 and 2 were edited to ensure consistency of 
terminology and clarification (in footnote c) of when dose 
adjustment is permissible.]
For patients rolling over from Study SD-809-C-
17, this study will consist of a 4-week screening 
period (up to 31 days) and up to 54 weeks of 
treatment.
[...]
Patients who have successfully completed any 
of the parent studies may be eligible to enroll in 
the current study after they complete a 1-week 
washout period and the final evaluation 
(week 13 in TV50717-CNS-30046 or week 9 in 
TV50717-CNS 30060) in the parent study.
[...]
Up to approximately 212 patients are planned 
to be enrolled (approximately 1 patient is 
estimated to enroll from the Phase 1b Study 
SD-809-C-17, up to approximately 85 patients 
are estimated to enroll from the Phase 2/3 Study 
TV50717-CNS-30046, and up to approximately 
126 patients are estimated to enroll from the 
Phase 3 Study TV50717-CNS-30060).
Patients who complete all scheduled visits will 
have procedures and assessments performed at 
the final visit (week 54).
[...]
The study schematic diagram is presented in 
Figure 1. An additional diagram that details the 
blinded, randomized drug withdrawal/titration 
post-drug withdrawal period (Part B of the 
study) is presented in Figure 2.
[Figures 1 and 2 were edited to ensure 
consistency of terminology and clarification (in 
Clarification on screening 
period length.
Corrected study identifier.
Updated numbers of 
patients, with clarification 
that these numbers are 
estimates.
Clarification.


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Figure 1 footnote c) of when dose adjustment is 
permissible.]
Section 3.1 General Design and Study Schematic Diagram (also affects Synopsis)
In the study period descriptions below, “week X” refers to the 
end of that week, which coincides with the study visit, unless 
stated otherwise. Some dose changes will occur at the start of a 
week rather than at the end of a week and will be indicated as 
such.
In the study period descriptions below, “week 
X” refers to the end of that week, which 
coincides with the study visit, unless stated 
otherwise. Some dose changes will occur at the 
start of a week rather than at the end of a week 
and will be indicated as such.
Clarification for consistent 
terminology to describe Part 
B.
Added clarification of 
“week” terminology to the 
end of the design overview.
Section 3.1.3 Titration Period (also affects the Synopsis)
3.1.3 Titration Period (7 weeks)
[...]
The dose of the IMP should be increased on a weekly basis until
one of the following occurs:
•
The investigator determines there has been a clinically 
meaningful reduction in tics, as indicated by a sustained 
reduction in the TS CGI.
3.1.3 Titration Period (7 weeks)
[...]
The dose of the IMP should be increased on a 
weekly basis until one of the following occurs:
•
The investigator determines there has been 
a clinically meaningful reduction in tics.
Added detail to heading. 
Removed unnecessary 
detail.
Section 3.1.4 Maintenance Period (also affects Sections 5.1, 5.5 and Synopsis)
As during titration, dose adjustments should be made based on 
all available information. After dose adjustment, if the 
maintenance dose for a patient is 6 mg, the dose should be taken 
once a day in the morning with food (other dose levels are taken 
twice daily).
During the maintenance period, in-person (in-clinic) study visits 
will be scheduled at weeks 8, 15, 34, 41, and 54 for assessments 
of safety and efficacy and telephone contacts will be scheduled 
for weeks 21 and 47 in order to assess adverse events and tic
severity. The randomized drug withdrawal and re-titration period 
As during titration, dose adjustments should be 
made based on all available information. After 
dose adjustment, if the maintenance dose for a 
patient is 6 mg, the dose should be taken once a 
day in the morning with food (other dose levels 
are taken twice daily).
During the maintenance period, in-person (in-
clinic) study visits will be scheduled at 
weeks 8, 15, 34, 41, and 54 for assessments of 
safety and efficacy and telephone contacts will 
Clarified dosing adjustment 
down to 6 mg.
Clarified that Part B occurs 
in the midst of Part A rather 
than afterward and that dose 
adjustments may occur 
during all of Part A (both 


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(Part B) will occur from the end of week 28 through the end of 
week 33, and then the Part A maintenance period will resume, 
along with the ability to make dose adjustments as described 
above.
be scheduled for weeks 21 and 47 in order to 
assess adverse events and tic severity. The 
randomized drug withdrawal and re-titration
period (Part B) will occur from the end of 
week 28 through the end of week 33, and then 
the Part A maintenance period will resume, 
along with the ability to make dose adjustments 
as described above.
before and after Part B).
Section 3.1.6 Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal Period (also affects Sections 3.5, 3.8, 
5.1, and Synopsis)
3.1.6.
Blinded, Randomized Drug Withdrawal Period and 
Titration Post-Drug Withdrawal Period (5 weeks)
At the week 28 visit, the patients will be randomized 2:1 to their 
current dose of TEV-50717 or placebo in order to check for 
return of symptoms. Because IMP is dispensed as enough doses 
for 2 weeks (current dose level and next dose level), the week 28 
visit (Day 196) is considered the first day of the randomized 
withdrawal period, although the patient will begin taking blinded 
IMP on Day 197. […]At the week 30 visit, patients who receive 
TEV-50717 during the randomized drug withdrawal period will 
continue at the same dose in a blinded manner from the start of 
week 31 to the start of week 34 dose of blinded active IMP.  
[...]Any patient who was randomized to placebo during this 
2-week period will undergo blinded begin re-titration. Patients 
will have a follow-up telephone contact for safety evaluation at 
weeks 31 and 33. All patients should be back at their 
maintenance dose on or before the start of week 34 and return to 
open label treatment for the remainder of the study.
3.1.6.
Blinded, Randomized Drug 
Withdrawal Period and Titration Post-Drug 
Withdrawal Period (5 weeks)
At the week 28 visit, the patients will be 
randomized 2:1 to their current dose of TEV-
50717 or placebo in order to check for return of 
symptoms. Because IMP is dispensed as 
enough doses for 2 weeks (current dose level 
and next dose level), the week 28 visit 
(Day 196) is considered the first day of the 
randomized withdrawal period, although the 
patient will begin taking blinded IMP on 
Day 197. […] At the week 30 visit, patients 
who receive TEV-50717 during the randomized 
drug withdrawal period will continue at the 
same dose in a blinded manner from the start of 
week 31 to the start of week 34. Any patient 
who was randomized to placebo during this 
2-week period will undergo blinded re-titration. 
Patients will have a follow-up telephone contact 
for safety evaluation at weeks 31 and 33.  
Added detail to heading. 
Clarified terminology and 
timing related to the 
blinded, randomized drug 
withdrawal period and 
titration post-drug 
withdrawal period (Part B).


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Section 3.1.7 Titration Post-Drug Withdrawal (Weeks 31, 32, and 33) [also affects Synopsis]
Any patient who was randomized to placebo during weeks 28 to 
30 between the week 28 and week 30 visits will undergo re-
titration to their previously established maintenance target dose 
over the 3 weeks of treatment following the randomized drug 
withdrawal period (start of week 31 to the start of week 34 [Days 
211 through 232]). The titration scheme and maximum dose will 
be determined based on the previously established maintenance 
dose according to Table 3 by body weight and CYP2D6 
impairment status.
[Moved last sentence of Section 3.1.6 to this section, with the 
following edits:
All patients should be back at their maintenance dose on or 
before the start of week 34 and return to open-label treatment for 
the remainder of the study (note that, because IMP is dispensed 
for 2-week periods, patients will use blinded bottles through the 
end of week 34; however, all patients will be known to be on 
active treatment at the start of week 34).
Any patient who was randomized to placebo 
between the week 28 and week 30 visits will 
undergo re-titration to their previously 
established maintenance dose over the 3 weeks 
of treatment following the randomized drug 
withdrawal period (start of week 31 to the start 
of week 34 [Days 211 through 232]). The 
titration scheme and maximum dose will be 
determined based on the previously established 
maintenance dose according to Table 3.
All patients should be back at their maintenance 
dose on or before the start of week 34 and 
return to open-label treatment for the remainder 
of the study (note that, because IMP is 
dispensed for 2-week periods, patients will use 
blinded bottles through the end of week 34; 
however, all patients will be known to be on 
active treatment at the start of week 34).
Clarified additional 
terminology and timing 
related to the titration 
post-drug withdrawal 
period.
(See also changes listed for 
Section 3.1.6.)
Section 3.2 Justification for Study Design and Placebo-Controlled Randomized Withdrawal (also affects Section 5.1)
3.2.Justification for Study Design and Placebo-Controlled 
Randomized Drug Withdrawal
[...]
A randomized, double blind, placebo controlled study of TEV
50717 (Study TV50717 CNS 30046 or Study TV50717 CNS 
30060) has recently begun. The goal of this study is to evaluate 
the efficacy and safety of TEV 50717 on the tics of patients with 
TS in a rigorous, controlled manner.
Two parent studies, TV50717-CNS-30046 and TV50717-CNS-
30060, are underway. They are randomized, double-blind, 
placebo-controlled studies of the efficacy and safety of TEV-
3.2.Justification for Study Design and 
Placebo-Controlled Randomized Drug 
Withdrawal
[...]
Two parent studies, TV50717-CNS-30046 and 
TV50717-CNS-30060, are underway. They are 
randomized, double-blind, placebo-controlled 
studies of the efficacy and safety of TEV-50717 
on the tics in patients with TS. 
[...]
[...]
Clarified heading.  
Updated descriptions of 
parent studies from which 
patients will roll over.


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50717 on the tics in patients with TS. 
[...]
Patients will receive twice daily dosing for up to 54 weeks (those 
on the 6-mg dose will receive once daily dosing), with an initial 
7-week titration period to allow for optimal dose selection. At 
the week 28 visit, patients will begin a 2-week blinded, 
randomized drug withdrawal period. The randomized drug 
withdrawal period will rigorously assess the long-term 
maintenance of effect. Patients will be randomized to their 
current dose of TEV-50717 or placebo for 2 weeks. After 
completing the 2 weeks, patients will continue their same dose of 
TEV-50717 in a blinded manner or will be retitrated (patients 
receiving placebo only) in a blinded manner for 3 weeks. At 
week 34, all patients will resume their maintenance dose.
Patients will receive twice daily dosing for up 
to 54 weeks (those on the 6-mg dose will 
receive once daily dosing), with an initial 
7-week titration period to allow for optimal 
dose selection. At the week 28 visit, patients 
will begin a 2-week blinded, randomized drug 
withdrawal period. The randomized drug 
withdrawal period will rigorously assess the 
long-term maintenance of effect. Patients will 
be randomized to their current dose of 
TEV-50717 or placebo for 2 weeks. After 
completing the 2 weeks, patients will continue 
their same dose of TEV-50717 in a blinded 
manner or will be retitrated (patients receiving 
placebo only) in a blinded manner for 3 weeks. 
At week 34, all patients will resume their 
maintenance dose.
Clarified regimen for the 
6 mg dose. Clarified that 
dosing is blinded for the 
3-week re-titration period.
3.3.Safety Measures and Time Points (also affects Sections 3.13.1, 7.2.2, and Synopsis)
Part A:
[…]
•
Children’s C-SSRS:

baseline Day 1/screening version scale: Sscreening 
only (ie, only for patients who completed Study 
SD-809-C-17)

Since Last Visit (SLV) version scale: Dday 1 (only 
for patients who completed Study SD-809-C-17) and 
weeks 2, 4, 8, 15, 34, 41, 54, and 55
•
CDI-2: Sscreening and day 1 (ie, only for patients who 
completed Study SD-809-C-17) and weeks 2, 4, 6, 8, 15, 34, 41, 
Part A:
[…]
•
Children’s C-SSRS:

baseline/screening version: 
screening only (ie, only for patients 
who completed Study 
SD-809-C-17)

Since Last Visit (SLV) version: day 
1 (only for patients who completed 
Study SD-809-C-17) and weeks 2, 
4, 8, 15, 34, 41, 54, and 55
•
CDI-2 (Parent and Self-Report versions): 
Clarified pregnancy test 
types to be performed at 
different time points.
Corrected C-SSRS 
description.
Week 6 assessment was 
removed for CDI-2.
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54, and 55
[…]
•
Ppregnancy testing (beta human chorionic gonadotropin 
[β-HCG]): Sscreening (ie, only for patients who completed 
Study SD-809-C-17); day 1 and weeks 4, 8, 15, 34, and 54 
(serum tests at screening and week 54 and urine tests at other 
visits)
[…]
Part B:
[…]
•
Children’s C-SSRS:

SLV versionscale: Weeks 28 and 30
•
12-lead ECG: week 28
•
clinical laboratory tests (serum chemistry, hematology, and 
urinalysis): week 28
screening and day 1 (ie, only for patients who 
completed Study SD-809-C-17) and weeks 2, 4, 
8, 15, 34, 41, 54, and 55
[β-human …]
•
Ppregnancy testing (β-HCG): screening (ie, 
only for patients who completed Study SD-809-
C-17); day 1 and weeks 4, 8, 15, 34, and 54 
(serum tests at screening and week 54 and urine 
tests at other visits)
[…]
Part B:
[…]
•
Children’s C-SSRS:

SLV version: Weeks 28 and 30
•
12-lead ECG: week 28
•
clinical laboratory tests (serum chemistry, 
hematology, and urinalysis): week 28
were listed under Part B.
3.4.1.
Efficacy Measures and Time Points (also affects Synopsis)
•
YGTSS (to calculate TTS): Screening (only for patients who 
completed Study SD-809-C-17); day 1 (ie, week 13 data from 
Study TV50717-CNS-30046 or week 9 data from Study 
TV50717-CNS-30060); and weeks 2, 4, 8, 15, 28, 30, 34, 41, 54, 
and 55
•
YGTSS: Screening (only for patients who 
completed Study SD-809-C-17); day 1 (ie, 
week 13 data from Study TV50717-CNS-30046 
or week 9 data from Study TV50717-
CNS-30060); and weeks 2, 4, 8, 15, 28, 30, 34, 
41, 54, and 55
Removed unnecessary 
detail.
3.4.2.
Exploratory Measures and Time Points (also affects Synopsis)
Part A and Part B:
 
Part A and Part B:
 
 


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[section deleted] Section 3.5 Pharmacokinetic Measures (also affects Section 8 and Synopsis)
Section 3.5 Pharmacokinetic Measures
A blood sample for the measurement of IMP concentration 
should be collected, if possible, from each patient experiencing a 
serious adverse event or an adverse event leading to 
discontinuation of IMP at any time during the study. If study 
center personnel are unable to obtain a blood sample in a timely 
fashion, this should be discussed with the medical monitor to 
determine whether the sample still needs to be obtained.
Not applicable
Pharmacokinetic 
assessments will no longer 
be conducted in this study. 
(See also changes listed for 
Section 3.13.3.2.1.)
Section 3.5 Randomization and Blinding (also affects Synopsis)
This is an otherwise open-label study that includes a 2-week, 
double-blind, placebo-controlled, randomized drug withdrawal 
period followed by a 3-week blinded re-titration period. At the
start of the randomized drug withdrawal period (end of week 
This is an otherwise open-label study that 
includes a 2-week, double-blind, placebo-
controlled, randomized drug withdrawal period 
followed by a 3-week blinded re-titration
Clarified terminology and 
timing related to Part B (see 
also changes listed for 
Section 3.1.6 above).


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28), the patients will be randomized 2:1 to the current dose or 
placebo in order to check for return of symptoms. At the end of 
this period, patients who receive TEV 50717 during the 
randomized drug withdrawal period will return to the most 
recent dose of TEV 50717 and patients who received placebo 
during the randomized drug withdrawal period will begin 
titration post drug withdrawal. During the entire 5-week period, 
patients randomized to TEV-50717 will stay on their established 
maintenance dose of blinded active IMP. Patients who receive 
placebo during the randomized drug withdrawal period will 
undergo blinded retitration post-drug withdrawal. All patients 
will return to open-label dosing at week 34 (note that, because 
IMP is dispensed for 2-week periods, patients will use blinded 
bottles through the end of week 34; however, all patients will be 
known to be on active treatment at the start of week 34).
During the blinded drug withdrawal and re-titration period, 
patients and investigators will remain blinded to treatment 
assignment. In addition, the sponsor’s and development partner’s 
clinical personnel and all vendors (with the exception of the 
Interactive Response Technology [IRT] vendor and the IMP 
packaging vendor) involved in the study will be blinded to the 
IMP identity until the database has been locked for analysis and 
the treatment assignments are revealed.
Patients will be centrally randomly assigned to the treatment 
groups by means of a computer-generated randomization list. 
The creation of the randomization list will be under the 
responsibility and oversight of INC Research.
The randomization treatment and medication allocation will be 
assigned to the relevant treatment groups through a qualified 
service provider (ie, via IRT). The management of the IRT 
system will be done by a qualified service provider under the 
oversight of Nuvelution TS Pharma, INC (referred to hereafter 
period. At the start of the randomized drug 
withdrawal period (end of week 28), the 
patients will be randomized 2:1 to the current 
dose or placebo in order to check for return of 
symptoms. During the entire 5-week period, 
patients randomized to TEV-50717 will stay on 
their established maintenance dose of blinded 
active IMP. Patients who receive placebo 
during the randomized drug withdrawal period 
will undergo blinded re-titration post-drug 
withdrawal. All patients will return to open-
label dosing at week 34 (note that, because IMP 
is dispensed for 2-week periods, patients will 
use blinded bottles through the end of week 34; 
however, all patients will be known to be on 
active treatment at the start of week 34).
During the blinded drug withdrawal and re-
titration period, patients and investigators will 
remain blinded to treatment assignment. In 
addition, the sponsor’s and development 
partner’s clinical personnel and all vendors 
(with the exception of the Interactive Response 
Technology [IRT] vendor and the IMP 
packaging vendor) involved in the study will be 
blinded to the IMP identity until the database 
has been locked for analysis and the treatment 
assignments are revealed.
Patients will be centrally randomly assigned to 
the treatment groups by means of a 
computer-generated randomization list. The 
creation of the randomization list will be under 
the responsibility and oversight of INC 
Added standard language 
related to blinding, 
including clarification of 
entities subject to blinding 
during the drug withdrawal 
and re-titration period.


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as Nuvelution TS Pharma).
The staff member at the investigational center who will dispense 
the IMP will not know the treatment given to each patient during 
the blinded drug withdrawal and re-titration period.
Research.
The randomization treatment and medication 
allocation will be assigned to the relevant 
treatment groups through a qualified service 
provider (ie, via IRT). The management of the 
IRT system will be done by a qualified service 
provider under the oversight of Nuvelution TS 
Pharma, INC (referred to hereafter as 
Nuvelution TS Pharma).
The staff member at the investigational center 
who will dispense the IMP will not know the 
treatment given to each patient during the 
blinded drug withdrawal and re-titration period.
Section 3.6 Maintenance of Randomization and Blinding
3.6.Maintenance of Randomization and Blinding
3.6.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure 
location at the service provider contracted to generate the codes. 
At the time of analysis (after the end of study), after receiving an 
unblinding request from the Teva statistician, the service 
provider will provide the unblinded IMP assignment according 
to the processes defined in the relevant Standard Operating 
Procedure (SOP).
3.6.2.
Blinding and Unblinding
In case of a serious adverse event, pregnancy, or in cases when 
knowledge of the IMP assignment is needed to make treatment 
decisions, the investigator may unblind the patient’s IMP 
assignment as deemed necessary, mainly in emergency 
3.6.Maintenance of Randomization and 
Blinding
3.6.1.
Maintenance of Randomization
Patient randomization codes will be maintained 
in a secure location at the service provider 
contracted to generate the codes. At the time of 
analysis (after the end of study), after receiving 
an unblinding request from the Teva 
statistician, the service provider will provide 
the unblinded IMP assignment according to the 
processes defined in the relevant Standard 
Operating Procedure (SOP).
3.6.2.
Blinding and Unblinding
In case of a serious adverse event, pregnancy, 
Added standard language 
related to blinding and 
randomization maintenance 
procedures.


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situations. The patient’s randomized treatment will be made 
available Individual randomization codes, indicating the IMP 
assignment for each randomized patient, will be available to the 
investigator(s) or pharmacist(s) at the investigational center via 
the IRT system. Randomization and Trial Supply Management, 
both via telephone and internet. If possible, the medical monitor
sponsor should be notified of the event before breaking of the 
code. If this is not possible, the medical monitor sponsor should 
be notified immediately afterward, and the patient’s randomized 
treatment IMP assignment should not be communicated to the 
medical monitor given. Breaking of the randomization code can 
always be performed by the investigational center without prior 
approval by the medical monitor sponsor.
When a blind is broken, the patient will be withdrawn from the 
study, and the event will be recorded on the case report form 
(CRF). The circumstances leading to the breaking of the code 
should be fully documented in the investigator’s study files and 
in the patient’s source documentation. Assignment of IMP 
should not be recorded in any study documents or source 
document.
In studies with blinding, for an adverse event defined as a 
suspected unexpected serious adverse reaction (SUSAR) (ie, 
reasonable possibility; see Section 7.1.4), Global Patient Safety 
and Pharmacovigilance may independently request that the blind 
code be broken (on a case-by-case basis) to comply with 
regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, 
blinding will be maintained for the investigator and for other 
personnel involved in the conduct of the study and analysis and 
reporting of the data.
or in cases when knowledge of the IMP
assignment is needed to make treatment 
decisions, the investigator may unblind the 
patient’s IMP assignment as deemed necessary, 
mainly in emergency situations. The patient’s 
randomized treatment will be made available to 
the investigator(s) via the IRT system. If 
possible, the medical monitor should be 
notified of the event before breaking of the 
code. If this is not possible, the medical monitor
should be notified immediately afterward, and 
the patient’s randomized treatment should not 
be communicated to the medical monitor.
Breaking of the randomization code can always 
be performed by the investigational center 
without prior approval by the medical monitor.
When a blind is broken, the patient will be 
withdrawn from the study, and the event will be 
recorded on the case report form (CRF). The 
circumstances leading to the breaking of the 
code should be fully documented in the 
investigator’s study files and in the patient’s 
source documentation. Assignment of IMP 
should not be recorded in any study documents 
or source document.
In studies with blinding, for an adverse event 
defined as a suspected unexpected serious 
adverse reaction (SUSAR) (ie, reasonable 
possibility; see Section 7.1.4), Global Patient 
Safety and Pharmacovigilance may 
independently request that the blind code be 
broken (on a case-by-case basis) to comply 
with regulatory requirements. The report will 


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be provided in an unblinded manner for 
regulatory submission. If this occurs, blinding 
will be maintained for the investigator and for 
other personnel involved in the conduct of the 
study and analysis and reporting of the data.


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3.7 Independent Data Monitoring Committee (IDMC) (also affects Section 7.12)
3.7.Independent Data Monitoring Committee (IDMC)
During the conduct of this study, an IDMC will review 
accumulating safety data on a regular basis to ensure the 
continuing safety of the study patients and to review any study 
conduct issues.
The IDMC will be composed of independent physicians with 
expertise in the relevant therapeutic field and other relevant 
experts, such as a statistician. The IDMC will receive safety data 
periodically, which will be presented by masked treatment 
groups. They will have the right to recommend modification of 
the study for safety reasons. 
IDMC sessions can be open or closed. During open sessions, 
representatives of the sponsor and development partner may be 
present, and information is provided and discussed in a blinded 
manner. During closed sessions, the only participants are 
members of the IDMC and the designated unblinded statistician 
(if approved to be present). 
If there is a request to unblind any individual treatment 
assignment, a written request from the IDMC (as a committee), 
signed by the IDMC chairperson, should be made to the 
unblinded statistician. The appropriate medical and operational 
personnel will be notified but will not receive the unblinded 
treatment information. Any use of unblinded treatment 
assignments should be clearly documented and reported to the 
sponsor at study termination.
The IDMC chairperson will communicate with Nuvelution TS 
Pharma in regard to issues resulting from the conduct and 
clinical aspects of the study. Nuvelution TS Pharma and INC 
Research will work closely with the committee to provide the 
necessary data for review.
3.7.Independent Data Monitoring Committee
During the conduct of this study, an IDMC will 
review accumulating safety data on a regular 
basis to ensure the continuing safety of the 
study patients and to review any study conduct 
issues.
The IDMC will be composed of independent 
physicians with expertise in the relevant 
therapeutic field and other relevant experts, 
such as a statistician. The IDMC will receive 
safety data periodically, which will be 
presented by masked treatment groups. They 
will have the right to recommend modification 
of the study for safety reasons. 
IDMC sessions can be open or closed. During 
open sessions, representatives of the sponsor 
and development partner may be present, and 
information is provided and discussed in a 
blinded manner. During closed sessions, the 
only participants are members of the IDMC and 
the designated unblinded statistician (if 
approved to be present). 
If there is a request to unblind any individual 
treatment assignment, a written request from 
the IDMC (as a committee), signed by the 
IDMC chairperson, should be made to the 
unblinded statistician. The appropriate medical 
and operational personnel will be notified but 
will not receive the unblinded treatment 
information. Any use of unblinded treatment 
assignments should be clearly documented and 
Added IDMC to the study 
and associated IDMC 
language to the protocol.


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The conduct and specific details regarding the IDMC sessions 
and requests to unblind any blinded treatment assignment are 
outlined in the IDMC charter.
reported to the sponsor at study termination.
The IDMC chairperson will communicate with 
Nuvelution TS Pharma in regard to issues 
resulting from the conduct and clinical aspects 
of the study. Nuvelution TS Pharma and INC 
Research will work closely with the committee 
to provide the necessary data for review.
The conduct and specific details regarding the 
IDMC sessions and requests to unblind any 
blinded treatment assignment are outlined in the 
IDMC charter.
3.8 IMP and Placebo Used in the Study (also affects Sections 1.2, 5.1, and Synopsis)
3.8 Drugs Investigational Medicinal Product and Placebo
Used in the Study 
During the open-label period, TEV-50717 tablets are available in 
the following dose strengths: 6, 9, and 12 mg.
[…]
During the randomized drug withdrawal and re-titration period, 
TEV-50717 tablets are available in the following dose strengths: 
6, 9, 12, 15, and 18 mg, all of which are identical in size, shape, 
and color (white). The IMP will be supplied in 20-count bottles.
Patients who receive TEV-50717 during the randomized drug 
withdrawal period will remain on their maintenance dose of 
blinded active IMP from the start of week 3031 to the start of
week 34; those assigned to placebo during the randomized drug 
withdrawal period will undergo blinded re-titration from the start 
of week 3031 to the start of week 34 back to their previously 
established maintenance dose from the end of week 28. Note 
that, because IMP is dispensed for 2 week periods, patients will 
use blinded bottles through the end of week 34; however, all 
patients will be known to be on active treatment at the start of 
3.8 Investigational Medicinal Product and 
Placebo Used in the Study 
During the open-label period, TEV-50717 
tablets are available in the following dose 
strengths: 6, 9, and 12 mg. 
[…]
During the randomized drug withdrawal and re 
titration period, TEV-50717 tablets are 
available in the following dose strengths: 6, 9, 
12, 15, and 18 mg, all of which are identical in 
size, shape, and color (white). The IMP will be 
supplied in 20-count bottles.
Patients who receive TEV-50717 during the 
randomized drug withdrawal period will remain 
on their maintenance dose of blinded active 
IMP from the start of week 31 to the start of 
week 34; those assigned to placebo during the 
randomized drug withdrawal period will 
undergo blinded re-titration from the start of 
Clarified which dose 
strengths are available 
during which study periods.
Clarified terminology and 
timing related to the 
blinded, randomized drug 
withdrawal period and 
titration post-drug 
withdrawal period (Part B; 
see also changes listed for 
Section 3.1.6 above). Note 
that the order of 
2 paragraphs was also 
changed (not shown).


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week 34.
week 31 to the start of week 34 back to their 
previously established maintenance dose from 
the end of week 28. Note that, because IMP is 
dispensed for 2 week periods, patients will use 
blinded bottles through the end of week 34; 
however, all patients will be known to be on 
active treatment at the start of week 34.
Section 3.9.2. Drug Accountability
Empty, partially used, and unused IMP will be disposed of
returned to the sponsor or its designee, as agreed with the 
sponsor/development partner.
Empty, partially used, and unused IMP will be 
disposed of, as agreed with the 
sponsor/development partner.
Clarified responsibilities 
related to drug disposal.
Section 3.10 Duration of Patient Participation and Justification (also affects Section 3.1 and Synopsis)
For patients rolling over from Study SD-809-C-17, this study 
will consist of up to a 4-week screening period (up to 31 days) 
and up to 5452 weeks of treatment. All participating patients are 
expected to participate in this study for its entire duration, which 
is a minimum of 56 weeks (for those rolling over from Study 
SD-809-C-17, this can be up to 60 weeks). Patients will have a 
follow-up telephone contact to evaluate safety 1 week after the 
end of the washout period (2 weeks after their last dose of IMP).
Patients are expected to participate in this study for its entire 
duration, which is a minimum of 56 weeks. See Section 12.4 for 
the definition of the end of the study.
For patients rolling over from Study SD-809-C-
17, this study will consist of a 4-week screening 
period (up to 31 days) and up to 54 weeks of 
treatment. All participating patients are 
expected to participate in this study for its 
entire duration, which is a minimum of 56 
weeks (for those rolling over from Study 
SD-809-C-17, this can be up to 60 weeks).
Patients will have a follow-up telephone contact 
to evaluate safety 1 week after the end of the 
washout period (2 weeks after their last dose of 
IMP). 
See Section 12.4 for the definition of the end of 
the study.
Corrected maximum 
treatment period (reflecting 
patients not randomized to 
placebo during Part B) and 
clarified what aspects of the 
duration apply to patients 
from all 3 parent studies.
3.13 Study Procedures and Assessments
Not applicable
Table 1 was updated to add/remove 
assessments, to adjust the timing of some 
assessments, and to update language. All 
In addition to changes made 
to align with the protocol 
text, the shading in the table 


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Reason/Justification for 
change
changes were made in alignment with the 
changes made throughout the protocol.
was corrected as needed.
3.13.1 Procedures for Screening and Enrollment (Visit 1) (also affects Sections 3.1, 3.1.1, 3.3, 4.1, 12.1, and Synopsis)
Written iInformed consent (and written /assent and/or co consent 
for patients 14 years of , depending on the child’s age and older, 
as appropriate), will be obtained; for before any study 
procedures are performed. For patients enrolled rolling over
from Study TV50717-CNS-30046 or Study TV50717-
CNS-30060, informed consent/assent and/or co consent for 
patients 14 years of age and older, as appropriate, may be 
obtained prior to the day 1 visit, up to 4 weeks in advance of 
open-label study participation.
For patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, screening data will be obtained 
from the parent study (see Table 1). Written informed consent/
(and written assent and/or co consent for patients 14 years of age 
and older, as appropriate,) must be given before any procedures 
related solely to Study TV50717-CNS-30047 are performed.
[…]
A signed and dated informed consent form will be obtained from 
each parent/legally acceptable representative, and a signed and 
dated assent and/or co consent form for patients 14 years of age 
and older, depending on the child’s age, as appropriate will be 
obtained from each patient before any screening procedures 
commence, according to national laws and local IEC/IRB 
requirements.
[…]
(Note: Details of rescreening must be approved by the medical 
monitor.)
[…]
Informed consent/assent, depending on the 
child’s age, as appropriate, will be obtained 
before any study procedures are performed. For 
patients rolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-0060, 
informed consent/assent, as appropriate, may be 
obtained prior to the day 1 visit, up to 4 weeks 
in advance of open-label study participation.
For patients rolling over from Study TV50717-
CNS-30046 or Study TV50717-CNS-30060, 
screening data will be obtained from the parent 
study (see Table 1). Informed consent/assent, as 
appropriate, must be given before any 
procedures related solely to Study TV50717-
CNS-30047 are performed.
[…]
A signed and dated informed consent form will 
be obtained from each parent/legally acceptable 
representative, and a signed and dated assent, 
depending on the child’s age, as appropriate 
will be obtained from each patient before any 
screening procedures commence, according to 
national laws and local IEC/IRB requirements.
[…]
(Note: Details of rescreening must be approved 
by the medical monitor.)
[…]
•
obtain written informed consent (and 
Informed consent/assent 
language was updated for 
global alignment and 
applicability to all countries.
Clarification and 
consistency edit was made 
regarding rescreening.


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New wording
Reason/Justification for 
change
•
obtain written informed consent (and written assent, 
depending on the child’s age and/or co consent for patients 14 
years of age and older, as appropriate) before any other study 
related procedures are performed
assent, depending on the child’s age, as 
appropriate) before any other study related 
procedures are performed
Section 3.13 Study Procedures and Assessments (global for Sections 3.13.2 and 3.13.3)
dispense IMP (sufficient doses for 2 weeks [current dose 
level and next dose level]) and patient diary
dispense IMP (sufficient doses for 2 weeks 
[current dose level and next dose level]) and 
patient diary
Clarified that patient diary is 
dispensed each time IMP is 
dispensed.
Section 3.13.2. Procedures Before Investigational Medicinal Product Treatment (Day 1)
•
perform clinical laboratory tests, including serum 
chemistry, hematology, and urine analyses (required for all 
patients)
•
perform clinical laboratory tests, including 
serum chemistry, hematology, and urine 
analyses
Removed unnecessary 
detail.
Section 3.13.3.2.1 In-Clinic Visits (Weeks 8, 15, 30, 32, 34, 41, and 54/ET) (also affects Section 4.4 and Synopsis)
3.13.3.2.1 In-Clinic Visits (Weeks 8, 15, 30, 32, 34, 41, and 
54/Early Termination Visit)
The following procedures/assessments will be performed at 
weeks 8, 15, 30, 32, 34, 41, and 54/ET:
•
measure vital signs (pulse, BP, body temperature, and 
respiratory rate); at weekweeks 8 and 54, orthostatic BP and 
pulse should be measured after the patient is in a standing 
position for at least 3 minutes
•
up to 2 blood samples separated by 2 hours or more should 
be collected, if possible, for patients discontinuing for 
insufficient efficacy (early termination)
•
perform UDS at week 54
3.13.3.2.1 In-Clinic Visits (Weeks 8, 15, 30, 
32, 34, 41, and 54/Early Termination Visit)
The following procedures/assessments will be 
performed at weeks 8, 15, 30, 32, 34, 41, and 
54/ET:
•
measure vital signs (pulse, BP, body 
temperature, and respiratory rate); at weeks 8 
and 54, orthostatic BP and pulse should be 
measured after the patient is in a standing 
position for at least 3 minutes
Clarification that ET 
procedures match those at 
week 54.
Corrected timing description 
for orthostatic BP and pulse 
assessment.
Removed pharmacokinetic 
samples (see also changes 
listed for Section 3.5.)
Removed end of treatment 
drug screen assessment.


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Reason/Justification for 
change
Section 3.13.3.3.2. In-clinic Visit (Weeks 30 and 32):
•
collect IMP/dispense IMP (sufficient doses to cover 
treatment until the following in-clinic visit) and patient diary
•
collect used and unused IMP bottles
•
dispense IMP (sufficient doses to cover 
treatment until the following in-clinic visit) and 
patient diary
•
collect used and unused IMP bottles.
Clarification
Section 4.1.Patient Inclusion Criteria (also affects the Synopsis)
i.
Females who are postmenarchal or ≥12 years of age 
whose male partners are potentially fertile (ie, no vasectomy) 
must use highly effective birth control methods for the duration 
of the study (ie, starting at screening) and for 30 days or 5 drug 
half lives, whichever is longer after last dose of IMP. Further 
details are included in Appendix L.
i.
Females who are postmenarchal or ≥12 
years of age whose male partners are 
potentially fertile (ie, no vasectomy) must use 
highly effective birth control methods for the 
duration of the study (ie, starting at screening) 
and for 30 days after last dose of IMP. Further 
details are included in Appendix L.
Removed unnecessary 
detail.
Section 4.2 Patient Exclusion Criteria
l.
Patient has received treatment with deep brain stimulation, 
transmagnetic stimulation, or transcranial direct current 
stimulation for reduction of tics within 4 weeks of the screening 
visit.
Not applicable
Removed criterion that is
not applicable for this study 
population.
Section 4.4 Withdrawal Criteria and Procedures (also affects Sections 7.1.7, 7.7, 9.7.2, and Synopsis)
If a post-day 1 QTcF value >500 msec or change from baseline 
(Study TV50717-CNS-30046 or Study TV50717-CNS-30060) or 
day 1 (Study SD-809-C-17), as appropriate (see Section 9.7.2) 
>60 msec is found, the investigator should repeat the ECG 
assessment twice and compare the average of the 2 pre-treatment 
QTcF values (ie, the parent study baseline and screening values 
for patients rolling over from Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060 or the day 1 and screening values 
from the current study for patient[s] who completed Study 
If a post-day 1 QTcF value >500 msec or 
change from baseline (Study TV50717-CNS-
30046 or Study TV50717-CNS-30060) or day 1
(Study SD-809-C-17), as appropriate (see 
Section 9.7.2) >60 msec is found, the 
investigator should repeat the ECG assessment 
twice and compare the average of the 2 pre-
treatment QTcF values (ie, the parent study 
baseline and screening values for patients 
Clarified baseline and 
pre-treatment calculations 
for ECG-based withdrawals 
depending on parent study 
(see also changes listed for 
Section 2.3.1 above).


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Reason/Justification for 
change
SD-809-C-17) to the average of the 3 post-day 1 QTcF values. 
The IMP must be stopped for any confirmed post-day 1 QTcF 
value >500 msec or increase from day 1 baseline (Study 
TV50717-CNS-30046 or Study TV50717-CNS-30060) or day 1 
(Study SD-809-C-17) >60 msec. 
rolling over from Study TV50717-CNS-30046 
or Study TV50717-CNS-30060 or the day 1 
and screening values from the current study for 
patient[s] who completed Study SD-809-C-17) 
to the average of the 3 post-day 1 QTcF values. 
The IMP must be stopped for any confirmed 
post-day 1 QTcF value >500 msec or increase 
from baseline (Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060) or day 1 
(Study SD-809-C-17) >60 msec.
Section 5.1 Investigational Medicinal Products Administered During the Study (also affects the Synopsis)
Although dose adjustments can be made up to and including the 
week 7 telephone call, if a stable dose is reached before then, the 
patient should continue taking that dose for the remainder of the 
titration period. and throughout maintenance dosing. If a patient 
experiences a “clinically significant” adverse event that is 
attributed to the IMP, the investigator will determine if a dose 
reduction or suspension is necessary. At the end of the titration 
period, the patient’s dose will be established for the maintenance 
period. If a patient experiences an adverse event during the 
maintenance period and the investigator believes a dose 
reduction is warranted, the dose may be reduced. Dose 
adjustments of TEV-50717 (upward or downward) may be made 
during the maintenance period, if necessary, but not more often 
than every 5 days and only in increments of 6 mg. During the 
maintenance period, if a patient’s weight shifts into a new 
category (see Table 2), and the investigator believes the patient 
is no longer at an optimal dose, the investigator may change the 
dose level.
IMP will be dispensed in the clinic. Patients should take their 
first dose in the evening on day 1 after their day 1 clinic visit.
Patients will receive sufficient doses to last until the next visit.
Although dose adjustments can be made up to 
and including the week 7 telephone call, if a 
stable dose is reached before then, the patient 
should continue taking that dose for the 
remainder of the titration period. If a patient 
experiences a “clinically significant” adverse 
event that is attributed to the IMP, the 
investigator will determine if a dose reduction 
or suspension is necessary. At the end of the 
titration period, the patient’s dose will be 
established for the maintenance period. If a 
patient experiences an adverse event during the 
maintenance period and the investigator 
believes a dose reduction is warranted, the dose 
may be reduced. Dose adjustments of TEV-
50717 (upward or downward) may be made 
during the maintenance period, if necessary, but 
not more often than every 5 days and only in 
increments of 6 mg.
IMP will be dispensed in the clinic. Patients 
should take their first dose in the evening on 
day 1 after their day 1 clinic visit. Patients will 
Updated language regarding 
dose administration, 
including dose adjustments.


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Reason/Justification for 
change
[...]
•
The starting dose is 6 mg in all patients. This dose will be 
administered in the evening on days 1 and 2, followed by AM 
administration for the remainder of week 1 (if body weight is 
<40 kg). Daily doses of 12 mg and higher will be administered 
twice daily in 2 divided doses, approximately 8 to 10 hours apart 
during the day (those on the 6-mg dose will have once-daily 
dosing). A minimum of 6 hours should elapse between doses. If 
a patient misses a dose, and it is within 6 hours of their next 
dose, the missed dose should be skipped. If patients experience 
insomnia while taking the initial 6 mg dose in the evening, they 
may switch to taking it as a morning dose on day 2.
[...]
•
Following re-titration, the dose of IMP should be kept stable,
if possible, but changes can be made as described for Part A.
receive sufficient doses to last until the next 
visit.
[...]
•
The starting dose is 6 mg in all patients. 
Daily doses will be administered twice daily, 
approximately 8 to 10 hours apart during the 
day (those on the 6-mg dose will have 
once-daily dosing). A minimum of 6 hours 
should elapse between doses. If a patient misses 
a dose and it is within 6 hours of their next 
dose, the missed dose should be skipped.
[...]
•
Following re-titration, the dose of IMP 
should be kept stable, if possible, but changes 
can be made as described for Part A.
Table 3: Daily Dose of IMP by Day 1 Body Weight Category, 
CYP2D6 Impairment,Previously Established Maintenance 
Dose and Study Week (Re tTitration Post-Drug Withdrawal) 
for Patients Randomized to Placebo During the Blinded, 
Randomized Drug Withdrawal Period
[Formerly content was the same as for Table 2.]
Table 3: Daily Dose of IMP by Previously 
Established Maintenance Dose and 
Study Week (Titration Post-Drug 
Withdrawal) for Patients Randomized to 
Placebo During the Blinded, Randomized 
Drug Withdrawal Period
Daily dose (mg) at the start 
of week
Updated title and content of 
Table 3 to reflect change in 
re-titration regimen.


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Original text with changes shown
New wording
Reason/Justification for 
change
Previously 
established 
maintenan
ce dose
a
(mg)
Day 
211 
(star
t of 
wee
k 31
)
Day 
218 
(star
t of 
wee
k 32
)
Day 
225 
(star
t of 
wee
k 33
)
Day 
232 
(start 
of 
week 3
4) 
mainte
nance 
dose
6
6
6
6
6
12
12
12
12
12
18
12
18
18
18
24
12
18
24
24
30
12
18
24
30
36
12
24
30
36
42
12
24
36
42
48
12
24
36
48
a The previously established maintenance dose is the 
dose administered at the end of Part A (Day 196 
[end of week 28]). The blinded, randomized drug 
withdrawal period will occur from the start of 
week 29 through the end of week 30.
IMP=investigational medicinal product.


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Original text with changes shown
New wording
Reason/Justification for 
change
Section 5.3 Prior and Concomitant Medication or Treatment
Any prior or concomitant therapy, medication, or procedure a 
patient receives during has had within 3 months before IMP 
administration and up to the end of the study period, including 
follow-up, will be recorded on the CRF. Generic or trade name, 
indication, and dosage will be recorded. In addition, only for 
patients who completed Study SD-809-C-17, any prior or 
concomitant therapy, medication, or procedure a patient has had 
within 3 months before IMP administration will be recorded on 
the CRF.
Any prior or concomitant therapy, medication, 
or procedure a patient receives during IMP 
administration and up to the end of the study 
period, including follow-up, will be recorded on 
the CRF. Generic or trade name, indication, and 
dosage will be recorded. In addition, only for 
patients who completed Study SD-809-C-17, 
any prior or concomitant therapy, medication, 
or procedure a patient has had within 3 months 
before IMP administration will be recorded on 
the CRF.
Removed duplicated 
prior/concomitant 
medication collection for 
patients rolling over from 
Study TV50717-
CNS-30046 or 
Study TV50717-
CNS-30060.
Section 5.5 Dose Reduction and Temporary Investigational Medicinal Product Discontinuation
Suspension of study medication for up to 1 week, if warranted 
for patient safety, is allowed.
Suspension of study medication for up to 
1 week, if warranted for patient safety, is 
allowed.
Clarified dose suspension 
criteria.
Section 5.6 Total Blood Volume
The total volume of blood to be collected for each patient in this 
study is approximately 3020 to 6040 mL, as detailed in Table 4.
[Table 4 footnotes]
a
For patients who completed Study TV50717-CNS-30046 or 
Study TV50717-CNS-30060, 30 to 40 mL will be collected.
b
For patients who completed Study SD-809-C-17, 50 to 
60 mL will be collected.
The total volume of blood to be collected for 
each patient in this study is approximately 30 to 
60 mL, as detailed in Table 4.
[Table 4 footnotes]
a
For patients who completed Study 
TV50717-CNS-30046 or Study TV50717-
CNS-30060, 30 to 40 mL will be collected.
b
For patients who completed 
Study SD-809-C-17, 50 to 60 mL will be 
collected.
Clarified how blood volume 
collection is dependent on 
parent study.
Section 6.1.2 Tourette Syndrome-Patient Global Impression of Impact
The TS-PGII is administered on day 1 (ie, week 13 data from 
The TS-PGII is administered on day 1 (ie, 
Aligned to match other 


Uncontrolled Study–Tourette Syndrome
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Original text with changes shown
New wording
Reason/Justification for 
change
Study TV50717-CNS-30046 or week 9 data from Study 
TV50717-CNS-30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 
55. Input from the caregiver/adultparent/legal guardian is 
permittedrequired.
week 13 data from Study TV50717-CNS-30046 
or week 9 data from Study TV50717-CNS-
30060) and weeks 4, 8, 15, 28, 34, 41, 54, and 
55. Input from the caregiver/adult is permitted.
assessments.
Section 6.1.3 Tourette Syndrome Patient Global Impression of Severity
The TS-PGIS uses a 5-point scale, ranging from no tics (1) to 
very severe tics (5), to assess overall response to therapy.
The TS-PGIS uses a 5-point scale, ranging from 
no tics (1) to very severe tics (5), to assess 
overall response to therapy.
Corrected scale description.
Section 7.5.2.2. Urine Drug Screen
A UDS will be performed at the time points specified in Table 1. 
The UDS detects the presence of drugs prohibited according to 
the laboratory manual. If a given parameter cannot be tested 
using urine, an alternative matrix (eg, serum) may be considered 
acceptable. The sponsor’s medical expert must be made aware in 
advance of, and provide approval for, drug screen parameters to 
which this will apply.
A positive result for any of the specified drugs or their 
metabolites, without medical explanation, will preclude the 
patient from enrollment or continued participation in the study.
A UDS will be performed at the time points 
specified in Table 1. A positive result for any of 
the specified drugs or their metabolites, without 
medical explanation, will preclude the patient 
from enrollment or continued participation in 
the study.
Removed unnecessary 
detail.
Section 9.2.1 Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all enrolled 
patients, regardless of whether or not a patient took any IMP. 
Enrolled subjects who are not randomized will be summarized 
separately as “Not randomized,” and randomized subjects will be 
analyzed based on their randomized treatment.
The intent-to-treat (ITT) analysis set will 
include all enrolled patients, regardless of 
whether or not a patient took any IMP. Enrolled 
subjects who are not randomized will be 
summarized separately as “Not randomized,” 
and randomized subjects will be analyzed based 
on their randomized treatment. 
Clarified and updated
analysis presentation.
Section 9.2.5 Randomized Withdrawal Modified Intent-to-Treat Population
The Randomized Withdrawal Modified Intent-to-Treat (mITT 
The Randomized Withdrawal Modified Intent-
Corrected score from AIMS 


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Original text with changes shown
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Reason/Justification for 
change
(RWmITT) Population will include all patientssubjects enrolled 
in the randomized drug withdrawal period who receive study 
drug and have a YGTSS TTScentrally read AIMS score at both 
the randomized drug withdrawal (week 28)period initial visit and 
the week 30 visit. All eEfficacy measures in the randomized 
drug withdrawal period will be analyzed using the (RWmITT)as 
described in Section 9.5.3.1.
to-Treat (RWmITT) Population will include all 
patients enrolled in the randomized drug 
withdrawal period who receive study drug and 
have a YGTSS TTS at both the randomized 
drug withdrawal (week 28) visit and the 
week 30 visit. Efficacy measures in the 
randomized drug withdrawal period will be 
analyzed as described in Section 9.5.3.1.
to YGTSS TTS and made 
editorial clarifications.
Section 9.2.6 Responder Randomized Withdrawal Modified Intent-to-Treat Population (also affects Sections 9.4 and 9.5.3.1)
Section 9.2.6.
Responder Randomized Withdrawal Modified 
Intent-to-Treat Population
The Responder Randomized Withdrawal mITT (RRWmITT) 
Population will include all patients enrolled in the randomized 
drug withdrawal period who receive study drug and have a 
YGTSS TTS at both the week 28 visit and the week 30 visit and 
a ≥25% reduction in the TTS from baseline in the parent 
protocol to week 28. Efficacy measures in the randomized drug 
withdrawal period will be analyzed as described in 
Section 9.5.3.1.
Section 9.2.6.
Responder Randomized 
Withdrawal Modified Intent-to-Treat 
Population
The Responder Randomized Withdrawal mITT 
(RRWmITT) Population will include all 
patients enrolled in the randomized drug 
withdrawal period who receive study drug and 
have a YGTSS TTS at both the week 28 visit 
and the week 30 visit and a ≥25% reduction in 
the TTS from baseline in the parent protocol to 
week 28. Efficacy measures in the randomized 
drug withdrawal period will be analyzed as 
described in Section 9.5.3.1.
Added another analysis 
population.
Section 9.5.3.1 Efficacy Analysis for the Blinded, Randomized Drug Withdrawal Portion (also affects the Synopsis)
Section 9.5.3.1 Efficacy Analysis for the Blinded, 
Randomized Drug Withdrawal Portion Study
For the randomized drug withdrawal portion of the study […] 
The primary analyses will be in the RRWmITT population; in 
addition, sensitivity testing will be done using the same analyses 
on the RWmITT population and a subpopulation of the 
RRWmITT who had a ≥35% reduction in the TTS from baseline 
in the parent protocol to week 28.
Section 9.5.3.1 Efficacy Analysis for the 
Blinded, Randomized Drug Withdrawal 
Portion
For the randomized drug withdrawal portion of 
the study […] The primary analyses will be in 
the RRWmITT population; in addition, 
sensitivity testing will be done using the same 
analyses on the RWmITT population and a 
Clarified use of a primary 
analysis and added 
sensitivity analyses due to 
addition of another analysis 
population (see also changes 
listed for Sections 9.2.5 and 
9.2.6 above).


Uncontrolled Study–Tourette Syndrome
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Original text with changes shown
New wording
Reason/Justification for 
change
subpopulation of the RRWmITT who had a 
≥35% reduction in the TTS from baseline in the 
parent protocol to week 28.


Uncontrolled Study–Tourette Syndrome
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237
17.4.
Amendment 04 Dated 22 May 2019
The primary reasons for this amendment are to address Regulatory Authority requirements; update the anticipated enrollment numbers 
to account for the increased sample size of Study TV50717-CNS-30046; include language on the addition of an interim analysis;
include additional nonclinical data observed in rat toxicology studies; further clarify procedures to be carried out during the screening 
and enrollment periods (eg, informed consent/assent stipulations); update requirements on drug storage, accountability, and security; 
update/clarify patient inclusion criteria, exclusion criteria, and withdrawal criteria; provide updates on allowed and prohibited 
medications; and include additional guidance for evaluation and management of suicidal ideation, suicidal behavior, and depression.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.


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Original text with changes shown
New wording
Reason/Justification for
change
Global
Update to CRO’s name
Part A
•
vital signs, height, and weight: screening (only for patients 
who completed Study SD 809 C 17; data from Study 
TV50717-CNS 30046 or Study TV50717-CNS 30060 should 
be used for the remaining patients); day 1; and weeks 2, 4, 6, 8, 
15, 34, 41, 54, and 55
Part B
•
vital signs, height, and weight: weeks 28, 30, and 32
•
vital signs, height, and weight: screening (only 
for patients who completed Study SD 809 C 17; data 
from Study TV50717-CNS 30046 or Study 
TV50717-CNS 30060 should be used for the 
remaining patients); day 1; and weeks 2, 4, 6, 8, 15, 
34, 41, 54, and 55
Part B
•
vital signs, height, and weight: weeks 28, 30, and 
32
Height has been added as an 
assessment to be performed at 
every in clinic visit in Part A 
and Part B. The Schedule of 
Procedures and Assessments 
has been updated accordingly.
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current Confidentiality 
Statement template text
Clinical Laboratory and Other Departments and Institutions
Legal Representative of the Sponsor in the EU
Syneos Health Netherlands B.V.
For protocol issues, contact the study leader listed below:
 
Legal Representative of the Sponsor in the EU
Syneos Health Netherlands B.V.
For protocol issues, contact the study leader listed 
below:
Chief Medical Officer, Nuvelution TS Pharma, Inc.
Update to Sponsor 
representatives and points of 
contact


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Email:
Chief Medical Officer, Nuvelution TS Pharma, INC.
Tel: +
Email: 
For medical issues, contact the physicians listed below:
Tel: 
Email: 
For medical issues, contact the physicians listed 
below:
 
 
 


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 PhD
 
 
For operational issues, contact the Head of 
Operations listed below:
 
For serious adverse events
Send by email to the local safety officer (LSO)/
Syneos Health. The email address will be provided in 
the serious adverse event report form. In the event of 
difficulty transmitting the form, contact the sponsor’s 
study personnel identified above for further 
instruction.


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ResearchSyneos Health. The email address will be provided in 
the serious adverse event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel 
identified above for further instruction.
Central Clinical Laboratory
Q2 Solutions (Quest) LLC
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Electronic Data Capture
Medidata RAVE (throughINC ResearchSyneos Health, LLC)
Contract Research Organization; Safety and Efficacy Data 
Analysis
INC Research
3201 Beechleaf Court
Suite 600
Raleigh 27604 1547 Syneos Health, LLC
1030 Sync Street
Morrisville, NC 27560
USA
Central Clinical Laboratory
Q2 Solutions(Quest) LLC
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Electronic Data Capture
Medidata RAVE (through Syneos Health, LLC)
Contract Research Organization Safety and 
Efficacy Data Analysis
Syneos Health, LLC
1030 Sync Street
Morrisville, NC 27560
USA


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1.3.1.3 Toxicology
The no-observed-adverse-effect level (NOAEL) for toxicities 
in juvenile rats is lower than that in adults; however, the total 
(α+β)-HTBZ exposure multiples or safety margins comparing 
rat to humans at the adult and juvenile age categories are 
similar. The potential for increased sensitivity to the effects of 
TEV-50717 in pediatric patients is mitigated by 2 factors. First, 
the effects of TEV-50717 on behavior and weight gain 
recovered with cessation of test article administration in the 
juvenile rat toxicology study. Second, the clinical significance 
of tremors and reduced body weight gain in rats dosed with 
TEV-50717 are unclear because these findings were not 
adverse events of note in adults or adolescent patients. While 
hypoactivity in rats has the potential to relate to clinical 
observations of somnolence, this adverse effect is controlled 
with dose reduction. In clinical comparison, the adverse event 
profile of tetrabenazine in adult patients is qualitatively similar 
to patients from approximately 22 months to 18 years of age 
(Jain et al 2006, Kenney et al 2007, Porta et al 2008).
The no-observed-adverse-effect level (NOAEL) for 
toxicities in juvenile rats is lower than that in adults; 
however, the total (α+β)-HTBZ exposure multiples or 
safety margins comparing rat to humans at the adult 
and juvenile age categories are similar. The potential 
for increased sensitivity to the effects of TEV-50717 
in pediatric patients is mitigated by 2 factors. First, 
the effects of TEV-50717 on behavior and weight 
gain recovered with cessation of test article 
administration in the juvenile rat toxicology study. 
Second, the clinical significance of tremors and 
reduced body weight gain in rats dosed with TEV-
50717 are unclear because these findings were not 
adverse events of note in adults or adolescent 
patients. While hypoactivity in rats has the potential 
to relate to clinical observations of somnolence, this 
adverse effect is controlled with dose reduction. In 
clinical comparison, the adverse event profile of 
tetrabenazine in adult patients is qualitatively similar 
to patients from approximately 22 months to 18 years 
of age (Jain et al 2006, Kenney et al 2007, Porta et al 
2008).
Added no-observed-adverse-
effect level for toxicities
1.3.2 Clinical Studies (Other sections affected: Section 1.3.2.1 Clinical Pharmacology Studies)

67 completed Phase 1 studies in healthy adult 
volunteers

2 ongoing Phase 1 studies in healthy adult volunteers

1 ongoingcompleted Phase 3 long-term safety study in 
patients with HD

12 completed Phase 2/3 study in patients with TD 

1 completed Phase 3 study in patients with TD

7 completed Phase 1 studies in healthy adult 
volunteers

2 ongoing Phase 1 studies in healthy adult 
volunteers

1 completed Phase 3 long-term safety study 
in patients with HD

2 completed Phase 2/3 study in patients with 
The clinical development plan 
for TEV-50717 has been 
updated to reflect the most 
current program information


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
1 ongoing Phase 3 long-term safety studiesstudy in 
patients with TD

1 completed Phase 1b study in patients with TS 

2 ongoing Phase 2/3 and Phase 3 studies in patients 
with TS

1 ongoing Phase 3 long-term safety study in patients 
with TS
Further details may be found in the IB (including the IB 
supplement for TS).
TD 

1 ongoing Phase 3 long-term safety study in 
patients with TD

1 completed Phase 1b study in patients with 
TS 

2 ongoing Phase 2/3 and Phase 3 studies in 
patients with TS

1 ongoing Phase 3 long-term safety study in 
patients with TS
Further details may be found in the IB.
1.8 Location and Study Duration
This study is planned to be conducted globally (per Study 
SD-809-C-17, Study TV50717-CNS-30046, and 
Study TV50717-CNS-30060) at approximately 120 centers. It 
is expected to start in May 2018 and conclude in 
October 2020January 2021, with a duration of approximately 
30 32 months.
This study is planned to be conducted globally (per 
Study SD-809-C-17, Study TV50717-CNS-30046, 
and Study TV50717-CNS-30060) at approximately 
120 centers. It is expected to start in May 2018 and 
conclude in January 2021, with a duration of 
approximately 32 months.
Updated the expected timing 
and duration of the study
3.1 General Design and Study Schematic Diagram (other sections effected: Section 9.9 Planned Interim Analysis and Figure 1: Overall Study 
Schematic Diagram)
Up to approximately 212227 patients are planned to be 
enrolled (approximately 1 patient is estimated to enroll from 
the Phase 1b Study SD-809-C-17, up to approximately 8599
patients are estimated to enroll from the Phase 2/3 
Study TV50717-CNS-30046, and up to approximately 
126127 patients are estimated to enroll from the Phase 3 
Study TV50717-CNS-30060).
When approximately 100 patients have completed the 28-week 
clinic visit, an interim analysis, including data from day 1 and 
Up to approximately 227 patients are planned to be 
enrolled (approximately 1 patient is estimated to 
enroll from the Phase 1b Study SD-809-C-17, up to 
approximately 99 patients are estimated to enroll 
from the Phase 2/3 Study TV50717-CNS 30046, and 
up to approximately 127 patients are estimated to 
enroll from the Phase 3 Study TV50717-CNS 30060).
When approximately 100 patients have completed the 
28-week clinic visit, an interim analysis, including 
data from day 1 and up to week 28 visit only, will be 
Updated the study design to 
include updated enrollment 
numbers and to account for 
inclusion of an interim 
analysis once approximately 
100 patients have completed 
the 28-week clinic visit


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up to week 28 visit only, will be conducted to provide 
descriptive, long-term safety and efficacy data to be used in 
regulatory submissions. To maintain data integrity of 
Study TV50717-CNS-30047, only a limited number of 
personnel who do not have contact with the sites will have 
access to this interim data in preparation for the regulatory 
filing. As no decisions regarding conduct of the study will be 
made based on the descriptive interim analysis, no alpha will 
be spent.
conducted to provide descriptive, long-term safety 
and efficacy data to be used in regulatory 
submissions. To maintain data integrity of Study 
TV50717-CNS-30047, only a limited number of 
personnel who do not have contact with the sites will 
have access to this interim data in preparation for the 
regulatory filing. As no decisions regarding conduct 
of the study will be made based on the descriptive 
interim analysis, no alpha will be spent.
3.1.1 Screening Period (up to 31 days) (other sections affected: 3.13.1 Procedures for Screening and Enrollment [Visit 1] and 3.13.2 
Procedures Before Investigational Medicinal Product Treatment [Day 1])
Patients may be rescreened 1 time if there is a change in the 
patient’s medical background, a modification of study entry 
criteria, or other relevant change. (Note: Details of a patient’s 
rescreening must be approved and documented by the medical 
monitor). and/or Clinical Surveillance and Training [CST] 
team.)
Patients may be rescreened 1 time if there is a change 
in the patient’s medical background, a modification 
of study entry criteria, or other relevant change. 
(Note: Details of a patient’s rescreening must be 
approved and documented by the medical monitor 
and/or Clinical Surveillance and Training [CST] 
team.)
Updated guidance language 
pertaining to patient 
rescreening
3.1.3 Titration Period (7 Weeks)
If a patient experiences a “clinically significant”depression, 
suicidal ideation or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes with daily 
activity, or adverse event that is related to the IMP, the 
investigator will determine if a dose reduction or suspension is 
necessary.
If a patient experiences depression, suicidal ideation 
or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes 
with daily activity, or adverse event that is related to 
IMP, the investigator will determine if a dose 
reduction or suspension is necessary.
Updated guidance language 
pertaining to dose reductions 
and suspensions
3.6.1 Maintenance of Randomization
Patient randomization codes will be maintained in a secure 
location at the service provider contracted to generate the 
codes.within Syneos Health. At the time of analysis (after the 
end of study), after receiving an unblinding request from the 
Teva, when treatment codes are needed, the Syneos Health
statistician, assigned to the service providerstudy will provide 
themake a request to unblind and will receive the unblinded 
codes and unblinded IMP assignment according to the 
Patient randomization codes will be maintained in a 
secure location within Syneos Health. At the time of 
analysis, when treatment codes are needed, the 
Syneos Health statistician assigned to the study will 
make a request to unblind and will receive the 
unblinded codes and unblinded IMP assignment 
according to the processes defined in the relevant 
Standard Operating Procedure (SOP).
Updated language on the 
responsibilities and 
maintenance of randomization
Dosing information and dose 
reduction guidelines were 
clarified


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processes defined in the relevant Standard Operating Procedure 
(SOP).
3.6.2 Blinding and Unblinding
When a blind is broken, the patient will be withdrawn from the 
study, and the event will be recorded on the case report form 
(CRF). However, if a patient is unblinded by mistake, the 
investigator should discuss with the medical monitor whether 
or not the patient should be withdrawn.
When a blind is broken, the patient will be withdrawn 
from the study, and the event will be recorded on the 
case report form (CRF). However, if a patient is 
unblinded by mistake, the investigator should discuss 
with the medical monitor whether or not the patient 
should be withdrawn.
Updated guidance on how to 
handle the unblinding of 
patients by mistake
3.9.1 Drug Storage and Security
The IMP (TEV-50717) mustshould be stored protected from 
light, at a controlled room temperature, 1520°C to 3025°C 
(68°F to 77°F); however, storage between 15°C and 20°C 
(59°F to 86°F),68°F) is acceptable if there is no alternative. 
The IMP should be stored in a dry, securely locked, 
substantially constructed cabinet or enclosure, with access 
limited to authorized staff.
The IMP (TEV-50717) should be stored protected 
from light, at a controlled room temperature, 20°C to 
25°C (68°F to 77°F); however, storage between 15°C 
and 20°C (59°F to 68°F) is acceptable if there is no 
alternative. The IMP should be stored in a dry, 
securely locked, substantially constructed cabinet or 
enclosure, with access limited to authorized staff.
Updated the direction for the 
storage temperatures and 
proper handling of the study 
drug


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3.13.1 Procedures for Screening and Enrollment (Visit 1) (other sections affected: 3.13.3.1.2 In-Clinic Visits [Weeks 2, 4, and 6], 3.13.3.2.1 In-
Clinic Visits [Weeks 8, 15, 30, 32, 34, 41, and 54/Early Termination Visits], 3.13.3.3.1 In-Clinic Visit [Week 28], 3.13.3.3.2 In-clinic Visit 
[Weeks 30 and 32], 3.13.4.1 In-Clinic Visit [Week 55], and 3.13.5 Unscheduled Visits)
•
conduct clinic visit
•
conduct clinic visit
This addition was made 
strictly for clarity. Clinic visits 
were already occurring at the 
specified visits in which this 
verbiage was added. This 
bullet was added at each week 
in which a clinic visit takes 
place.
3.13.2 Procedures Before Investigational Medicinal Product Treatment (Day 1)
•
conduct clinic visit
•
measure vital signs (orthostatic pulse and BP [after 
standing for at least 3 minutes]), height, and weight
•
dispense IMP (sufficient doses for 2 weeks [current 
dose level and next dose level])] to cover the telephone 
contacts) and patient diary
•
conduct clinic visit
•
measure vital signs (orthostatic pulse and BP 
after standing for at least 3 minutes), height, and 
weight
•
dispense IMP (sufficient doses for 2 weeks 
[current dose level and next dose level] to cover 
the telephone contacts) and patient diary
Clinic visits were already 
occurring at the specified 
visits in which this verbiage of 
“conduct clinic visit” was 
added. This bullet was added 
at each week in which a clinic 
visit takes place.
Other minor additions were 
included for clarity and to
include height as a specific 
assessment at each in clinic 
visit.
4.1 Patient Inclusion Criteria 
i.
Females who are postmenarchal or ≥12 years of age whose 
male partners are potentially fertile (ie, no vasectomy) must use 
highly effective birth control methods for the duration of the 
study (ie, starting at screening) and for 30 days or 5 half-lives, 
whichever is longer after last dose of IMP. Further details are 
included in Appendix L.
i.
Females who are postmenarchal or ≥12 years of 
age whose male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth control 
methods for the duration of the study (ie, starting at 
screening) and for 30 days or 5 half-lives, whichever 
is longer after last dose of IMP. Further details are 
included in Appendix L
Updated criteria “i” to include 
additional duration criteria for 
the use of birth control 
methods.
4.2 Patient Exclusion Criteria (other sections affected: Appendix A Allowed and Disallowed Medications)
k. Patient has received any of the following concomitant 
k. Patient has received any of the following 
Added cannabidiol oil and 


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medications for tics within the following specified 
exclusionary windows of screening prior to dosing for 
washout:
within 4 weeks: cannabidiol oil and valbenazine
Note: Use of stimulant medications, including amphetamine, 
methylphenidate, and lisdexamfetamine, is allowed if primary 
use is for the treatment of ADHD and dosing has been stable 
for at least 2 weeks before screening. 
Note: Use of atomoxetine is allowed if the primary use is for 
the treatment of ADHD, dosing has been stable for at least 4 
weeks before screening.
Note: Use of guanfacine or clonidine is allowed regardless of 
indication (ie, if prescribed for tics or Tourette syndrome) if the 
dosing has been stable for at least 4 weeks before screening 
and no changes to dose or frequency are anticipated during the 
course of the study. 
concomitant medications for tics within the following 
specified exclusionary windows of screening prior to 
dosing for washout:
within 4 weeks: cannabidiol oil and 
valbenazine
Note: Use of stimulant medications, including 
amphetamine, methylphenidate, and 
lisdexamfetamine, is allowed if primary use is for the 
treatment of ADHD and dosing has been stable for at 
least 2 weeks before screening. 
Note: Use of atomoxetine is allowed if the primary 
use is for the treatment of ADHD, dosing has been 
stable for at least 4 weeks before screening.
Note: Use of guanfacine or clonidine is allowed 
regardless of indication (ie, if prescribed for tics or 
Tourette syndrome) if the dosing has been stable for 
at least 4 weeks before screening and no changes to 
dose or frequency are anticipated during the course of 
the study. 
valbenazine as concomitant 
medications
Included notes for various 
different concomitant 
medications and stipulations
4.4 Withdrawal Criteria and Procedures for the Patient
The investigator also has the right to withdraw a patient from 
the IMP in study if any of the event of following events occur:
a.
intercurrent illness 
b.
adverse events (any patient who experiences an adverse 
event may be withdrawn from the study or from study 
treatment at any time at the discretion of the investigator or 
sponsor as indicated in Section 7.1.7)
c.
pregnancy (see Section 7.3), or )
d.
other reasons concerning the health or well-being of the 
patient, or in the event of
The investigator also has the right to withdraw a 
patient from the study if any of the following events 
occur:
a.
intercurrent illness
b.
adverse events (any patient who experiences an 
adverse event may be withdrawn from the study or 
from study treatment at any time at the discretion of 
the investigator or sponsor as indicated in 
Section 7.1.7)
c.
pregnancy (see Section 7.3)
d.
other reasons concerning the health or well-being 
Updated format, procedures,
and withdrawal criteria due to 
adverse event


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e.
lack of cooperation. If a
f.
post-day 1baseline QTcF value >500 msec or change from 
baseline (Study TV50717 CNS 30046 or Study TV50717
CNS 30060) or day 1 (Study SD 809 C 17), as appropriate (see 
Section 9.7.2(>60 msec is found, the (as described in 
Section 7.1.7). The investigator should repeat the ECG 
assessment twice and compare the average of the 2 pre-
treatment QTcF values (baseline and screening) to the average 
of the 3 post-day 1baseline QTcF values. The IMP must be 
stopped for any confirmed post-baseline QTcF value 
>500 msec or increase from baseline (Study TV50717 CNS
30046 or Study TV50717 CNS 30060) or day 1 (Study SD 809 
C 17), as appropriate (see Section 9.7.2(>60 msec. In addition, 
a patient may be withdrawn from the IMP as described in 
Sections 3.11, 3.13.3.2.2, 5.4, and7.1.7.
g.
when a blind is broken due to safety concerns (see 
Section 3.6.2). If a patient is unblinded by mistake, the 
investigator should discuss with the medical monitor whether 
or not the patient should be withdrawn.
h.
if the investigator or the sponsor determines that the patient 
is not in compliance with the study protocol, the investigator 
and the sponsor should determine whether the patient should be 
withdrawn from the study (Section 5.4).
In addition, a patient may be withdrawn from the study as 
described in Sections 3.11, 3.6, 5.4, 7.1.7, and 3.13.
For patients who withdraw prematurely, an early termination 
visit should be conducted as soon as possible after the last dose 
of IMP. All patients who discontinue early will have a follow
up telephone contact for safety evaluation 2 weeks after their 
last dose of IMP; evaluations will be as described for the week 
54 visit.
All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after their last 
of the patient
e.
lack of cooperation
f. post-baseline QTcF value >500 msec or change 
from baseline >60 msec (as described in 
Section 7.1.7). The investigator should repeat the 
ECG assessment twice and compare the average of 
the 2 pre-treatment QTcF values (baseline and 
screening) to the average of the 3 post-baseline QTcF 
values. The IMP must be stopped for any confirmed 
post-baseline QTcF value >500 msec or increase 
from baseline >60 msec.
g.
when a blind is broken due to safety concerns 
(see Section 3.6.2). If a patient is unblinded by 
mistake, the investigator should discuss with the 
medical monitor whether or not the patient should be 
withdrawn.
h.
if the investigator or the sponsor determines that 
the patient is not in compliance with the study 
protocol, the investigator and the sponsor should 
determine whether the patient should be withdrawn 
from the study (Section 5.4).
In addition, a patient may be withdrawn from the 
study as described in Sections 3.11, 3.6, 5.4, 7.1.7, 
and 3.13.
All patients who discontinue early will have a follow-
up telephone contact for safety evaluation 2 weeks 
after their last dose of IMP (Section 3.13.4.2).


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dose of IMP (Section 3.13.4.2).
5.1.1 Drug Administration
If a patient experiences a “clinically significant”depression, 
suicidal ideation or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes with daily 
activity, or adverse event that is attributedrelated to the IMP, 
the investigator will determine if a dose reduction or 
suspension is necessary.
IMP will be administered as follows:
•
The total daily dose, as provided in Table 2, is divided into 
a twice daily administration.
•
… A dose cap for impaired metabolizers will bepatients is 
prespecified by the IRT and presented in Table 2.
If a patient experiences depression, suicidal ideation 
or behavior, anxiety, akathisia, parkinsonism, 
somnolence, any other adverse event that interferes 
with daily activity, or adverse event that is related to 
IMP, the investigator will determine if a dose 
reduction or suspension is necessary.
IMP will be administered as follows:
•
The total daily dose, as provided in Table 2, is 
divided into a twice daily administration.
•
… A dose cap for impaired patients is 
prespecified by the IRT and presented in Table 2.
This subsection was added to 
provide greater clarity as to 
what details this section of the 
protocol included.
Further details on 
determination of dose 
reduction or suspension were 
provided.
Additional IMP administration 
information was added for 
clarity
5.2 Restrictions
The additionuse of a strong CYP2D6 inhibitor isquinidine and 
terbinafine are prohibited (see Appendix A, Table 9).
The use of quinidine and terbinafine are prohibited 
(see Appendix A, Table 9).
Medication restrictions were 
updated
5.5 Dose Reduction and Temporary Investigational Medicinal Product Discontinuation
Dose Suspension
Suspensions of study medication for adverse events must be 
reviewed with the medical monitor before therapy is 
restarted. Similarly, suspensions for more than 7 days must 
be reviewed by the medical monitor to determine if there is 
adequate time for patients to be reiterated and complete 
study evaluationsIf a subject’s serum potassium or 
magnesium were tested and found to be below the lower limit 
of normal and clinically significantly, the laboratory test should 
be repeated at least once. If the abnormality in the repeated 
laboratory test is consistent with the prior laboratory test, the 
IMP must be suspended. The medical monitor must be 
contacted to determine the appropriate investigation and 
treatment. TEV-50717 may only be restarted once serum 
potassium or magnesium have normalized.
Dose Suspension
Suspensions of study medication for adverse 
events must be reviewed with the medical monitor 
before therapy is restarted. If a subject’s serum 
potassium or magnesium were tested and found to be 
below the lower limit of normal and clinically 
significantly, the laboratory test should be repeated at 
least once. If the abnormality in the repeated 
laboratory test is consistent with the prior laboratory 
test, the IMP must be suspended. The medical 
monitor must be contacted to determine the 
appropriate investigation and treatment. TEV-50717 
may only be restarted once serum potassium or 
magnesium have normalized.
Updated dose suspension text 
to provide further guidance to 
the investigators


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7.1.5.3.1 Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events 
that occur during the study, regardless of judged relationship to 
administration of the IMP, must be reported to the sponsor by 
the investigator according to the instructions provided on the 
serious adverse event form.
To satisfy regulatory requirements, all serious 
adverse events that occur during the study, regardless 
of judged relationship to administration of the IMP, 
must be reported by the investigator according to the 
instructions provided on the serious adverse event 
form.
Updated guidance for 
investigator reporting of 
adverse events
7.2.2 Columbia-Suicide Severity Rating Scale
The C-SSRS is administered through an interview by trained 
study personnel.
Suicidal ideation

Patients with a positive C-SSRS suicidal ideation score 
on either items 1 or 2 or a change on the CDI-2 Parent 
or Self-Report Profiles consistent with increasing 
depressive symptoms must be 1) discussed with the 
medical monitor, 2) re-evaluated within 2 to 3 days in 
a clinic visit, and 3) treated according to the 
investigator’s medical judgment. Consultation with a 
child and adolescent psychiatrist or licensed 
child/adolescent mental health provider is advised, 
followed by close ongoing monitoring.

If patients endorse or report a C-SSRS suicidal ideation 
level of 3, 4, or 5, subjects will be evaluated 
immediately by the study investigator and referred for 
psychiatric evaluation. The medical monitor will be 
immediately consulted. If it is determined by the 
investigator, after consultation with the medical 
monitor and the consulting psychiatrist, that exposure 
to the IMP may have contributed to this change in C-
SSRS and/or increased depressive symptoms, IMP will 
be immediately discontinued and the patient terminated 
from the study. In cases where it is determined that 
IMP did not contribute to changes in depression or 
The C-SSRS is administered through an interview by 
trained study personnel.
Suicidal ideation

Patients with a positive C-SSRS suicidal 
ideation score on either items 1 or 2 or a 
change on the CDI-2 Parent or Self-Report 
Profiles consistent with increasing depressive 
symptoms must be 1) discussed with the 
medical monitor, 2) re-evaluated within 2 to 
3 days in a clinic visit, and 3) treated 
according to the investigator’s medical 
judgment. Consultation with a child and 
adolescent psychiatrist or licensed 
child/adolescent mental health provider is 
advised, followed by close ongoing 
monitoring.

If patients endorse or report a C-SSRS 
suicidal ideation level of 3, 4, or 5, subjects 
will be evaluated immediately by the study 
investigator and referred for psychiatric 
evaluation. The medical monitor will be 
immediately consulted. If it is determined by 
the investigator, after consultation with the 
medical monitor and the consulting 
psychiatrist, that exposure to the IMP may 
Added guidance on how to 
handle suicidal ideation and 
suicidal behavior descriptions 
as identified by the C-SSRS


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suicidality, the investigator will consult with the 
medical monitor, the consulting psychiatrist, and/or 
sponsor to determine whether the patient should 
continue in the study.
Suicidal behavior

Actual attempt: 
If patients report any suicidal behavior that is an actual 
attempt as assessed in the C-SSRS, they will be 
evaluated immediately by the study investigator, 
referred for psychiatric evaluation, and terminated 
from the study.

Interrupted attempt, aborted attempt, or Preparatory 
Acts or Behavior: 
If patients report any suicidal behavior that is 
interrupted, aborted, or preparatory as assessed in the 
C-SSRS, they will be evaluated immediately by the 
study investigator and referred for psychiatric 
evaluation. In cases where it is determined in the 
psychiatric evaluation that IMP did not contribute to 
changes in suicidal behavior, the investigator will 
consult with the medical monitor, the consulting 
psychiatrist, and/or sponsor to determine whether the 
patient should continue in the study.
have contributed to this change in C-SSRS 
and/or increased depressive symptoms, IMP 
will be immediately discontinued and the 
patient terminated from the study. In cases 
where it is determined that IMP did not 
contribute to changes in depression or 
suicidality, the investigator will consult with 
the medical monitor, the consulting 
psychiatrist, and/or sponsor to determine 
whether the patient should continue in the 
study.
Suicidal behavior

Actual attempt: 
If patients report any suicidal behavior that is 
an actual attempt as assessed in the C-SSRS, 
they will be evaluated immediately by the 
study investigator, referred for psychiatric 
evaluation, and terminated from the study.

Interrupted attempt, aborted attempt, or 
Preparatory Acts or Behavior: 
If patients report any suicidal behavior that is 
interrupted, aborted, or preparatory as 
assessed in the C-SSRS, they will be 
evaluated immediately by the study 
investigator and referred for psychiatric 
evaluation. In cases where it is determined in 
the psychiatric evaluation that IMP did not 
contribute to changes in suicidal behavior, 
the investigator will consult with the medical 
monitor, the consulting psychiatrist, and/or 
sponsor to determine whether the patient 
should continue in the study.
7.9 Assessment of Suicidality


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Consideration should be given to discontinuing TEV-50717 in 
participants who experience signs of suicidal ideation or 
behavior.,detailed recommendations are provided in 
Section 7.2.2.
Families and caregivers of participants being treated with TEV
50717 should be instructed to monitor participants for the 
emergence of unusual changes in behavior, as well as the 
emergence of suicidal ideation and behavior, and to report such 
symptoms immediately to the study investigator.
Depression and Suicidality as an Adverse Event 
Families and caregivers of patients subjects will be instructed 
to monitor patients for any changes in or new onset of 
depressive symptoms; unusual changes in mood, cognition, or 
behavior; or onset of and/or changes in suicidal ideation or 
behavior, and to report such symptoms immediately to the 
study investigator. Telephone contacts and clinic visits also 
allow opportunities for investigators to assess adverse events.
If a relevant change in status is identified, patients will be seen 
immediately for an unscheduled visit by the study investigator 
and discussed with the medical monitor. The patient will be 
referred for further psychiatric evaluation if there is any 
suspected suicidal ideation with any level of intent, suicidal 
behavior, or clinical findings suggesting that the patient may be 
dangerous to self or others, and/or experiencing depression. 
The investigator will record these symptoms as an adverse 
event of depression and/or suicidality. If it is determined by the 
investigator, after consultation with the medical monitor and 
the consulting psychiatrist, that exposure to the IMP may have 
contributed to the adverse event of depression or suicidality, 
IMP will be immediately discontinued and the patient will be 
terminated from the study. Follow up with a pediatric 
psychiatrist or licensed child and adolescent mental health 
clinician will be arranged.
Consideration should be given to discontinuing TEV-
50717 in participants who experience signs of 
suicidal ideation or behavior; detailed 
recommendations are provided in Section 7.2.2.
Depression and Suicidality as an Adverse Event 
Families and caregivers of patients will be instructed 
to monitor patients for any changes in or new onset of 
depressive symptoms; unusual changes in mood, 
cognition, or behavior; or onset of and/or changes in 
suicidal ideation or behavior, and to report such 
symptoms immediately to the study investigator. 
Telephone contacts and clinic visits also allow 
opportunities for investigators to assess adverse 
events.
If a relevant change in status is identified, patients 
will be seen immediately for an unscheduled visit by 
the study investigator and discussed with the medical 
monitor. The patient will be referred for further 
psychiatric evaluation if there is any suspected 
suicidal ideation with any level of intent, suicidal 
behavior, or clinical findings suggesting that the 
patient may be dangerous to self or others, and/or 
experiencing depression. The investigator will record 
these symptoms as an adverse event of depression 
and/or suicidality. If it is determined by the 
investigator, after consultation with the medical 
monitor and the consulting psychiatrist, that exposure 
to the IMP may have contributed to the adverse event 
of depression or suicidality, IMP will be immediately 
discontinued and the patient will be terminated from 
the study. Follow up with a pediatric psychiatrist or 
licensed child and adolescent mental health clinician 
will be arranged.
Added further descriptions and 
guidance on depression and 
suicidality assessed as adverse 
events


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In cases where it is determined that IMP did not contribute to 
the adverse event of depression or suicidality, the investigator 
will consult with the medical monitor and/or sponsor to 
determine whether the patient should continue in the study.
In cases where it is determined that IMP did not 
contribute to the adverse event of depression or 
suicidality, the investigator will consult with the 
medical monitor and/or sponsor to determine whether 
the patient should continue in the study.
7.11 Concomitant Medication or Treatment (other sections affected: Appendix A: ALLOWED AND DISALLOWED MEDICATIONS
The tables for allowed and prohibited medications are not 
comprehensive and may not include all possible concomitant 
medications.
The medical monitor must be contacted if a patient is receiving 
(or has to begin or stop receiving during the study) a 
medication that is associated with QTc prolongation or that is a 
known strong CYP inhibitor. , or if there are any questions 
regarding any medication not listed in Appendix A.
Prohibited medications that are associated with QTc 
prolongation are listed in Table 8, while prohibited
antipsychotic drugs are listed in Table 7.
The tables for allowed and prohibited medications are 
not comprehensive and may not include all possible 
concomitant medications.
The medical monitor must be contacted if a patient is 
receiving (or has to begin or stop receiving during the 
study) a medication that is associated with QTc 
prolongation or that is a known strong CYP inhibitor, 
or if there are any questions regarding any medication 
not listed in Appendix A.
Prohibited medications that are associated with QTc 
prolongation are listed in Table 8, while prohibited 
antipsychotic drugs are listed in Table 7.
Included a few more details on 
the list of concomitant 
medications
9.1 Sample Size and Power Considerations
This study is safety-oriented in nature; therefore, no formal 
hypothesis testing is planned for Part A. Based on the number 
of patients in the previous studies, up to approximately 
212227 patients (approximately 1 patient from the Phase 1b 
Study SD-809-C-17, up to approximately 85 99 patients from 
the Phase 2/3 Study TV50717-CNS-30046, and up to 
approximately 126 127 patients from the Phase 3 
Study TV50717-CNS-30060) are estimated to enroll.
 
 
This study is safety oriented in nature; therefore, no 
formal hypothesis testing is planned for Part A. Based 
on the number of patients in the previous studies, up 
to approximately 227 patients (approximately 1 
patient from the Phase 1b Study SD-809-C-17, up to 
approximately 99 patients from the Phase 2/3 Study 
TV50717-CNS-30046, and up to approximately 127 
patients from the Phase 3 Study TV50717-CNS-
30060) are estimated to enroll.
All patients who complete Study TV50717-CNS-
30060 or Study TV50717-CNS-30046 are eligible to 
participate in Study TV50717-CNS-30047. As the 
number of patients to be randomized in parent Study 
Updated the anticipated 
enrollment numbers to account 
for the increased sample size 
of Study TV50717-CNS-
30046


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For the randomized drug withdrawal period, enrolling at least
190 patients to be included in the analysis will provide
approximately at least 90% power to detect a difference 
between TEV-50717-treated and placebo-treated patients 
assuming a difference in YGTSS TTS of 4.5 with a standard 
deviation of 9 assuming a type 1 error rate of 5%using a 
two-sided test for difference at a significance level of 0.05.
TV50717-CNS-30046 has increased, the number of 
patients anticipated to be randomized into Study 
TV50717-CNS-30047 has also increased. The 
rationale for the increased sample size in Study 
TV50717-CNS-30046 is provided that protocol.
For the randomized drug withdrawal period, 190 
patients to be included in the analysis will provide 
approximately 90% power to detect a difference 
between TEV-50717-treated and placebo-treated 
patients assuming a difference in YGTSS TTS of 4.5 
with a standard deviation of 9 using a two sided test 
for difference at a significance level of 0.05.
9.5.3.1 Efficacy Analysis for the Blinded, Randomized Drug Withdrawal PortionPeriod
For the randomized drug withdrawal portion of the study, an 
analysis of covariance model will be used as the primary 
analysis model with the change from randomized-withdrawal 
week 28 to week 30 in YGTSS TTS as the dependent variable, 
and treatment group, randomized-withdrawal week 28 TTS, 
and age group at baseline as covariates. The least squares mean 
of the change in TTS from week 28 to week 30 will be 
compared (the active treatment arm and placebo arm) using a 
2-sided test at the alpha=0.05 level of significance. In addition, 
actual values and changes in TTS will be summarized using 
descriptive statistics.
The primary analysesanalysis will be in the RRWmITT 
population; in (see Section 9.2.6). In addition, sensitivity 
testing will be done using the same analyses onmodel in the 
RWmITT population and in a subpopulation of the RRWmITT 
who had a ≥35% reduction in the TTS from baseline in the 
parent protocol to week 28.
For the randomized drug withdrawal portion of the 
study, an analysis of covariance model will be used as 
the primary analysis model with the change from 
randomized-withdrawal week 28 to week 30 in 
YGTSS TTS as the dependent variable, and treatment 
group, randomized-withdrawal week 28 TTS, and age 
group at baseline as covariates The least squares 
mean of the change in TTS from week 28 to week 30 
will be compared (the active treatment arm and 
placebo arm) using a 2-sided test at the alpha=0.05 
level of significance. 
The primary analysis will be in the RRWmITT 
population (see Section 9.2.6). In addition, sensitivity 
testing will be done using the same model in the 
RWmITT population and in a subpopulation of the 
RRWmITT who had a ≥35% reduction in the TTS 
from baseline in the parent protocol to week 28.
Included edits to the 
randomized drug withdrawal 
period for clarity on the 
planned analysis.
9.9 Planned Interim Analysis
No interim analysis is planned for this study.
When approximately 100 patients have completed the 
28-week clinic visit, an interim analysis, including 
Included language on the 
addition of an interim analysis 


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When approximately 100 patients have completed the 28-week 
clinic visit, an interim analysis, including data from day 1 and 
up to week 28 visit only, will be conducted to provide 
descriptive, long-term safety and efficacy data to be used in 
regulatory submissions. To maintain data integrity of Study 
TV50717-CNS-30047, only a limited number of personnel 
who do not have contact with the sites will have access to this 
interim data in preparation for the regulatory filing. As no 
decisions regarding conduct of the study will be made based on 
the descriptive interim analysis, no alpha will be spent.
data from day 1 and up to week 28 visit only, will be 
conducted to provide descriptive, long-term safety 
and efficacy data to be used in regulatory 
submissions. To maintain data integrity of Study 
TV50717-CNS-30047, only a limited number of 
personnel who do not have contact with the sites will 
have access to this interim data in preparation for the 
regulatory filing. As no decisions regarding conduct 
of the study will be made based on the descriptive 
interim analysis, no alpha will be spent.
once ~100 patients have 
completed the 28-week clinic 
visit.
Appendix A ALLOWED AND DISALLOWED MEDICATIONS
Table 9:
Other Prohibited Drugs
Generic
Class/clinical use
Note
Cannabidiol oil Cannabis
Also 
includes 
other forms 
of 
cannabinoid
s 
Valbenazine
Vesicular monoamine 
transporter 2 inhibitor
Ingrezza 
off-label
Quinidine
Class I antiarrhythmic agent
Strong 
CYP2D6 
inhibitor
Terbinafine
Antifungal medication 
Weak 
CYP2D6 
inhibitor 
Table 9:
Other Prohibited Drugs
Generic
Class/clinical use
Note
Cannabidiol 
oil
Cannabis
Also 
includes 
other 
forms of 
cannabino
ids 
Valbenazine
Vesicular monoamine 
transporter 2 inhibitor
Ingrezza 
off-label
Quinidine
Class I antiarrhythmic 
agent
Strong 
CYP2D6 
inhibitor
Terbinafine
Antifungal medication 
Weak 
CYP2D6 
inhibitor 
The list of allowed and 
disallowed medications was 
updated to align with the 
updated exclusion criteria. 
Updated Appendix A to 
include a table (Table 9) for 
other prohibited drugs


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APPENDIX A. ALLOWED AND DISALLOWED MEDICATIONS
Medications that are allowed, provided that conditions outlined in the table are met, are shown in 
Table 6. Tables for allowed and prohibited medications are not exhaustive and may not include 
all possible concomitant medications.
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving 
during the study) a medication that is associated with QTc prolongation or that is a known strong 
cytochrome P450 inhibitor, or if there are any questions regarding any medication not listed in 
the tables below.
Prohibited antipsychotic drugs are listed in Table 7. Prohibited medications that are associated 
with QTc prolongation are listed in Table 8.
Table 6:
Allowed Medications
Generic/Drug class
Condition
Stable medications allowed according to inclusion/exclusions criteria
Hormonal birth control
Must be receiving stable treatment (including dose) for at least 3 months before 
screening.
Antidepressants
Must be receiving stable treatment (including dose) for at least 6 weeks before 
screening.
Benzodiazepines
Primary use must not be for tics; dosing must have been stable QT for at least 
4 weeks before screening.
Note: PRN (as needed) use is prohibited.
Topiramate 
(up to 200 mg/day)
Must be receiving stable treatment (including dose) for at least 4 weeks before 
screening.
Guanfacine
Allowed regardless of indication (ie, if prescribed for tics or Tourette 
syndrome). Must be receiving stable treatment (including dose) for at least 
4 weeks before screening and no changes to dose or frequency are anticipated 
during the course of the study.
Clonidine
Allowed regardless of indication (ie, if prescribed for tics or Tourette 
syndrome). Must be receiving stable treatment (including dose) for at least 
4 weeks before screening and no changes to dose or frequency are anticipated 
during the course of the study.
Stimulants
Including amphetamine, methylphenidate, and lisdexamfetamine. Primary use is 
for the treatment of ADHD; dosing must have been stable for at least 2 weeks 
before screening.
SNRIs
Including atomoxetine. Primary use is for the treatment of ADHD; dosing must 
have been stable for at least 4 weeks before screening.
Additional medications allowed with preapproval from medical monitor
Albuterol, levalbuterol
Asthma
Guaifenesin
Cold symptoms


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Table 6:
Allowed Medications (Continued)
Generic/Drug class
Condition
Stable medications allowed according to inclusion/exclusions criteria
Antihistamines
Allergies
Melatonin
Insomnia
Allowed strong CYP inhibitorsa
Bupropion
Antidepressant (aminoketone)
Fluoxetine
Antidepressant (selective serotonin reuptake inhibitor)
Paroxetine
Antidepressant (selective serotonin reuptake inhibitor)
a The use of these medications will affect the maximum daily dose of IMP, as shown in Table 2.
ADHD=attention-deficit/hyperactivity disorder; CYP=cytochrome P450; IMP=investigational medicinal product; 
SNRIs=serotonin-norepinephrine reuptake inhibitor.
Note: No dosing changes can be made during the study.
Table 7:
Prohibited Antipsychotic Drugs
Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Chlorpromazine
Aripiprazole
Haloperidol
Asenapine maleate 
Loxapine
Clozapine 
Molindone
Iloperidone
Perphenazine
Lurasidone 
Pimozide
Olanzapine
Prochlorperazine
Olanzapine / fluoxetine
Thioridazine
Paliperidone
Thiothixene
Quetiapine
Trifluoperazine
Risperidone
Promethazine-containing compounds
Ziprasidone
Fluphenazine
Tiapride
Table 8:
Prohibited QTc Prolonging Drugs
Generic
Class/clinical use
Note
Azithromycina
Antibiotic/bacterial infection
Chloroquine/Mefloquine
Anti-malarial/malaria infection
Clarithromycinb
Antibiotic/bacterial infection
Domperidone
Anti-nausea/nausea
Not available in 
USA


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Table 8:
Prohibited QTc Prolonging Drugs (Continued)
Generic
Class/clinical use
Note
Droperidol
Sedative; anti-nausea/anesthesia adjunct, nausea
Erythromycin0
Antibiotic; gastrointestinal (GI) stimulant; GI 
motility
Moxifloxacin
Antibiotic/bacterial infection
Sevoflurane
Anesthetic, general/anesthesia
Probucol
Antilipemic/hypercholesterolemia
Not available in 
USA
Sparfloxacin
Antibiotic/bacterial infection
Not available in 
USA
a Allowed dose of Azithromycin is up to 500 mg/day 
b Systemic use only. Topical use is allowed.
GI=gastrointestinal; USA=United States of America.
Table 9:
Other Prohibited Drugs
Generic
Class/clinical use
Note
Cannabidiol oil
Cannabis
Also includes other 
forms of 
cannabinoids 
Valbenazine
Vesicular monoamine transporter 2 inhibitor
Ingrezza off-label
Quinidine
Class I antiarrhythmic agent
Strong CYP2D6 
inhibitor
Terbinafine
Antifungal medication 
Weak CYP2D6 
inhibitor 


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APPENDIX B. DISTRIBUTION OF AUC BY WEIGHT CATEGORIES
AND CYP2D6 STATUS
Figure 3:
Distribution of AUC of Total (α+β)-HTBZ for Selected Doses Based on 
Weight Categories
AUC=area under the curve; CYP2D6=cytochrome P450 2D6; α/β-HTBZ=alpha/beta-dihydrotetrabenazine.


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APPENDIX C. MINI INTERNATIONAL NEUROPSYCHIATRIC 
INTERVIEW FOR CHILDREN AND ADOLESCENTS
The sample provided in this appendix is for reference only.
Modules: 
Major Depressive Episode (Module A), 
(Hypo) Manic Episode (Module D), 
OCD (Module J), 
Alcohol Dependence/Abuse (Module L), 
Substance Dependence/Abuse (Non-alcohol; Module M), 
ADHD (Module O), 
Conduct Disorder (Module P), and 
Psychotic Disorders and Mood Disorders with Psychotic Features (Module R).


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APPENDIX D. CHILDREN’S DEPRESSION INVENTORY, SECOND 
EDITION
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CDI-2 ParentProfile


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APPENDIX E.
 
The sample provided in this appendix is for reference only.
Children’s Baseline/Screening


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Children’s Since Last Visit


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APPENDIXF.
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APPENDIX G.
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APPENDIX H.
 
The sample provided in this appendix is for reference only.
 
 
 
 
 
 
 


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APPENDIX I.
 


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APPENDIX J.
The sample provided in this appendix is for reference only.


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APPENDIX K.
 
 
The sample provided in this appendix is for reference only.


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APPENDIX L. FEMALES OF CHILDBEARING POTENTIAL AND 
BIRTH CONTROL METHODS 
Females of childbearing potential are defined as:

not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

postmenarchal or ≥12 years of age 
Highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly are considered. Such methods include:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
1 month before the first dose of IMP.

Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at least 1 month before the first 
dose of IMP.

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) need to be 
in place at least 2 months before screening.

Bilateral tubal occlusion

Vasectomized partner provided he is the sole sexual partner and has received medical 
assessment of the surgical process.

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency, MHRA).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
An Open-Label, Long-Term Safety Study Including a Double-Blind, Placebo-
Controlled, Randomized Withdrawal Period of TEV-50717 (Deutetrabenazine) for 
the Treatment of Tourette Syndrome in Children and Adolescents 
 
Study Number TV50717-CNS-30047 
 
 
NCT03567291 
 
 
SAP Approval Date: 29 Oct 2019 


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