Conditions: Tourette Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
Standard placebo-controlled, double-blind study design (TEV-50717 \[low dose and high dose\] vs. placebo in a 1:1:1 ratio) was chosen to determine whether study drug treatment results in a statistically significant effect on the tics in participants with TS.

Detailed description:

Arms:
arm 1: TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 8 weeks arm 2: TEV-50717 tablets BID up to 36 mg/day orally for a total of 8 weeks arm 3: Placebo matched to TEV-50717 for a total of 8 weeks

Interventions: intervention 1: TEV-50717 intervention 2: Placebo
Intervention descriptions: intervention 1: 6-, 9-, 12-, 15-, and 18 mg oral tablets intervention 2: Placebo matched to TEV-50717 tablets will be taken BID.

Protocol document:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the 
Treatment of Tics Associated with Tourette Syndrome 
 
 
Study Number TV50717-CNS-30060 
 
 
NCT03571256 
 
 
Protocol with Amendment 03 Approval Date: 05 May 2019 


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
1
 
Clinical Study Protocol with Amendment 03
Study Number TV50717-CNS-30060
A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the Treatment 
of Tics Associated with Tourette Syndrome
A Study to Test if TEV-50717 is Effective in Relieving Tics Associated with Tourette 
Syndrome
Efficacy and Safety Study TV50717-CNS-30060 (Phase 3)
IND number: 127692;
NDA number: NA;
BLA number: NA;
EudraCT number: 2017-002976-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Original Protocol Approval Date: 13 July 2017
Protocol Amendment 03 Approval Date: 05 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 Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; 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.


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
2
AMENDMENT HISTORY
The protocol for Study TV50717-CNS-30060 (original protocol dated 13 July 2017) has been 
amended and reissued as follows:
Amendment 03
05 May 2019
78 patients randomized/enrolled to date
Amendment 02
25 March 2019
50 patients randomized/enrolled to date
Amendment 01
20 November 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 15.


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
3
INVESTIGATOR AGREEMENT
Original Protocol Dated 13 July 2017
Amendment 03 Dated 05 May 2019
IND number: 127692;
EudraCT number: 2017-002976-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the Treatment 
of Tics Associated with Tourette Syndrome
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 03 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


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
4
SPONSOR PROTOCOL APPROVAL


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
5
COORDINATING INVESTIGATOR AGREEMENT


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
6
COORDINATING INVESTIGATOR AGREEMENT


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
7
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Sponsor’s Authorized Representative
 
Legal Representative of the Sponsor in the EU
For protocol issues, contact the following study 
leaders (right)
Sponsor’s Medical Expert/Contact Point 
designated by the Sponsor for Further 
Information on the Study
Tel
Email: 
Tel: 
Study Principal Investigator
Tel: 
 
 
Tel: 
For medical issues, contact the following 
physicians (right)
Sponsor’s Representative of Global Patient 
Safety and Pharmacovigilance
For serious adverse events:
Send by email to the local safety officer/contract 
research organization (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.
USA
Tel: 
Cell: 
Email: 
 


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
8
 
For operational issues, contact the Head of 
Operations listed (right)
Sponsor’s Clinical Operations Contact
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.
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


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
9
Electronic Data Capture
Medidata RAVE (through Syneos Health)
Contract Research Organization
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


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
10
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV50717-CNS-30060
Title of Study: A Well-Controlled, Fixed-Dose Study of TEV-50717 (Deutetrabenazine) for the 
Treatment of Tics Associated with Tourette Syndrome
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
EudraCT Number: 2017-002976-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Name of Test Investigational Medicinal Product (IMP): TEV-50717 (previously SD-809)
EudraVigilance (EV) code for the IMP, if applicable: SUB179485
Type of the Study: Efficacy and Safety Study (Phase 3)
Indication: Treatment of Tourette syndrome (TS)
Is this study conducted to investigate the New Use of an approved, marketed product? Yes
Number of Investigational Centers Planned: Approximately 55
Countries Planned: North America, Latin America, Australia, Ukraine, South Korea, and 
Europe
Planned Study Period: Planned start in January 2018 with a duration of approximately 
17 months
Number of Patients Planned (total): 150 (50 per treatment arm; 
TEV-50717 [high]:TEV-50717 [low]: placebo randomized 1:1:1 ratio)
Study Population: Male and female patients between 6 and 16 years of age (inclusive) with tics 
associated with Tourette syndrome 
Primary and Secondary Objectives and Endpoints
The purpose of the study is to determine whether TEV-50717 is effective in the treatment of tics 
associated with TS in male and female patients between 6 and 16 years of age.


Placebo-Controlled Study–Tourette Syndrome
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Study TV50717-CNS-30060
11
Objectives
Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of fixed doses of TEV-50717 
to reduce motor and phonic tics 
associated with Tourette 
Syndrome (TS).
The primary efficacy endpoint is the change in the Total Tic 
Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) 
from baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated patients.
Secondary objectives
The secondary efficacy endpoints are as follows:
1. change in the Tourette Syndrome-Clinical Global 
Impression (TS-CGI) score from baseline to week 8 
between high-dose TEV-50717-treated patients and 
placebo-treated patients
2. change in the TTS of the YGTSS from baseline to 
week 8 for low-dose TEV-50717 and placebo will be 
tested
3. change in the TS-CGI score from baseline to week 8 
between low-dose TEV-50717-treated patients and 
placebo-treated patients
4. change in the Tourette Syndrome-Patient Global 
Impression of Impact (TS-PGII) score from baseline to 
week 8 between high-dose TEV-50717-treated patients 
and placebo-treated patients
5. change in the TS-PGII score from baseline to week 8 
between low-dose TEV-50717-treated patients and 
placebo-treated patients
6. change in the Child and Adolescent Gilles de la 
Tourette Syndrome – Quality of Life- scale 
(C&A-GTS-QOL) activities of daily living (ADL)
subscale from baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated 
patients
7. change in the C&A-GTS-QOL ADL subscale from 
baseline to week 8 between low-dose 
TEV-50717-treated patients and placebo-treated 
patients
The hierarchy of testing of secondary endpoints regarding dose 
level to control type I error is specified in the section entitled 
“Analysis of Key Secondary Endpoints.”


Placebo-Controlled Study–Tourette Syndrome
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Study TV50717-CNS-30060
12
Exploratory Endpoints: 
 
 
 
 
 
 
 
Safety Endpoints: 
Objectives
Endpoints
A secondary objective
is to evaluate the safety 
and tolerability of 
TEV-50717.
The safety endpoints are as follows:
incidence of adverse events
observed values and changes from baseline in vital signs
observed values and change from baseline in the Children’s 
Depression Inventory Second Edition (CDI-2; Parent and Self-
report Profiles)
observed values in the children’s Columbia Suicide Severity 
Rating Scale (C-SSRS)
observed values and changes from baseline in electrocardiogram 
(ECG) parameters and shifts from baseline for clinically significant 
abnormal findings
observed values and changes from screening in clinical laboratory 
parameters (hematology, chemistry, and urinalysis)
In addition to routine monitoring of adverse events, clinical laboratory 


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
13
Objectives
Endpoints
parameters, 12-lead ECGs and safety scales, an independent Data 
Monitoring Committee will monitor safety during the conduct of the 
study.
Pharmacokinetic Endpoint:
The pharmacokinetics of the alpha-dihydrotetrabenazine (α-HTBZ) and 
beta-dihydrotetrabenazine (β-HTBZ) metabolites of TEV-50717 will be explored based on 
sparse sampling (2 samples) at week 8.
General Study Design: This is a Phase 3, randomized, double-blind, placebo-controlled, 8-week
treatment study in which patients with tics associated with TS will be invited to participate. 
Patients will be randomized to low-dose TEV-50717, high-dose TEV-50717, or placebo (1:1:1). 
The target dose for each patient receiving TEV-50717 will be based on the group to which they 
are randomized, body weight at baseline, and cytochrome P450 2D6 (CYP2D6) impairment 
status. 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. CYP2D6 status will be used by Interactive Response Technology (IRT) for 
randomization into the study.
Prescreening period (up to 3 months before baseline): For patients who require discontinuation 
of certain prohibited concomitant medications 3 months before baseline (depot neuroleptics, 
botulinum toxin, or tetrabenazine), informed consent/assent, depending on the child’s age, as 
appropriate, should be obtained prior to discontinuing the prohibited medication.
Screening period (up to 31 days): 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, 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. The Mini 
International Neuropsychiatric Interview for Children and Adolescents (MINI Kid), is a short 
questionnaire (largely yes/no questions) to screen for clinically significant underlying psychiatric 
illness that may affect the subject’s eligibility. The assessment will focus on detecting major 
depression, mania/hypomania, obsessive/compulsive disorder, alcohol and substance abuse, 
attention deficit hyperactivity and conduct disorders, and psychotic disorders.
At the discretion of the investigator, the screening visit may be divided into 2 visits to reduce the 
burden on patients. If the screening visit is divided into 2 visits, the blood sample should be 
obtained during the first of the 2 visits. Patients will return to the clinic on day 1 for baseline 
procedures and to re-confirm eligibility. Patients may be rescreened 1 time if there is a change in 
the status of the patient regarding eligibility for the study. (Note: Details of rescreening must be 
approved and documented by the medical monitor and/or Clinical Surveillance and Training 
[CST] team.)
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 8/early termination visits. However, if due to 


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
14
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.
Treatment period (8 weeks): Patients who continue to remain eligible for participation in the 
study will be randomized at the baseline visit (day 1) and will receive blinded IMP to begin that 
same day (day 1) with food. Tablets should be taken with food (eg, a snack) and should not be 
taken on an empty stomach. Patients and their caregiver/adult will interact regularly with the
clinical research staff, either by telephone contact or clinic visit to assure adherence with study 
procedures and to evaluate safety and efficacy. To this end, clinic visits will be performed at 
weeks 2, 4, and 8 after baseline, in order to evaluate safety; assess tic severity with the YGTSS, 
TS-CGI, TS-PGII, and the C&A-GTS-QOL; and perform safety rating scales to augment adverse 
event reporting, concomitant medication usage, clinical laboratory examination, and 12-lead 
ECGs. Telephone contacts will occur at the end of weeks 1, 3, 6, and 7.
As this is a fixed-dose study, patients will undergo dose escalation (ie, forced titration) to their 
target dose over the first 4 weeks of treatment. If a patient experiences depression, suicidal 
ideation or behavior, anxiety, akathisia, parkinsonism, or somnolence, or any other adverse event 
that interferes with daily activity, or any adverse event that is related to IMP, a single dose 
reduction is permitted. The investigator must discuss any further dose adjustments (eg, holding 
the dose or doses) with the medical monitor.
In case of such an adverse event, the investigator will determine if a dose reduction or 
suspension is necessary. If a determination is made that a dose reduction or suspension is 
required, the medical monitor must be contacted. All available information, including the patient 
and caregiver/adult reports of adverse events, the clinical assessment of safety by the 
investigator, and information from rating scales should be incorporated in the decision. This 
reduced dose will become the patient’s dose for the remainder of the study.
Patients will return to the clinic at week 8 for the final on-treatment assessment of safety and 
efficacy. At this visit, patients will undergo a complete evaluation, including performance of all 
efficacy measures, including assessment of tic severity with the YGTSS; and complete safety 
testing, including physical and neurological examination, safety laboratory testing, 12-lead ECG, 
and all rating scales. In addition, patients will undergo pharmacokinetic sampling at week 8, at 
which time 2 pharmacokinetic specimens will be obtained 2 to 3 hours apart. Prior to the clinic 
visit on week 8, patients will be reminded to record in their diary the start time of their last meal 
and the time of their last dose of study medication before the week 8 visit. The site will 
document the date and time of the sample collection. 
Follow-up: All patients will discontinue IMP at the week 8 visit and will return 1 week later for 
evaluation of safety and tic reduction (week 9). 
Patients who complete the study may be eligible to begin participation in an open-label safety 
extension study of TEV-50717 (Study TV50717-CNS-30047). For this study, the follow-up 
period is defined as 1 week of washout for patients who will participate in the open-label safety 
extension Study TV50717-CNS-30047 and 2 weeks after the last dose of IMP (1 week after the 
end of the washout period) for patients who will not roll over into the open-label safety extension
Study TV50717-CNS-30047. Patients not participating in the open-label safety extension study 
for TEV-50717 will have a follow-up telephone contact for safety evaluation 1 week after the 
end of the treatment period (2 weeks after their last dose of IMP).


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 03
Study TV50717-CNS-30060
15
Prohibited drugs will remain the same during the washout period for patients who will participate 
in the open-label extension Study TV50717-CNS-30047. Patients who will not participate in the 
extension study may begin/resume tic therapy medication after the first week of the washout 
period. 
Brief Summary of Study Design for the Trial Registry(s):
Standard placebo-controlled, double-blind study design (TEV-50717 [low dose and high dose] 
vs. placebo in a 1:1:1 ratio) was chosen to determine whether IMP treatment results in a 
statistically significant effect on the tics in patients with TS.
Method of Randomization and Blinding: Patients will be randomly assigned to receive 
treatment with TEV-50717 (low dose, high dose) or matching placebo in a 1:1:1 ratio using an 
IRT based on their baseline weight and CYP impairment status. The patients will be stratified 
into 2 age groups (6- to 11-years and 12- to 16-years). The sponsor will monitor enrollment in 
age strata to ensure there is adequate representation in each stratum. Patients and investigators 
will remain blinded to treatment assignment during the study. In addition, the sponsor’s clinical 
personnel and all vendors (with the exception of the IRT vendor and the bioanalytical sample 
analysis 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. However, if a prioritized 
sample analysis is needed, bioanalytical personnel may be unblinded. After unblinding of this 
study, the study site may remain blinded to patient treatment assignments until completion of the 
safety extension Study TV50717-CNS-30047.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate
Test IMP: TEV-50717 (previously SD-809), deutetrabenazine
Daily Dose of IMP by Baseline Body Weight Category, CYP2D6 Impairment, and Study 
Week
Dose group
Baseline weight (kg)
Daily dose (mg) at the start of visit/weeka
Week 1
(Days 1-7)
Week 2
(Days 8-14)
Week 3
(Days 15-21)
Week 4 main dose
(Days 22-28) to Week 8 
main dose (Days 50-56)
Low dose
≥40 
12
24
30
36
≥40, CYP impaired
6
12
18
18
30 to <40
6
12
18
24
30 to <40, CYP impaired
6
12
12
12
20 to <30
6
12
18
18
20 to <30, CYP impaired
6
6
6
6
High dose
≥40 
12
24
36
48


Placebo-Controlled Study–Tourette Syndrome
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Study TV50717-CNS-30060
16
Dose group
Baseline weight (kg)
Daily dose (mg) at the start of visit/weeka
Week 1
(Days 1-7)
Week 2
(Days 8-14)
Week 3
(Days 15-21)
Week 4 main dose
(Days 22-28) to Week 8 
main dose (Days 50-56)
≥40, CYP impaired
6
15
24
30
30 to <40
12
24
30
36
30 to <40, CYP impaired
6
12
18
18
20 to <30
12
18
24
30
20 to <30, CYP impaired
6
12
12
12
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.
CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor metabolizer.
Placebo IMP: Placebo tablets match TEV-50717 tablets
Duration of Patient Participation and Maximal Exposure to IMP: This study will consist of 
a prescreening period of up to 3 months, a screening period of up to 31 days, an 8-week 
double-blind treatment period, and a follow-up period. For this study, the follow-up period is 
defined as 1 week of washout for patients who will participate in the open-label safety extension 
Study TV50717-CNS-30047 and 2 weeks after the last dose of IMP (1 week after the end of the 
washout period) for patients who will not roll over into the open-label safety extension 
Study TV50717-CNS-30047. Patients who complete the study may be eligible 1 week after their 
last dose of IMP to begin participation in an open-label safety extension study of TEV-50717. 
Patients not participating in the open-label safety extension study for TEV-50717 will have a 
follow-up telephone contact to evaluate safety 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 11 weeks and 
a maximum of 14 weeks.
Study Duration: Approximately 17 months from January 2018
End of Study: End of study is defined as the date of the week 10 telephone contact with the last 
participant.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study:
Patients who complete the study may be eligible to begin participation in an open-label safety 
extension study of TEV-50717 (Study TV50717-CNS-30047). 
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria: 
a.
Patient is 6 to 16 years of age, inclusive, at baseline.
b. Patient weighs at least 44 pounds (20 kg) at baseline.
c.
Patient meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-V™) diagnostic criteria for TS and, in the opinion of the investigator, 
patient, and caregiver/adult, the patient’s active tics are causing distress or 
impairment.


Placebo-Controlled Study–Tourette Syndrome
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Study TV50717-CNS-30060
17
d. Patient has a TTS of 20 or higher on the YGTSS at screening and baseline. 
e.
Patient is able to swallow study medication whole.
f.
Patient and caregiver/adult are willing to adhere to the medication regimen and to 
comply with all study procedures.
g. Patient is in good general health, as indicated by medical and psychiatric history as 
well as physical and neurological examination.
h. 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.
i.
Patient and caregiver/adult provided written informed consent/assent, depending on 
the child’s age, as appropriate, according to local regulations.
j.
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 at baseline or are 
sterile.
k. 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. 
l.
The patient must be willing and able to comply with study restrictions and to remain 
at the clinic for the required duration during the study period and willing to return to 
the clinic for the follow-up evaluation as specified in this protocol.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria:
a.
Patient has a neurologic disorder other than TS that could obscure the evaluation of 
tics.
b. The patient’s predominant movement disorder is stereotypy (coordinated movements 
that repeat continually and identically) associated with autism spectrum disorder. 
c.
Patient has clinically significant obsessive-compulsive disorder (OCD) at baseline 
that, in the opinion of the investigator, is the primary cause of impairment.
d. Patient has clinically significant depression at screening or baseline. 
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 6 weeks before baseline.
e.
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
f.
Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
g. Patient has a first-degree relative who has completed suicide.
h. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another 
psychotic disorder.


Placebo-Controlled Study–Tourette Syndrome
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18
i.
Patient has a DSM diagnosis based on the Mini International Neuropsychiatric 
Interview For Children and Adolescents Inventory at screening that, in the opinion of 
the investigator, makes the patient unsuitable for the study. 
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 
following specified exclusionary windows of first dose:

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, 
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 Attention 
Deficit Hyperactivity Disorder (ADHD), dosing has been stable for at least 
2 weeks before screening, and no changes to dose or frequency are anticipated 
during the course of the study.
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, and no 
changes to dose or frequency are anticipated during the course of the study.
Note: Use of benzodiazepines is allowed if 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 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 TS) 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. If discontinuation of either medication is anticipated due to 
ineffectiveness, poor tolerability, or patient/caregiver preference, discontinuation 
should occur 4 or more weeks prior to the screening visit.
l.
Patient has received treatment with deep brain stimulation, transmagnetic stimulation, 
or transcranial direct current stimulation within 4 weeks of the screening visit for 
reduction of tics. 
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 a 12-lead electrocardiogram (ECG) at screening, or requires 
treatment with drugs known to prolong the QT interval.
n. Patient has a history of torsades de pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart failure.
o. Patient has evidence of hepatic impairment, as indicated by the following:


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
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 >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 total bilirubin. 
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 baseline 
visit.
r.
Patient has a known allergy to any of the components of the IMP product.
s.
Patient has participated in an investigational drug or device study and received 
IMP/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
t.
Patient is a pregnant or lactating female or plans to be pregnant during the study.
u. Patient has a history of or acknowledges alcohol-related disorder in the previous 
12 months, as defined in the DSM-V™.
v. Patient has a positive urine drug screen test result or is unable to refrain from 
substance abuse throughout the study.
Statistical Considerations
Sample Size Rationale: It is estimated that approximately 50 patients per arm will enable a 
power of at least 90% to detect a beneficial standardized effect of 68% or more when the 
TEV-50717 arm is compared to placebo (difference of 6.5 in the change from baseline to week 8
in TTS, assuming a standard deviation of 9.5 in each arm) in a 2-sided type I error rate of 5% 
after accounting for potential dropouts.
Analysis of Primary Endpoint: The primary efficacy endpoint for this study is the change in 
the TTS of the YGTSS from baseline to week 8 between high-dose TEV-50717-treated and
placebo-treated patients. The primary analysis will be a mixed-model repeated-measures model 
with the change in the TTS as the dependent variable. The model will include fixed effects for 
treatment group, week (3 levels: weeks 2, 4, and 8), and the treatment group-by-week 
interaction. The baseline TTS, region, and age group at baseline (2 levels: 6 to 11 years, 12 to 16 
years) will be included as covariates. The unstructured covariance matrix for repeated 
observations within patients will be used. The least squares means of the change in TTS from 
baseline at week 8 will be compared between the high-dose treatment arm and the placebo arm 
using a 2-sided test at the alpha = 0.05 level of significance. In addition, actual values and 
changes in the TTS from baseline to each visit will be summarized using descriptive statistics.
Analysis of Key Secondary Endpoints: A hierarchical (fixed-sequence) testing approach will 
be used for the analysis of the key secondary endpoints. If an endpoint is not statistically 
significant, confirmatory hypothesis testing will not be carried out on the remaining hypotheses, 
and remaining hypotheses will be considered exploratory rather than confirmatory. The 
following analyses of key secondary endpoints will be conducted:


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1. The change from baseline to week 8 in TS-CGI will be analyzed using a similar model as 
the primary analysis; however, instead of change in YGTSS TTS as the dependent 
variable and baseline YGTSS TTS as a covariate, the corresponding TS-CGI values will 
be used. The comparison between high-dose TEV-50717 and placebo will be tested.
2. Using the same model as for the primary analysis, the comparison between the change in 
the TTS of the YGTSS from baseline to week 8 for low-dose TEV-50717 and placebo 
will be tested.
3. Using the same model as described in endpoint #1 above for TS-CGI, the comparison 
between the change in the TS-CGI values from baseline to week 8 for low-dose 
TEV-50717 and placebo will be tested.
4. The change from baseline to week 8 in TS-PGII will be analyzed using a 
Cochran-Mantel-Haenszel row mean score test with modified ridit scoring controlling for 
age group. The comparison between high-dose TEV-50717 and placebo will be tested.
5. Using the same model as described in endpoint #4 above for TS-PGII, the comparison 
between the change in the TS-PGII values from baseline to week 8 for low-dose 
TEV-50717 and placebo will be tested.
6. The change from baseline to week 8 in C&A-GTS-QOL ADL subscale will be analyzed 
using a similar model as the primary analysis; however, instead of change in YGTSS 
TTS as the dependent variable and baseline YGTSS TTS as a covariate, the 
corresponding C&A-GTS-QOL ADL subscale values will be used. The comparison 
between high-dose TEV-50717 and placebo will be tested.
7. Using the same model as described in endpoint #6 above for C&A-GTS-QOL ADL 
subscale, the comparison between the change in the C&A-GTS-QOL ADL subscale 
scores from baseline to week 8 for low-dose TEV-50717 and placebo will be tested.
Exploratory Analyses:
 
 
 
 
 
 
 
 
 
 
 


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Multiple Comparisons and Multiplicity: The hierarchical testing method will be used to 
maintain the experiment-wise type I error of 5% level for the primary and key secondary 
analyses. The primary efficacy endpoint will first be tested at the 5% type I error level. If the 
p-value of the primary analysis is ≤0.05, the secondary hypotheses will be tested in the order 
listed for the analysis of key secondary endpoints until either an analysis produces a p-value 
>0.05 or all analyses result in a p-value ≤0.05. 
Analysis of Pharmacokinetic Endpoint: Samples collected for pharmacokinetic analysis will 
be quantified for α-HTBZ and β-HTBZ metabolite plasma concentrations and will be pooled 
with previous data and analyzed using population pharmacokinetic techniques. Analysis methods 
will be detailed in a separate population pharmacokinetic analysis plan. Exploratory 
pharmacokinetic/pharmacodynamic (PD) analysis may be performed on PD/safety endpoints.
Safety Analyses: 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 study treatment, serious adverse events, 
and adverse events causing withdrawal from the study. Summaries will be presented by 
treatment group and for all patients. Patient listings of serious adverse events and adverse events 
leading to withdrawal will be presented.
Observed values and changes from baseline 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. In addition, the number and percentage of patients with 
on-treatment QTcF values >450, >480, or >500 msec and change from baseline >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.


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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 by treatment group for all patients. 
Sensitivity Analysis: Sensitivity analyses of primary and key secondary endpoints will be 
conducted using the per-protocol analysis set. Sensitivity analyses for missing data and the 
statistical model will be provided in the statistical analysis plan.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
SPONSOR PROTOCOL APPROVAL ...........................................................................................4
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS ...........7
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................10
LIST OF ABBREVIATIONS........................................................................................................31
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................35
1.1.
Introduction.................................................................................................................35
1.2.
Name and Description of Investigational Product......................................................36
1.3.
Findings from Nonclinical and Clinical Studies.........................................................36
1.3.1.
Nonclinical Studies.....................................................................................................36
1.3.1.1.
Nonclinical Pharmacology..........................................................................................36
1.3.1.2.
Nonclinical Pharmacokinetics and Drug Metabolism................................................37
1.3.1.3.
Toxicology..................................................................................................................37
1.3.2.
Clinical Studies...........................................................................................................38
1.3.2.1.
Clinical Pharmacology Studies...................................................................................38
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................39
1.3.2.3.
Pharmacometrics Analysis of TEV-50717 Active Metabolites to Support 
Dose Selection and Pharmacokinetic Characterization in a Pediatric 
Population...................................................................................................................39
1.4.
Known and Potential Benefits and Risks to Patients..................................................40
1.4.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product.......................................................................................................40
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................41
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................41
2.1.1.
Justification of Primary Endpoint...............................................................................42
2.2.
Exploratory Endpoints................................................................................................42
2.3.
Safety Endpoints.........................................................................................................43
2.4.
Pharmacokinetic Endpoint..........................................................................................43


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3.
STUDY DESIGN .......................................................................................................44
3.1.
General Study Design and Study Schematic Diagram ...............................................44
3.2.
Planned Number of Patients and Countries................................................................47
3.3.
Justification for Study Design and Selection of Population.......................................47
3.4.
Drug Administration...................................................................................................47
3.5.
Stopping Rules for the Study......................................................................................48
3.6.
Schedule of Study Procedures and Assessments........................................................49
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................54
4.1.
Patient Inclusion Criteria ............................................................................................54
4.2.
Patient Exclusion Criteria...........................................................................................55
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................57
4.4.
Replacement of Patients .............................................................................................58
4.5.
Rescreening.................................................................................................................58
4.6.
Screening Failure........................................................................................................58
5.
TREATMENTS..........................................................................................................59
5.1.
Investigational Medicinal Products Used in the Study...............................................59
5.1.1.
Test Investigational Medicinal Product......................................................................59
5.1.1.1.
Starting Dose and Dose Levels...................................................................................59
5.1.1.2.
Dose Modification and Dose Stratification ................................................................59
5.1.2.
Placebo Investigational Medicinal Product ................................................................59
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................61
5.2.1.
Storage and Security...................................................................................................61
5.2.2.
Labeling......................................................................................................................61
5.2.3.
Accountability.............................................................................................................61
5.3.
Justification for Investigational Medicinal Products..................................................62
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................62
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................62
5.4.
Treatment after the End of the Study..........................................................................62
5.5.
Restrictions .................................................................................................................62
5.6.
Prior and Concomitant Medication or Therapy..........................................................63
5.7.
Procedures for Monitoring Patient Compliance .........................................................63
5.8.
Temporary Discontinuation of Investigational Medicinal Product ............................64
5.9.
Randomization and Blinding......................................................................................64


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5.10.
Maintenance of Randomization and Blinding............................................................65
5.10.1.
Maintenance of Randomization..................................................................................65
5.10.2.
Blinding and Unblinding ............................................................................................65
5.10.3.
Data Monitoring Committee.......................................................................................66
5.11.
Total Blood Volume ...................................................................................................67
6.
ASSESSMENT OF EFFICACY ................................................................................68
6.1.
Primary Efficacy Measure and Justification...............................................................68
6.2.
Key Secondary Efficacy and Exploratory Measures..................................................68
6.2.1.
Tourette Syndrome–Clinical Global Impression........................................................68
6.2.2.
Tourette Syndrome-Patient Global Impression of Impact..........................................68
6.2.3.
69
6.2.4.
Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life Scale.........69
6.2.5.
Yale Global Tic Severity Scale...................................................................................69
6.2.6.
......................................................................................69
6.2.7.
70
7.
ASSESSMENT OF SAFETY.....................................................................................71
7.1.
Adverse Events ...........................................................................................................71
7.1.1.
Definition of an Adverse Event ..................................................................................71
7.1.2.
Recording and Reporting of Adverse Events .............................................................72
7.1.3.
Severity of an Adverse Event .....................................................................................73
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............73
7.1.5.
Serious Adverse Events..............................................................................................73
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................74
7.1.5.2.
Expectedness...............................................................................................................75
7.1.5.3.
Reporting a Serious Adverse Event............................................................................75
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................77
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................77
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................77
7.2.
Psychometric Rating Scales........................................................................................77
7.2.1.
Mini International Neuropsychiatric Interview for Children and Adolescents ..........78
7.2.2.
Columbia-Suicide Severity Rating Scale....................................................................78
7.2.3.
Children’s Depression Inventory, Second Edition .....................................................79
7.3.
Pregnancy ...................................................................................................................79


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7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................80
7.5.
Clinical Laboratory Tests ...........................................................................................81
7.5.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................82
7.5.2.
Other Clinical Laboratory Tests .................................................................................82
7.5.2.1.
Human Chorionic Gonadotropin Tests.......................................................................82
7.5.2.2.
Urine Drug Screen ......................................................................................................83
7.5.2.3.
Cytochrome P450 2D6 Genotyping............................................................................83
7.6.
Physical Examinations................................................................................................83
7.7.
Vital Signs ..................................................................................................................83
7.8.
Electrocardiography....................................................................................................84
7.9.
Assessment of Suicidality...........................................................................................84
7.10.
Neurological Examinations ........................................................................................85
7.11.
Concomitant Medication or Treatment.......................................................................85
7.12.
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data.............................................................................................................................86
8.
ASSESSMENT OF PHARMACOKINETICS / PHARMACODYNAMICS............87
8.1.
Pharmacokinetic Assessment......................................................................................87
8.2.
Pharmacodynamics Assessment.................................................................................87
8.3.
Pharmacogenetics .......................................................................................................87
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics....................................................................87
9.
STATISTICS ..............................................................................................................89
9.1.
Sample Size and Power Considerations .....................................................................89
9.2.
Analysis Sets...............................................................................................................89
9.2.1.
Intent-to-Treat Analysis Set........................................................................................89
9.2.2.
Modified Intent-to-Treat Analysis Set........................................................................89
9.2.3.
Safety Analysis Set.....................................................................................................89
9.2.4.
Per-Protocol Analysis Set...........................................................................................89
9.2.5.
Additional Analyses Sets............................................................................................90
9.3.
Data Handling Conventions........................................................................................90
9.4.
Study Population.........................................................................................................90
9.4.1.
Patient Disposition......................................................................................................90
9.4.2.
Demographic and Baseline Characteristics ................................................................90


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9.5.
Efficacy Analysis........................................................................................................90
9.5.1.
Primary Endpoint........................................................................................................90
9.5.2.
Key Secondary Endpoints...........................................................................................90
9.5.3.
Exploratory Endpoints................................................................................................91
9.5.4.
Safety Endpoints.........................................................................................................91
9.5.5.
Planned Method of Analysis.......................................................................................91
9.5.5.1.
Primary Efficacy Analysis..........................................................................................92
9.5.5.2.
Sensitivity Analysis ....................................................................................................92
9.5.5.3.
Key Secondary Efficacy Analyses..............................................................................92
9.5.5.4.
Exploratory Analyses..................................................................................................93
9.6.
Multiple Comparisons and Multiplicity......................................................................94
9.7.
Safety Analysis ...........................................................................................................94
9.7.1.
Safety Analysis ...........................................................................................................94
9.8.
Tolerability Analysis ..................................................................................................95
9.9.
Pharmacokinetic Analysis ..........................................................................................95
9.10.
Planned Interim Analysis............................................................................................95
9.11.
Reporting Deviations from the Statistical Plan ..........................................................95
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................96
11.
COMPLIANCE STATEMENT..................................................................................96
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................96
13.
FINANCING AND INSURANCE.............................................................................97
14.
REFERENCES ...........................................................................................................98
15.
SUMMARY OF CHANGES TO PROTOCOL .......................................................100
15.1.
Amendment 03 Dated 05 May 2019.........................................................................100
15.2.
Amendment 02 Dated 25 March 2019......................................................................103
15.3.
Amendment 01 Dated 20 November 2017 ...............................................................132
APPENDIX A.
DISTRIBUTION OF AUG BY WEIGHT CATEGORIES AND 
CYP2D6 STATUS....................................................................................................153
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................154
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................163
APPENDIX D.
ETHICS ...........................................................................................................165
APPENDIX E.
 
...........................................................................................167


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APPENDIX F.
LOST TO FOLLOW-UP .................................................................................168
APPENDIX G.
HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR IMP ..................................................................................................................169
APPENDIX H.
ALLOWED AND PROHIBITED MEDICATIONS ......................................170
APPENDIX I.
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW FOR 
CHILDREN AND ADOLESCENTS.......................................................................177
APPENDIX J.
CHILDREN’S DEPRESSION INVENTORY SECOND EDITION, 
PARENT AND SELF-REPORT PROFILES...........................................................195
APPENDIX K.
CHILDREN’S COLUMBIA-SUICIDE SEVERITY RATING SCALE........203
APPENDIX L.
.......209
APPENDIX M.
YALE GLOBAL TIC SEVERITY SCALE ...................................................222
APPENDIX N.
...............231
APPENDIX O.
 
.....................................................................................232
APPENDIX P.
.........................................................234
APPENDIX Q.
 
 
......................................................................................................235
APPENDIX R.
PRODUCT COMPLAINTS ............................................................................240
APPENDIX S.
DATA MANAGEMENT AND RECORD KEEPING....................................242


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LIST OF TABLES
Table 1:
Daily Dose of IMP by Baseline Body Weight Category, CYP2D6 
Impairment, and Study Week .....................................................................................48
Table 2:
Study Procedures and Assessments............................................................................50
Table 3:
Investigational Medicinal Products Used in the Study...............................................60
Table 4:
Blood Volumes...........................................................................................................67
Table 5:
The Relationship of an Adverse Event to the IMP.....................................................73
Table 6:
Clinical Laboratory Tests ...........................................................................................82
Table 7:
Allowed Medications................................................................................................170
Table 8:
Allowed Strong CYP Inhibitors at Baseline............................................................171
Table 9:
Prohibited Antipsychotic Drugs ...............................................................................172
Table 10:
Prohibited QTc Prolonging Drugs............................................................................176
Table 11:
Other Prohibited Drugs.............................................................................................176


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................46
Figure 2:
Distribution of AUC of Total (α+β)-HTBZ for Selected Doses Based on 
Weight Categories ....................................................................................................153


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LIST OF ABBREVIATIONS
Abbreviation
Term
α-HTBZ
alpha-dihydrotetrabenazine
β-HTBZ
beta-dihydrotetrabenazine
β-HCG
beta-human chorionic gonadotropin
λz
apparent plasma terminal elimination rate constant
ADHD
Attention Deficit Hyperactivity Disorder
ALT
alanine aminotransferase (SGPT)
ALP
alkaline phosphatase
AST
aspartate aminotransferase (SGOT)
AUC
area under the plasma concentration-time curve
AUC0-t
area under the plasma concentration-time curve from time 0 to the time of the last 
measurable IMP concentration
AUC0–tmax
area under the plasma concentration-time curve from time 0 to the time of median tmax
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
BLA
Biological License Application
BMI
body mass index
BP
blood pressure
CA
Competent Authority
CDI-2
Children’s Depression Inventory Second Edition
CDMS
clinical data management system
CFR
Code of Federal Regulations (USA)
CGI-C
Clinical Global Impression of Change
CIOMS
Council for International Organizations of Medical Sciences
CL/F
apparent total plasma clearance (except for metabolites)
Cmax
maximum observed concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CST
Clinical Surveillance and Training


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Abbreviation
Term
CTA
Clinical Trial Application
CTFG
Clinical Trial Facilitation Group
CYP
cytochrome P4502D6
C&A-GTS-QOL
Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life scale
DMC
Data Monitoring Committee
DSM-V™
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EC
Ethics Committee
ECG
electrocardiogram
EMA
European Medicines Agency
ERA
European Regulatory Affairs
EU
European Union
EudraCT
European Clinical Trials
EV
EudraVigilance 
GCP
Good Clinical Practice
GCO
Global Clinical Operations
GPSP
Global Patient Safety and Pharmacovigilance
GQA
Global Quality Assurance
GRA
Global Regulatory Affairs
HD
Huntington disease
IB
Investigator’s Brochure
ICF
informed consent form
ICH
The International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug
INN
international nonproprietary name
IRB
Institutional Review Board
ITT
intent-to-treat
LAM
lactational amenorrhea methods 


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Abbreviation
Term
LSO
local safety officer
MAA
Marketing Authorisation Application
MINI Kid
Mini International Neuropsychiatric Interview for Children and Adolescents
mITT
modified intent to treat
MTD
maximum tolerated dose
n
number
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NIMP
Non-Investigational Medicinal Products
NOAEL
no-observed-adverse-effect level
OCD
obsessive-compulsive disorder
OTC
over-the-counter
PD
pharmacodynamics
PGx
pharmacogenetics
PND
postnatal day
PP
per-protocol
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RA
Regulatory Affairs
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOP
Standard Operating Procedure
SpO2
saturation of peripheral oxygen
SUSAR
suspected unexpected serious adverse reaction
t½
elimination half-life
TD
tardive dyskinesia
TS
Tourette syndrome
TS-CGI
Tourette Syndrome-Clinical Global Impression
TS-PGII
Tourette Syndrome-Patient Global Impression of Impact
TTS
Total Tic Score


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Abbreviation
Term
UDS
urine drug screen
ULN
upper limit of normal
US
United States (of America)
USA
United States of America
V
visit
VAS
visual analog scale
Vz/F
apparent total volume of distribution (except for metabolites)
W
week
WHO
The World Health Organization
WHO Drug
World Health Organization Drug Dictionary
YGTSS
Yale Global Tic Severity Scale


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and 
phonic tics that frequently co-occurs with a variety of behavioral and psychiatric problems 
(Jankovic 2001, Jankovic and Kurlan 2011). Studies have suggested that the prevalence 
estimates of TS among children vary widely from 0.4% to 5% in community samples (Bitsko et 
al 2014). 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 and
clonidine), typical neuroleptics (haloperidol, pimozide, and fluphenazine), or atypical 
neuroleptics (olanzapine, ziprasidone, and 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, developed deutetrabenazine (referred to 


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as TEV-50717, previously SD-809) that is eliminated more slowly than 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 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 (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 approved for the treatment of chorea associated with HD and for the treatment 
of TD on 03 April 2017 and 30 August 2017, respectively.
The purpose of the study is to determine whether TEV-50717 is effective in the treatment of tics 
associated with TS in male and female patients between 6 and 16 years of age.
1.2.
Name and Description of Investigational Product
TEV-50717 (deutetrabenazine), the investigational medicinal product (IMP), 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. 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 40-count tablets per dose 
strength per blister pack.
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 Investigator’s Brochure (IB).
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 non-deuterated forms (Scherman et al 1988). 
Off-target binding occurs at a similar extent with deuterated and non-deuterated 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 
known response in rats to drugs which reduce central nervous system dopamine concentrations 
(Fuenmayor and Vogt 1979), was similar in magnitude after TEV-50717 and tetrabenazine 
administration. 


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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, and 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 isozymes or transporters nor an inducer of CYP isozymes. M4, a major 
metabolite of tetrabenazine and TEV-50717 is neither an inhibitor of major CYP isozymes or 
transporters nor an inducer of CYP isozymes.
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 subsequent 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 was 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).


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The NOAEL (no-observed-adverse-effect level) 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:

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 and Phase 3 studies in patients with TD

1 completed Phase 1b 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 subjects. In
addition, sparse pharmacokinetic sampling was included in the Phase 3 studies with HD and TD 
patients where a population pharmacokinetic analyses including these data have been performed 
to extensively evaluate both the pharmacokinetics and pharmacokinetic-pharmacodynamic 
relationship of TEV-50717. A summary of the clinical pharmacology findings is provided in the 
IB.
Pharmacometric analyses of the active metabolites of TEV-50717 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 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 a pharmacologic activity indistinguishable from tetrabenazine, a VMAT2 
inhibitor with established efficacy in treating the motor and phonic tics associated with TS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.2.3.
Pharmacometrics Analysis of TEV-50717 Active Metabolites to Support Dose 
Selection and Pharmacokinetic Characterization in a Pediatric Population
Population pharmacokinetic modeling of the TEV-50717 active metabolites -HTBZ and 
β-HTBZ has been performed throughout the clinical development program. Based on robust 
pharmacokinetic sampling data obtained in healthy volunteers in the Phase 1 program, a 
structural population pharmacokinetic model was developed to guide dose selection for HD 
patients with chorea (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 
pharmacokinetic 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 A). 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 provides the basis for the dosing recommendations in Section 5.1. 
1.4.
Known and Potential Benefits and Risks to Patients
1.4.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product
Additional information regarding benefits and risks to patients may be found in the IB and the 
United States prescribing information for AUSTEDO™(deutetrabenazine).


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2.
STUDY OBJECTIVES AND ENDPOINTS
This is a Phase 3 study to evaluate the efficacy and safety of deutetrabenazine (TEV-50717) 
tablets for the reduction of motor and phonic tics associated with TS in children and adolescents 
6 through 16 years of age.
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of the 
study is to evaluate the 
efficacy of fixed doses of 
TEV-50717 to reduce motor 
and phonic tics associated 
with TS.
The primary efficacy endpoint is the change in the Total Tic Score 
(TTS) of the Yale Global Tic Severity Scale (YGTSS) from 
baseline to week 8 between high-dose TEV-50717-treated patients 
and placebo-treated patients.
Secondary objectives
The secondary efficacy endpoints are as follows:
1. change in the TS-CGI score from baseline to week 8 between 
high-dose TEV-50717-treated patients and placebo-treated 
patients
2. change in the TTS of the YGTSS from baseline to week 8 for 
low-dose TEV-50717 and placebo will be tested
3. change in the TS-CGI score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated 
patients
4. change in the Tourette Syndrome-Patient Global Impression 
of Impact (TS-PGII) score from baseline to week 8 between 
high-dose TEV-50717-treated patients and placebo-treated 
patients
5. change in the TS-PGII score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated 
patients
6. change in the Child and Adolescent Gilles de la Tourette 
Syndrome – Quality of Life- scale (C&A-GTS-QOL) 
activities of daily living (ADL) subscale from baseline to 
week 8 between high-dose TEV-50717-treated patients and 
placebo-treated patients
7. change in the C&A-GTS-QOL ADL subscale from baseline 
to week 8 between low-dose TEV-50717-treated patients and 
placebo-treated patients
The hierarchy of testing of secondary endpoints regarding dose 
level to control type I error is specified in the section entitled 
“Analysis of Key Secondary Endpoints.”


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2.1.1.
Justification of Primary Endpoint
 
 
2.2.
Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 


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2.3.
Safety Endpoints
Objectives
Endpoints
A secondary objective is to 
evaluate the safety and 
tolerability of TEV-50717.
The safety endpoints are as follows:

incidence of adverse events

observed values and changes from baseline in vital 
signs

observed values and change from baseline in the 
Children’s Depression Inventory Second Edition (CDI-
2; Parent and Self-report Profiles)

observed values in the children’s Columbia Suicide 
Severity Rating Scale (C-SSRS)

observed values and changes from baseline in 
electrocardiogram (ECG) parameters and shifts from 
baseline for clinically significant abnormal findings

observed values and changes from screening in clinical 
laboratory parameters (hematology, chemistry, and 
urinalysis)
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.
2.4.
Pharmacokinetic Endpoint
The pharmacokinetics of the α-HTBZ and β-HTBZ metabolites of TEV-50717 will be explored 
based on sparse sampling (2 samples) at week 8.


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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a Phase 3, randomized, double-blind, placebo-controlled, 8-week treatment study in 
which patients with tics associated with TS will be invited to participate. Patients will be 
randomized to low-dose TEV-50717, high-dose TEV-50717, or placebo (1:1:1). The target dose 
for each patient receiving TEV-50717 will be based on the group to which they are randomized, 
body weight at baseline, and cytochrome P450 2D6 (CYP2D6) impairment status. 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, which 
will be used only by IRT for randomization into the study.
Prescreening period (up to 3 months before baseline): For patients who require discontinuation 
of certain prohibited concomitant medications 3 months before baseline (depot neuroleptics, 
botulinum toxin, or tetrabenazine), informed consent/assent, depending on the child’s age, as 
appropriate, should be obtained prior to discontinuing the prohibited medication.
Screening period (up to 31 days): 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, 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. The Mini 
International Neuropsychiatric Interview for Children and Adolescents, or MINI Kid, is a short 
questionnaire (largely yes/no questions) to screen for clinically significant underlying psychiatric 
illness that may affect the subject’s eligibility. The assessment will focus on detecting major 
depression, mania/hypomania, obsessive/compulsive disorder, alcohol and substance abuse, 
attention deficit hyperactivity and conduct disorders, and psychotic disorders.
At the discretion of the investigator, the screening visit may be divided into 2 visits to reduce the 
burden on patients. If the screening visit is divided into 2 visits, the blood sample should be 
obtained during the first of the 2 visits. Patients will return to the clinic on day 1 for baseline 
procedures and to re-confirm eligibility. Patients may be rescreened 1 time if there is a change in 
the status of the patient regarding eligibility for the study. (Note: Details of rescreening must be 
approved and documented by the medical monitor and/or Clinical Surveillance and Training 
[CST] team.)
Treatment period (8 weeks): Patients who continue to remain eligible for participation in the 
study will be randomized at the baseline visit (day 1) and will receive blinded IMP to begin that 
same day (day 1). Tablets should be taken with food (eg, a snack) and should not be taken on an 
empty stomach. Patients and their caregiver/adult will interact regularly with the clinical research 
staff, either by telephone contact or clinic visit to assure adherence with study procedures and to 
evaluate safety and efficacy. To this end, clinic visits will be performed at weeks 2, 4, and 8 after 
baseline to evaluate safety; assess tic severity with the YGTSS, TS-CGI, TS-PGII, and the 
C&A-GTS-QOL; and perform safety rating scales to augment adverse event reporting, 
concomitant medication usage, clinical laboratory examination, and 12-lead ECGs. Telephone 
contacts will occur at the end of weeks 1, 3, 6, and 7.


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As this is a fixed-dose study, patients will undergo dose escalation (ie, forced titration) to their 
target dose over the first 4 weeks of treatment. If a patient experiences depression, suicidal 
ideation or behavior, anxiety, akathisia, parkinsonism, or somnolence, or any other adverse event
that interferes with daily activity, or any adverse event that is related to IMP, a single dose 
reduction is permitted. The investigator must discuss any further dose adjustments (eg, holding 
the dose or doses) with the medical monitor.
In case of such an adverse event, the investigator will determine if a dose reduction or 
suspension is necessary. If it is determined that a dose reduction or suspension is required, the 
medical monitor must be contacted. All available information, including the patient and 
caregiver/adult reports of adverse events, the clinical assessment of safety by the investigator, 
and information from rating scales should be incorporated in the decision. This reduced dose will 
become the patient’s dose for the remainder of the study.
Patients will return to the clinic at week 8 for the final on-treatment assessment of safety and 
efficacy. At this visit, patients will undergo a complete evaluation, including performance of all 
efficacy measures (including assessment of tic severity with the YGTSS), and complete safety 
testing (including physical and neurological examination, safety laboratory testing, 12-lead ECG, 
and all rating scales). In addition, patients will undergo pharmacokinetic sampling at week 8, at 
which time 2 pharmacokinetic specimens will be obtained 2 to 3 hours apart. Prior to the clinic 
visit on week 8, patients will be reminded to record in their diary the start time of their last meal 
and the time of their last dose of study medication before the week 8 visit. The site will 
document the date and time of the sample collection. 
Follow-up: All patients will discontinue IMP at the week 8 visit and will return 1 week later for 
evaluation of safety and tic reduction (week 9). 
Patients who complete the study may be eligible to begin participation in an open-label safety 
extension Study TEV-50717 (Study TV50717-CNS-30047). For this study, the follow-up period 
is defined as 1 week of washout for patients who will participate in the open-label safety 
extension Study TV50717-CNS-30047 and 2 weeks after the last dose of IMP (1 week after the 
end of the washout period) for patients who will not roll over into the open-label safety extension 
Study TV50717-CNS-30047. Patients not participating in the open-label safety extension study 
for TEV-50717 will have a follow-up telephone contact for safety evaluation 1 week after the 
end of the treatment period (2 weeks after their last dose of IMP).
The end of study is defined as the date of the week 10 telephone contact with the last participant.
Prohibited drugs will remain the same during the washout period for patients who will participate 
in the open-label extension Study TV50717-CNS-30047. Patients who will not participate in the 
extension study may begin/resume tic therapy medication after the first week of the washout 
period. 
The study duration will be approximately 17 months from January 2018.
The study schematic diagram is presented in Figure 1.


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Figure 1:
Overall Study Schematic Diagram
6-36 mg
(Week 4/ 
Days 22-28)
6-30 mg
(Week 3/ 
Days 15-21) 
6-24 mg
(Week 2/ 
Days 8-14)
6-12 mg
(Week 1/ 
Days 1-7)
Screening
Escalation Perioda
Maintenance Period
Follow-Up
Week 1
Week 2
Baseline
Up to 31
days
Week 8/ET End-of-Study Visit
Option of 
participation 
in long-term 
safety study
In-clinic visit
Telephone call
1 Week
Stable maintenance dose
a
If a stable dose is reached before the indicated time, the patient should continue taking that dose for the 
remainder of the escalation period and throughout the maintenance period. See Table 1 for the maximum 
dose of IMP and escalation by CYP impairment status, week, and baseline body weight category.
b
This is a telephone contact for safety evaluation, required only for patients who will not participate in the 
open-label safety extension study for TEV-50717.
c
Ranges account for different dosing schedules for patients with baseline weight ≥40 kg; 
≥40 kg, CYP impaired; 30 to <40 kg; 30 to <40 kg, CYP impaired; 20 to <30 kg; and 20 to <30 kg, 
CYP impaired. See Table 1 for daily dose by category.
CYP=cytochrome P4502D6; CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a 
CYP2D6 poor metabolizer; ET=early termination visit.
Note: An unscheduled visit will require a clinic visit. 
Day 1 
Week 3
Week 4
Week 7
Week 8
Week 9
Week 10b
1:1:1 Randomization TEV-50717 high; TEV-50717 low; Placebo
N=150, 50 per treatment arm
Dose rangec
(low dose)
Week 6  
Dose rangec
(high dose)  
6-12 mg 
(Week 1/ 
Days 1-7)
12-24 mg 
(Week 2/ 
Days 8-14)
12-36 mg 
(Week 3/ 
Days 15-21) 
12-48 mg 
(Week 4/ 
Days 22-28) 
Stable maintenance dose


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3.2.
Planned Number of Patients and Countries
The number of evaluable patients is planned to be 150. Details on sample size are given in
Section 9.
The study is planned to be conducted in approximately 10 countries in approximately 
55 investigational centers. The study is expected to start in January 2018 and last for 
approximately 17 months. 
3.3.
Justification for Study Design and Selection of Population
Standard placebo-controlled, double-blind study design (TEV-50717 [low dose and high dose] vs 
placebo in a 1:1:1 ratio) was chosen to determine whether IMP treatment results in a statistically 
significant effect on tics in patients with TS.
The population to be studied includes children and adolescents, 6 through 16 years of age. Per 
eligibility criteria, the participants’ tics need to be troublesome and cause distress or impairment
based on the assessment of the patient, parent/guardian, and investigator. Based on these criteria, 
this is a study population in need of treatment.
3.4.
Drug Administration
IMP will be administered as follows:

IMP should be swallowed whole and 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 at the baseline 
visit, as shown in Table 1.

The total daily dose, as provided in Table 1, is divided into a twice-daily 
administration. Two tablets will be taken twice daily starting at day 1 per Table 1. 
Daily doses will be administered twice daily, approximately 8 to 10 hours apart 
during the day. Depending on the dose and arm assigned, TEV-50717 tablets and/or 
placebo tablets will be taken to maintain the blind. 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 escalations may not occur more frequently than once every 5 days.

The dose of IMP will be escalated weekly during the escalation period, according to 
Table 1.

In the case of an adverse event, the investigator is permitted to perform a single dose 
reduction of 6 mg. The investigator must discuss any further dose adjustments 
(eg, holding the dose or doses) with the medical monitor.

During the titration period, the dose of the IMP will be adjusted weekly according to 
Table 1. Investigators will be blinded to CYP status, with a dose cap for poor 
metabolizers prespecified by the IRT.
IMP will be packaged in blister packs and provided for patients to take at home (see Section 5.1).


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Table 1:
Daily Dose of IMP by Baseline Body Weight Category, CYP2D6 Impairment, 
and Study Week
Dose group
Baseline weight (kg)
Daily dose (mg) at the start of visit/weeka
Week 1
(Days 1-7)
Week 2
(Days 8-14)
Week 3
(Days 15-21)
Week 4 main dose 
(Days 22-28) to Week 8 
main dose (Days 50-56)
Low dose
≥40 
12
24
30
36
≥40, CYP impaired
6
12
18
18
30 to <40
6
12
18
24
30 to <40, CYP impaired
6
12
12
12
20 to <30
6
12
18
18
20 to <30, CYP impaired
6
6
6
6
High dose
≥40 
12
24
36
48
≥40, CYP impaired
6
15
24
30
30 to <40
12
24
30
36
30 to <40, CYP impaired
6
12
18
18
20 to <30
12
18
24
30
20 to <30, CYP impaired
6
12
12
12
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.
CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor metabolizer.
Pharmacokinetic data will be reviewed at the week 8 visit. Evaluation of pharmacokinetic data 
will include review of the measurement of plasma concentrations of TEV-50717 
(deutetrabenazine), α-HTBZ, β-HTBZ, and other metabolites, as required.
3.5.
Stopping Rules for the Study
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of the following:

new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment

discontinuation of the development of the IMP


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3.6.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 2. During a visit, 
study procedures and assessments should be performed in the order specified in the study 
manual. Detailed descriptions of each method of procedures and assessments are provided in 
Section 6 (efficacy assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetic 
and other assessments). Study procedures and assessments by visit are listed in Appendix B.


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Table 2:
Study Procedures and Assessments
Prescreening Screening BLa
Escalation period (weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unscheduled
Study weekb
Up to 
3 months
Up to 
31 days
Day 1
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 42)
7
(Day 49)
8/
ETc
(Day 56)
9
(Day 
63)
10d
(Day70)
Visit window (days)
0
±3 days
±3 days from 
week 8
Informed 
consent/assent
X
X
Randomization 
X
Clinic visit
Xe
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
Dose escalationf
X
X
X
Xg
Eligibility criteria
X
X
Medical and 
psychiatric history
X
Demographics
X
Vital signs and 
weighth
X
Xi
X
Xi
Xi
X
X
Physical examination
X
X
Xj
Neurological 
examination
X
X
Xj
Height
X
X
12-Lead ECGk
X
X
X
X
Xj
PK blood sampling
Xl
Chemistry / 
hematology / 
urinalysis
X
X
Xj


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Table 2:
Study Procedures and Assessments (Continued)
Prescreening Screening BLa
Escalation period (weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unscheduled
Study weekb
Up to 
3 months
Up to 
31 days
Day 1
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 42)
7
(Day 49)
8/
ETc
(Day 56)
9
(Day 
63)
10d
(Day70)
Visit window (days)
0
±3 days
±3 days from 
week 8
Urine drug screen
X
X
Xj
CYP2D6 genotypem
X
β-HCG testn
X
X
X
X
Xj
MINI Kido
X
CDI-2 (Parent and 
Self-report Profiles)p
X
X
X
X
X
X
Xj
C-SSRS (Children’s 
Baseline/Screening)q
X
C-SSRS (Children’s 
Since Last Visit)q
X
X
X
X
X
Xj
YGTSSr s
X
X
Xt
X
X
Xt
TS-CGIs
X
X
X
X
X
TS-PGIIs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xu
X
Xu
C&A-GTS-QOLq
X
X
X
Xj
Dispense IMPv
X
X
X
Xj
Collect IMP
X
X
X
Xj


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Table 2:
Study Procedures and Assessments (Continued)
Prescreening Screening BLa
Escalation period (weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unscheduled
Study weekb
Up to 
3 months
Up to 
31 days
Day 1
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 42)
7
(Day 49)
8/
ETc
(Day 56)
9
(Day 
63)
10d
(Day70)
Visit window (days)
0
±3 days
±3 days from 
week 8
Assess IMP 
accountability / 
compliance / supply
Xw
X
Xw
X
Xw
Xw
X
Xj
Assess AEs
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
a The baseline visit (day 1) will occur the same day as the scheduled first dose of the IMP (day 1).
b Assessment will be performed at the end of study week (±3 days). 
c For patients who withdraw prematurely, an early termination visit should be conducted as soon as possible after the last dose of IMP. In addition, 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 10. 
d This visit is a telephone contact for safety evaluation, required only for patients who will not roll over into the open-label safety extension study for 
TEV-50717. 
e The screening visit may be conducted over 2 separate visits at the discretion of the investigator. If the screening visit is divided into 2 visits, the blood sample 
should be obtained during the first of the 2 visits.
f Patients will be provided with a diary at baseline, week 2, week 4, and at unscheduled visits, to record critical information on dosing. The date and time of the 
last dose of study medication before the week 8 visit should be recorded in the diary by the patient or caregiver/adult. The site will document the date and time 
of the sample collection. Prior to the clinic visit on week 8, patients will be reminded to record the start time of their last meal and the time of their last dose in 
their diary.
g Dose escalation will only occur during the dose escalation period (ie, from week 1 to week 4).
h Weight must be measured with shoes and outerwear off.
i Orthostatic blood pressure and pulse will be measured after patient is in standing position for at least 3 minutes.
j Assessment will be completed at investigator’s discretion.
k All ECGs will be performed after at least 5 minutes of rest in a supine or semi-supine position.
l Two samples will be collected. The first sample will be collected upon arrival at the clinic. The second sample will be collected within 2 to 3 hours after the 
first PK sample collection. Patients with early morning visits (ie, within 2 hours of their scheduled AM dosing) should take their IMP dose in the clinic after the 
first PK sample is collected.


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m The patient’s genotype for CYP2D6 will be blinded during the conduct of the study, except for the sample analysis and IRT vendor.
n For females who are postmenarchal or ≥12 years of age, a urine test will be administered at baseline and at week 4, while a serum test will be administered at 
screening, week 8, and if clinically indicated.
o MINI Kid (children and adolescents) modules to be used are 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 Children 6 years of age at baseline will not complete the self-report version; the caregiver/adult will complete the parent version.
q 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.
r Input from the caregiver/adult is required.
s The YGTSS, TS-CGI, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG assessments.
t 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).
u Perform the Severity Ratings of OCD symptoms (Questions 1 through 10) only. Checklist does not need to be performed.
v Contact IRT and dispense IMP and patient diary. 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 during escalation. See Table 1 for baseline weight-based dosing titration. At week 4, patients will receive doses for 4 
weeks of treatment.
w The site needs to discuss the drug status during the telephone contacts to ensure that the patient has adequate tablets, inform the patient if they should escalate, 
and remind them to bring completed blister packs to the next in-clinic visit.
AE=adverse event; ADHD=Attention Deficit Hyperactivity Disorder; β-HCG=beta-human chorionic gonadotropin; BL=baseline visit; 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- scale; IMP=Investigational Medicinal Product; IRT=Interactive Response Technology; MINI Kid=Mini 
International Neuropsychiatric Interview For Children and Adolescents; OCD=obsessive-compulsive disorder; PK=pharmacokinetic; TS-CGI=Tourette 
Syndrome-Clinical Global Impression; TS-PGII=Tourette Syndrome-Patient Global Impression of Impact; 
 
; YGTSS=Yale Global Tic Severity Scale.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix C).
4.1.
Patient Inclusion Criteria
Patients may be included in this study only if they meet all of the following criteria:
a.
Patient is 6 to 16 years of age, inclusive, at baseline. 
b. Patient weighs at least 44 pounds (20 kg) at baseline.
c.
Patient meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-V™) diagnostic criteria for TS and, in the opinion of the investigator, 
patient, and caregiver/adult, the patient’s active tics are causing distress or 
impairment.
d. Patient has a TTS of 20 or higher on the YGTSS at screening and baseline. 
e.
Patient is able to swallow study medication whole.
f.
Patient and caregiver/adult are willing to adhere to the medication regimen and to 
comply with all study procedures.
g. Patient is in good general health, as indicated by medical and psychiatric history as 
well as physical and neurological examination.
h. 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.
i.
Patient and caregiver/adult provided written informed consent/assent, depending on 
the child’s age, as appropriate, according to local regulations.
j.
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 at baseline or are 
sterile. Definitions of sterile are given in Appendix E.
k. 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 the last dose of IMP. Further details are included 
in Appendix E.
l.
The patient must be willing and able to comply with study restrictions and to remain 
at the clinic for the required duration during the study period and willing to return to 
the clinic for the follow-up evaluation as specified in this protocol.


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4.2.
Patient Exclusion Criteria
Patients will not be randomized/enrolled in this study if they meet any of the following criteria: 
a.
Patient has a neurologic disorder other than TS that could obscure the evaluation of 
tics.
b. The patient’s predominant movement disorder is stereotypy (coordinated movements 
that repeat continually and identically) associated with autism spectrum disorder. 
c.
Patient has clinically significant obsessive-compulsive disorder (OCD) at baseline 
that, in the opinion of the investigator, is the primary cause of impairment.
d. Patient has clinically significant depression at screening or baseline. 
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 
6 weeks before baseline (see Table 9 for prohibited antidepressants).
e.
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
f.
Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
g. Patient has a first-degree relative who has completed suicide.
h. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another 
psychotic disorder.
i.
Patient has a DSM diagnosis based on the Mini International Neuropsychiatric 
Interview For Children and Adolescents Inventory at screening that, in the opinion of 
the investigator, makes the patient unsuitable for the study. 
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 
following specified exclusionary windows of first dose:

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 H, Table 9), metoclopramide, levodopa, and dopamine agonists


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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, and no 
changes to dose or frequency are anticipated during the course of the study.
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, and no 
changes to dose or frequency are anticipated during the course of the study.
Note: Use of benzodiazepines is allowed if 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 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 TS) 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. If discontinuation of either medication is anticipated 
due to ineffectiveness, poor tolerability, or patient/caregiver preference, 
discontinuation should occur 4 or more weeks prior to the screening visit.
l.
Patient has received treatment with deep brain stimulation, transmagnetic stimulation, 
or transcranial direct current stimulation within 4 weeks of the screening visit for 
reduction of tics. 
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 a 12-lead electrocardiogram (ECG) at screening, or requires 
treatment with drugs known to prolong the QT interval (see Appendix H, Table 10 for 
a complete list of prohibited QT-prolonging drugs).
n. Patient has a history of torsades de pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart failure. 
o. Patient has evidence of hepatic impairment, as indicated by the following:

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 >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 total bilirubin.
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 baseline 
visit.


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r.
Patient has a known allergy to any of the components of the IMP product.
s.
Patient has participated in an investigational drug or device study and received 
IMP/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
t.
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 DSM-V™.
v. Patient has a positive urine drug screen test result or is unable to refrain from 
substance abuse throughout the study.
4.3.
Withdrawal Criteria and Procedures for the Patient
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
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 (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 5.10.2). 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 5.7).
In addition, a patient may be withdrawn from the study as described in 
Sections 3.5, 5.10, 5.7, 7.1.7, and Appendix B. 
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 Appendix B.


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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 (Appendix B). 
4.4.
Replacement of Patients
A patient who is enrolled but does not complete the treatment period will not be replaced.
4.5.
Rescreening
A patient who is screened but not enrolled may be rescreened 1 time if there is a change in the 
status of the patient regarding eligibility for the study. (Note: Details of rescreening must be 
approved and documented by the medical monitor and/or Clinical Surveillance and Training 
[CST] team.) 
If the patient is rescreened, an informed consent/assent form (ICF) will need to be resigned.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/enrolled in the study. Minimal information includes but is not 
limited to demography, screening failure details, eligibility criteria, and any serious adverse 
events.


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5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
IMP is defined as the test IMPs, reference IMPs, and matching placebo IMPs to the respective 
test and reference IMPs.
5.1.1.
Test Investigational Medicinal Product
The investigational product is a matrix formulation and is designed as a tablet to be administered 
with food (eg, a snack) 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. TEV-50717 tablets will be 
supplied as 6-, 9-, 12-, 15-, and 18-mg tablets and will be packaged in blister packs and labeled 
according to applicable regulatory guidelines. Each blister pack (40-count tablets per dose 
strength per blister pack) will contain a sufficient supply of drug until the next specified 
visit/telephone contact, plus overage to account for potential delays in study visits. 
Additional details may be found in the IB for TEV-50717.
5.1.1.1.
Starting Dose and Dose Levels
Two active-dose levels were selected for this study. The target population, children 6 to 16 years 
of age, inclusive, will vary considerably in body weight. There will also be varying impairment 
of the drug metabolizing enzyme CYP2D6, whether from use of certain concomitant medications 
that inhibit the enzyme or genetic predisposition to poor metabolism of CYP2D6 substrates. 
5.1.1.2.
Dose Modification and Dose Stratification
As this is a fixed dose study, patients will undergo dose escalation (ie, forced titration) to their 
target dose over the first 4 weeks of treatment (see Section 3.4 and Table 1). If a patient 
experiences depression, suicidal ideation or behavior, anxiety, akathisia, parkinsonism, or
somnolence, or any other adverse event that interferes with daily activity, or any adverse event 
that is related to IMP, a single dose reduction is permitted. The investigator must discuss any 
further dose adjustments (eg, holding the dose or doses) with the medical monitor. 
In case of such an adverse event, the investigator will determine if a dose reduction or 
suspension is necessary. If a determination is made that a dose reduction or suspension is 
required, the medical monitor must be contacted. All available information, including the patient 
and caregiver/adult reports of adverse events, the clinical assessment of safety by the
investigator, and information from rating scales should be incorporated in the decision. This 
reduced dose will become the patient’s dose for the remainder of the study.
5.1.2.
Placebo Investigational Medicinal Product
Placebo tablets match TEV-50717 tablets. The packaging will be the same as described for 
TEV-50717 above.


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Table 3:
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Reference IMP
(None)
Trade name and INN, if 
applicable, or 
company-assigned number
TEV-50717 (previously SD-809), deutetrabenazine
Not applicable
Not applicable
Formulation
film-coated tablet
film-coated tablet
Not applicable
Unit dose strength(s) / Dosage 
level(s)
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). IMP
will be supplied in 40-count tablets per dose 
strength per blister pack
Not applicable
Not applicable
Route of administration
oral
oral
Not applicable
Dosing instructions
The total daily dose, as provided in Table 1, is 
divided into a twice-daily administration. Two
tablets will be taken twice daily starting at day 1 per 
Table 1. Daily doses will be administered twice 
daily, approximately 8 to 10 hours apart during the 
day. Depending on the dose and arm assigned, 
TEV-50717 tablets and/or placebo tablets will be 
taken to maintain the blind. 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. Tablets should be 
swallowed whole and taken with food (eg, a snack) 
and should not be taken on an empty stomach.
The total daily dose, as provided in Table 1, is 
divided into a twice-daily administration. Two
tablets will be taken twice daily starting at day 1 
per Table 1. Daily doses will be administered twice 
daily, approximately 8 to 10 hours apart during the 
day. Depending on the dose and arm assigned, 
TEV-50717 tablets and/or placebo tablets will be 
taken to maintain the blind. 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. Tablets should be 
swallowed whole and taken with food (eg, a snack) 
and should not be taken on an empty stomach.
Not applicable
Packaging
IMP will be provided in blister packs
Placebo IMP will be provided in blister packs
Not applicable
Manufacturer
Not applicable
IMP=Investigational Medicinal Product


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5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.2.1.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The IMP (TEV-50717 and the placebo) 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 
and 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.
Diversion is considered to have occurred when the legal supply chain of prescription analgesic 
medicinal products is broken, and medicinal products are transferred from a licit to an illicit 
channel of distribution or use.
5.2.2.
Labeling
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language.
5.2.3.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs 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.
Only patients enrolled in the study may receive IMPs, and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator (or designee) will instruct the patient to store the IMP according to the 
instructions on the label, if applicable; or will give instructions in an appropriate form.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study 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 blister packs IMP 
will be disposed of, as agreed with the sponsor/development partner.


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5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
As body weight and CYP2D6 impairment are known predictors for exposure to the active 
circulating metabolites of TEV-50717, the “high” and “low” doses will represent a target 
exposure (area under the plasma concentration-time curve [AUC], maximum observed 
concentration (Cmax) rather than a fixed milligram amount of drug. The high dose targets a mean 
(CV%) AUC of approximately 1500 ng▪hr/mL (60%) and a mean (CV%) Cmax of approximately 
100 ng/mL (39%). These targets were chosen as they represent exposure in another population 
(HD patients) receiving up to 48 mg/day that was associated with robust efficacy and favorable 
tolerability. The low dose group targets a mean (CV%) AUC of approximately 1000 ng▪hr/mL 
(60%) and a Cmax of approximately 80 ng/mL (39%). Based on Phase 3 studies in both HD and 
TD patients, exposures associated with an AUC of approximately 1000 ng▪hr/mL are still 
anticipated to be efficacious.
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
A standard placebo-controlled, double-blind study design (TEV-50717 [low dose and high dose] 
vs placebo in a 1:1:1 ratio) was chosen to determine whether IMP treatment results in a 
statistically significant effect on the tics of patients with TS. As TS is not a progressive 
neurological disorder, and available treatments are for symptomatic control, the use of placebo is 
justified in a short-term study where safety is carefully monitored. Moreover, a placebo control is 
ideal for characterizing the efficacy and safety of an experimental agent in a new study 
population.
5.4.
Treatment after the End of the Study
Patients who complete the study may be eligible to begin participation in an open-label safety 
extension study of TEV-50717 (Study TV50717-CNS-30047). Patients not participating in the 
open-label safety extension study for TEV-50717 will have a follow-up telephone contact for 
safety evaluation 1 week after the end of the treatment period (2 weeks after their last dose of 
IMP).
5.5.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.6. 
While patients receiving strong CYP2D6 inhibitors such as paroxetine, fluoxetine, and 
bupropion at baseline 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 CYP inhibitor is prohibited. The use of quinidine and terbinafine are prohibited (see 
Appendix H, Table 11).
Restrictions in regard to sexual activity and required laboratory values are provided in the 
inclusion and exclusion criteria. 


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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.
5.6.
Prior and Concomitant Medication or Therapy
Any prior or concomitant medication a patient has had within 3 months before IMP 
administration and up to the end of study, including follow-up, will be recorded on the CRF. 
Generic or trade name, indication, dose, and start and end dates of the administered medication 
will be recorded. The sponsor will encode all medication according to the World Health 
Organization (WHO) drug dictionary (WHO Drug).
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. 
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. Allowed strong CYP inhibitors at baseline are shown in Appendix H, Table 8.
Addition of a strong CYP inhibitor is prohibited.
Prohibited antipsychotic drugs are listed in Appendix H, Table 9. Prohibited medications that are 
associated with QTc prolongation are listed in Appendix H, Table 10.
Concomitant medication and treatment will be monitored throughout the study.
5.7.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance until completion of the 
IMP administration according to the protocol or discontinuation from IMP. A check of 
compliance with IMP intake will be performed during each visit after the IMP has been 
dispensed; 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 from the study. The IEC/IRB should be notified as required by national and local 
regulations.
Exposure to IMP will be assessed as required.


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5.8.
Temporary Discontinuation of Investigational Medicinal Product
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. In the case of an adverse event, the investigator 
is permitted to perform a single dose reduction of 6 mg. The investigator must discuss any 
further dose adjustments (eg, holding the dose or doses) with the medical monitor.
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 2. 
Patients who withdraw from the study will proceed as described in Section 4.3.
5.9.
Randomization and Blinding
This is a Phase 3, randomized, double-blind, placebo-controlled, 8-week-treatment study in 
which patients with tics associated with TS will be invited to participate. Patients will be 
randomized to either TEV-50717 (low-dose, high-dose) or matching placebo in a 1:1:1 ratio 
using an Interactive Response Technology (IRT) based on their baseline weight and CYP 
impairment status. The patients will be stratified into 2 age groups (6 to 11 years and 
12 to 16 years). Patients and investigators will remain blinded to treatment assignment during the 
study. 
Patients will be centrally randomly assigned to the treatment groups by means of a 
computer-generated randomization list after confirmation of all eligibility criteria. The creation 
of the randomization list will be under the responsibility and oversight of Syneos Health.


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In addition, the sponsor’s clinical personnel and all vendors (with exception of the IRT vendor 
and the bioanalytical sample analysis vendor) involved in the study will be blinded to the IMP
identity until the database is locked for analysis and the treatment assignment revealed. After 
unblinding of this study, the study site may remain blinded to patient treatment assignments until 
completion of the safety extension Study TV50717-CNS-30047. 
The randomization list and treatment will be assigned to the relevant treatment groups through a 
qualified service provider (ie, via IRT). The generation of the medication list and 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.
5.10.
Maintenance of Randomization and Blinding
Patients will be randomly assigned to receive treatment with TEV-50717 (low dose, high dose) 
or matching placebo in a 1:1:1 ratio using an IRT based on their baseline weight and CYP 
impairment status. The patients will be stratified into 2 age groups (6- to 11-years and 12- to 16-
years). The sponsor will monitor enrollment in age strata to ensure there is adequate 
representation in each stratum. Patients and investigators will remain blinded to treatment 
assignment during the study. In addition, the sponsor’s clinical personnel and all vendors (with 
the exception of the IRT vendor and the bioanalytical sample analysis 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. However, if a prioritized sample analysis is needed, 
bioanalytical personnel may be unblinded.
5.10.1.
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.
5.10.2.
Blinding and Unblinding
Blinded pharmacokinetic data may be assessed during the study. For patients who have 
pharmacokinetic sample bioanalysis or data analysis conducted, the individuals responsible for 
sample bioanalysis and other responsible personnel will know who received active IMP and who 
received placebo during the study (of those patients only). Personnel responsible for bioanalysis 
will be provided with the randomization code to facilitate the analysis. However, the personnel 
responsible for bioanalysis and pharmacokinetic data analysis will not have access to clinical 
safety and efficacy data, and will provide concentration data to other personnel in a manner that 
will not identify individual patients (ie, a dummy patient identifier will be linked to the 
concentration data of an individual patient).
For information about personnel who may be aware of IMP assignments, see Section 5.9. These 
individuals will not be involved in the conduct of any study procedures or assessment of any 
adverse events.


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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. 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 Randomization and Trial 
Supply Management (RTSM), both via telephone and internet. If possible, the sponsor should be 
notified of the event before breaking of the code. If this is not possible, the sponsor should be 
notified immediately afterwards and the patient’s IMP assignment should not be given. Breaking 
of the randomization code can always be performed by the investigational center without prior 
approval by the sponsor.
When a blind is broken, the patient will be withdrawn from the study and the event will be 
recorded on the 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. 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 blinded studies, 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 (GPSP) 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.
5.10.3.
Data Monitoring Committee
During the conduct of this study, an IDMC will review accumulating safety and efficacy data on 
a regular basis to ensure the continuing safety of the study patients and 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 may 
be present, and information is provided and discussed in a blinded fashion. 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.


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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.
5.11.
Total Blood Volume
The total volume of blood to be collected for each patient in this study is approximately 35 mL, 
as detailed in Table 4.
Table 4:
Blood Volumes
Type of samples
Volume per sample
Total number of samples
Total volume
(maximum)
Clinical laboratory 
(chemistry/hematology)
10 mL
2
20 mL
Pharmacokinetic 
5 mL
1 time point (week 8) × 2 samples
10 mL
CYP2D6 genotyping
3 mL
1
3 mL
Optional 
pharmacogenetic sample
2 mL
1
2 mL
Total
35 mL
CYP2D6=cytochrome P450 2D6.
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 YGTSS and 
, and self-administered efficacy 
scales include 
 TS-PGII, 
, and C&A-GTS-QOL. 
6.1.
Primary Efficacy Measure and Justification
The primary efficacy measure is the TTS of YGTSS. 
The YGTSS is administered at screening; baseline; and weeks 2, 4, 8, and 9:

Complete assessment (Checklist and Severity Ratings) at screening, baseline, and 
weeks 4 and 8

Severity Ratings assessment only at weeks 2 and 9

Input from caregiver/adult is required for all subjects irrespective of age
The choice of YGTSS (specifically the TTS) as a primary efficacy measure is supported by its 
wide use in clinical practice for the evaluation of symptoms associated with TS and its successful 
use in the Phase 1b Study SD-809-C-17 (Section 1.3.2.2).
The YGTSS rating scale is a semi-structured clinician rating instrument that provides an 
evaluation of the number, frequency, intensity, complexity, and interference of motor and phonic 
tics (Leckman et al 1989). The items pertaining to the tic ratings are scored on 2 subscales: 
Motor Tics and Vocal Tics. Behaviors are rated on a 6-point scale. The scale has a look-back 
period of 1 week. Additionally, the scale assesses the severity of tics, which includes overall 
impairment of the patient, and combines motor and visual tic information into a TTS score. A 
GSS can then be determined by combining the patient’s severity rating with the TTS.
A reference sample is provided in Appendix I.
6.2.
Key Secondary Efficacy and Exploratory Measures
6.2.1.
Tourette Syndrome–Clinical Global Impression
The TS-CGI is administered at baseline and at weeks 2, 4, 8, and 9. 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 N.
6.2.2.
Tourette Syndrome-Patient Global Impression of Impact
The TS-PGII is administered at baseline and weeks 2, 4, 8, and 9. Input from the caregiver/adult
is permitted.
The TS-PGII is a single-item questionnaire that asks the patient to assess their 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 


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have face validity and have been shown to correlate with disability for a number of chronic 
conditions.
A reference sample is provided in Appendix O.
6.2.3.
 
 
 
 
6.2.4.
Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life Scale
The C&A-GTS-QOL is administered at baseline, week 4, and week 8. 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&A-GTS-QOL is a 27-item questionnaire specific to TS patients that asks the patient to 
assess the extent to which their quality of life is impacted by their symptoms. The C&A-GTS-
QOL contains 6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-
compulsive, and ADL) and uses a 5-point Likert scale ranging from no problem to extreme 
problem. Patients will also be asked how satisfied they feel overall with their life at that moment 
by using a VAS scale between 0 and 100 (Su et al 2017).
A reference sample is provided in Appendix Q.
6.2.5.
 
6.2.6.
 
 
 
 
 
 
 


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6.2.7.
 
 
 
 
 
 
 
 
 
 


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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 
medications, 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 (Note: A condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and that occurs during this study should 
be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or during any washout period 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 study 
treatment are not considered adverse events.)


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7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse event, the study period is defined for each patient as the time period 
from signature of the informed consent/assent form to the end of the follow-up period. For this 
study, there will be 1 week of washout for patients who will participate in the open-label safety 
extension Study TV50717-CNS-30047 and 2 weeks after the last dose of IMP for patients who 
will not roll over into the open-label safety extension Study TV50717-CNS-30047.
For subjects who experience an adverse event or serious adverse event after signing a 
prescreening ICF for Study TV50717-CNS-30060, the event will be documented in the subject 
source documents and Electronic Data Capture (EDC) systems. For serious adverse events, the 
serious adverse event form must be completed in addition, and the serious adverse event must be 
reported immediately to the sponsor (Section 7.1.5.3.1). If the subject attends the screening visit, 
the adverse event or serious adverse event identified during the prescreening period will be 
considered medical history. For data entry purposes in EDC, the stop date for the prescreening 
adverse event or serious adverse event will be the date of the screening visit, and the start date 
for the associated medical history will be the date of the screening visit.
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 (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.


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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
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:
Table 5:
The Relationship of an Adverse Event to the IMP
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
An additional blood sample for the measurement of IMP concentration should be collected, if 
possible, from each patient experiencing a serious 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.


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For recording of serious adverse event, 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 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:

results in death

is life-threatening adverse event (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 and caregiver/adult signed the informed 
consent/assent form will not be considered serious adverse events, unless there was 
worsening of the pre-existing 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

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 
>3x the upper limit of normal (ULN)

total bilirubin increase of >2x ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP])
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.


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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.
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 of that patient 
has ended should be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the LSO or designee (a CRO 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 GPSP.
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


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
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

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 GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file to the LSO/CRO 
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.
Blinding will be maintained for all study personnel. Therefore, in case of a SUSAR, only the 
LSO/CRO will receive the unblinded report for regulatory submission; the others will receive a 
blinded report. 
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 7.2).
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 action may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study


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
modifying the existing consent/assent 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.
7.1.7.
Withdrawal Due to an Adverse Event
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. 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 >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.
In addition, a blood sample should be obtained for the measurement of IMP concentrations, if 
possible. 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/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 CDI-2. 


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7.2.1.
Mini International Neuropsychiatric Interview for Children and Adolescents
Select MINI Kid modules are administered at screening only. 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-V™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 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 I.
7.2.2.
Columbia-Suicide Severity Rating Scale
The C-SSRS children’s baseline/screening scale assesses past and current suicidal ideation and 
behaviors to determine suicide risk and is administered at screening. C-SSRS children’s SLV 
scale is administered at baseline and at weeks 2, 4, 8, and 9. 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 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 suicidality, the investigator will consult with 


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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.
A reference sample is provided in Appendix K.
7.2.3.
Children’s Depression Inventory, Second Edition
The CDI-2 (Parent and Self-report Profiles) is administered at screening; baseline; and weeks 2, 
4, 8, and 9. As the CDI-2 is designed for children 7 to 17 years of age, children 6 years of age at 
baseline 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 J.
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 individual 
identified in the Clinical Study Personnel Contact Information section of this protocol, and the 
investigator must provide the sponsor (LSO/CRO) with the completed pregnancy form. The 


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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 baseline, 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 Products
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
(Appendix C), or as a deviation, in the patients source documents, regardless of whether or not 
an adverse event occurs as a result.
The following are types of medication errors and special situations:
1. 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.
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), 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.


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6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
7. Breastfeeding: Suspected adverse reactions which 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 value will be evaluated by the criteria described in the 
laboratory manual and by the judgement 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 
withdrawal of IMP, or further diagnostic work-up. (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.).


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Table 6:
Clinical Laboratory Tests
Serum Chemistry
Hematology
Urinalysis
calcium
phosphorus
sodium
potassium
chloride
creatinine
glucose
magnesium
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
7.5.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the 
time points detailed in Table 2. Clinical laboratory tests will be performed using the central 
laboratory. Specific laboratory tests to be performed are provided in Table 6.
7.5.2.
Other Clinical Laboratory Tests
7.5.2.1.
Human Chorionic Gonadotropin Tests
β-HCG tests in serum or urine will be performed for all females who are postmenarchal or ≥12 
years of age as detailed in Table 2 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.


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7.5.2.2.
Urine Drug Screen
A urine drug screen (UDS) will be performed at the time points specified in Table 2. 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 above drugs or their metabolites, without medical explanation, 
will preclude the patient from enrollment or continued participation in the study.
7.5.2.3.
Cytochrome P450 2D6 Genotyping
One 3-mL sample for CYP2D6 genotyping will be collected from all patients in the study at 
screening. Sample testing results will not be provided to the study team until the study is 
unblinded. 
This assessment potentially includes the association analysis of the variation in CYP2D6 gene 
with clinical treatment responses to the IMP (eg, efficacy, pharmacokinetic, tolerability, and 
safety features or disease susceptibility and severity features). 
7.6.
Physical Examinations
Physical examination, 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 2.
Weight must be measured with shoes and outerwear off.
Any physical examination finding that is judged by the investigator as a 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. 
7.7.
Vital Signs
Vital signs (pulse, BP, body temperature, and respiratory rate) will be measured at the time 
points detailed in Table 2. 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

abnormal and clinically significant
Before BP and pulse are measured, the patient must rest in a supine or semi-erect/seated position 
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 value, 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.


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7.8.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 2. 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-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 >60 msec.
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; detailed recommendations are provided in Section 7.2.2.
Baseline assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation 
and behavior will be assessed during the study using the Columbia-Suicide Severity Rating Scale
described in Section 7.2.2.
Depression and Suicidality as an Adverse Event 
Families and caregivers of 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.


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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 K.
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 2. 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 
Appendix H, 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 H. 
Prohibited medications that are associated with QTc prolongation are listed in Appendix H, 
Table 10, while prohibited antipsychotic drugs are listed in Appendix H, Table 9.


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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 clinical project physician/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 3.6. Procedures for 
recording safety data are discussed in Appendix S, and methods of analyses are discussed in 
Section 9.7.


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8.
ASSESSMENT OF PHARMACOKINETICS / 
PHARMACODYNAMICS
8.1.
Pharmacokinetic Assessment
Blood samples will be obtained for the measurement of plasma concentrations of TEV-50717 
(deutetrabenazine), α-HTBZ, β-HTBZ, and other metabolites, as required. 
Blood sampling for pharmacokinetics will be performed at the week 8 visit. Two samples will be 
collected. The first sample will be collected upon arrival at the clinic. The second sample will be 
collected 2 to 3 hours after the first pharmacokinetic sample collection. The time between 
samples should be maximized in order to provide the most useful information. Patients with 
early morning visits (ie, within 2 hours of their scheduled AM dosing) should take their dose in 
the clinic after the first pharmacokinetic sample is collected.
Patients will be provided with a diary to provide critical information on dosing at baseline, 
week 2, week 4, and at unscheduled visits. The date and time of the last dose of study medication 
before the week 8 visit should be recorded in the diary by the patient or caregiver/adult. The site 
will document the date and time of the sample collection. Prior to the clinic visit at week 8, 
patients will be reminded to record the start time of their last meal and the time of their last dose 
in their diary.
Blood samples (5 mL) will be collected via venipuncture for plasma concentration measurements 
of TEV-50717 and metabolites or other analytes. 
The dates and times of IMP administration and the date and time of each pharmacokinetic
sample will be recorded on the source documentation and transcribed onto the CRF. 
An exploratory analysis of the pharmacokinetics of active metabolites on the pharmacodynamics
or safety endpoints may be performed.
Additional details regarding sampling and handling as well as shipment and analysis of samples 
will be provided in the laboratory manual.
8.2.
Pharmacodynamics Assessment
Exposure-response (eg, pharmacodynamic [PD] and/or safety endpoints) may be assessed if the 
appropriate data are available.
8.3.
Pharmacogenetics
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics
At the screening visit, a blood sample (3 mL) will be obtained for analysis of CYP2D6 genotype. 
The patient’s genotype for CYP2D6 will remain blinded during the conduct of the study. If the 
patient elects for pharmacogenetics (PGx) evaluation on the optional informed consent/assent, a 
PGx sample (2 mL) will be obtained and stored for exploratory PGx evaluation. This PGx 
assessment will investigate the relationship between subjects’ genetic variability and study 
outcomes. Candidate genes included in this assessment may be related to, or hypothesized to be 


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related to, pharmacokinetics, safety features, drug mechanism of action, Tourette syndrome, or 
related diseases. The final list of genes to be evaluated will be determined at the time of analysis 
to be able to account for the most current research.


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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 CSR.
9.1.
Sample Size and Power Considerations
It is estimated that approximately 50 patients per arm will enable a power of at least 90% to 
detect a beneficial standardized effect of 68% or more when the TEV-50717 arm is compared to 
placebo (difference of 6.5 in the change from baseline to week 8 in TTS, assuming a standard 
deviation of 9.5 in each arm) in a 2-sided type I error rate of 5% after accounting for potential 
dropouts.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients, regardless of whether 
or not a patient took any IMP. In this population, treatment will be assigned based on the 
treatment to which patients were randomized, regardless of which treatment they actually 
received.
9.2.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of IMP and who have both a baseline and at least 
1 postbaseline YGTSS assessment.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. All primary and 
secondary analyses will be based on the mITT set.
9.2.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment the patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
9.2.4.
Per-Protocol Analysis Set
The per-protocol analysis set will include patients who are compliant with study medication 
(80% to 105%), have a YGTSS assessment at baseline and at weeks 2, 4, and 8, and who have 
not taken prohibited concomitant medications as indicated in exclusion criterion, and who have 
no major protocol deviations that affect the validity of the efficacy measurements. The list of 
protocol deviations will be reviewed before unblinding, and major protocol deviations that could 
affect the primary and secondary variables will be determined. 


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9.2.5.
Additional Analyses Sets
The pharmacokinetic analysis set will include those patients from the safety analysis set who 
have sufficient data to be included in the population pharmacokinetic analysis.
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data, unless otherwise specified. For the sensitivity 
analysis of the primary and key secondary efficacy endpoints, detailed data imputation rules will 
be described in the statistical analysis plan.
9.4.
Study Population
The mITT analysis set (see Section 9.2.2) will be used for all efficacy summaries and analyses 
unless otherwise noted. The safety analyses set will be used for all safety summaries. Sensitivity 
analyses of primary and key secondary endpoints will be conducted using the per-protocol 
analysis set. Summaries will be presented by treatment group and for all patients.
9.4.1.
Patient Disposition
Data from patients screened; patients screened but not randomized (and reason not randomized); 
patients who are randomized; patients randomized but not treated (and reason); patients in the 
ITT, safety, and other analysis sets; 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, including medical history, prior medications, 
and ECG findings, will be examined to assess the comparability of the treatment groups and will 
be summarized using descriptive statistics. For continuous variables, descriptive statistics 
(number [n], 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
9.5.1.
Primary Endpoint
The primary efficacy endpoint is the change in the TTS of the YGTSS from baseline to week 8 
between high-dose TEV-50717-treated patients and placebo-treated patients.
9.5.2.
Key Secondary Endpoints
1. Change in the TS-CGI score from baseline to week 8 between high-dose TEV-50717 
treated patients and placebo treated patients
2. Change in the TTS of the YGTSS from baseline to week 8 for low-dose TEV-50717 and 
placebo will be tested 


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3. Change in the TS-CGI score from baseline to week 8 between low dose 
TEV-50717-treated patients and placebo-treated patients
4. Change in the TS- PGII score from baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated patients
5. Change in the TS-PGII score from baseline to week 8 between low-dose 
TEV-50717-treated patients and placebo-treated patients
6. Change in the C&A-GTS-QOL ADL subscale from baseline to week 8 between 
high-dose TEV-50717-treated patients and placebo-treated patients
7. Change in the C&A-GTS-QOL ADL subscale from baseline to week 8 between low-dose 
TEV-50717 treated patients and placebo treated patients
9.5.3.
Exploratory Endpoints

 
 
 
 
 
 
9.5.4.
Safety Endpoints
9.5.5.
Planned Method of Analysis
The mITT analysis set (Section 9.2.2) will be used for all efficacy analyses. Summaries will be 
presented by treatment group.


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9.5.5.1.
Primary Efficacy Analysis
The primary efficacy endpoint for this study is the change in the TTS of the YGTSS from 
baseline to week 8 between high-dose TEV-50717-treated and placebo-treated patients. The 
primary analysis will be a mixed-model repeated-measures model with the change in the TTS as 
the dependent variable. The model will include fixed effects for treatment group, week (3 levels: 
weeks 2, 4, and 8), and the treatment group-by-week interaction. The baseline TTS, region, and 
age group at baseline (2 levels: 6 to 11 years, 12 to 16 years) will be included as covariates. The 
unstructured covariance matrix for repeated observations within patients will be used. The least 
squares means of the change in TTS from baseline at week 8 will be compared between the high-
dose treatment arm and the placebo arm using a 2-sided test at the alpha = 0.05 level of 
significance. In addition, actual values and changes in the TTS from baseline to each visit will be 
summarized using descriptive statistics.
9.5.5.2.
Sensitivity Analysis
Sensitivity analyses for missing data and the statistical model will be provided in the statisitical 
analysis plan.
9.5.5.3.
Key Secondary Efficacy Analyses
A hierarchical (fixed-sequence) testing approach will be used for the analysis of the key 
secondary endpoints. If an endpoint is not statistically significant, confirmatory hypothesis 
testing will not be not carried out on the remaining hypotheses, and remaining hypotheses will be 
considered exploratory rather than confirmatory. The following analyses of key secondary 
endpoints will be conducted:
1. The change from baseline to week 8 in TS-CGI will be analyzed using a similar model as 
the primary analysis; however, instead of change in YGTSS TTS as the dependent 
variable and baseline YGTSS TTS as a covariate, the corresponding TS-CGI values will 
be used. The comparison between high-dose TEV-50717 and placebo will be tested.
2. Using the same model as for the primary analysis, the comparison between the change in 
the TTS of the YGTSS from baseline to week 8 for low-dose TEV-50717 and placebo 
will be tested.
3. Using the same model as described in endpoint #1 above for TS-CGI, the comparison 
between the change in the TS-CGI values from baseline to week 8 for low-dose 
TEV-50717 and placebo will be tested.
4. The change from baseline to week 8 in TS-PGII will be analyzed using a 
Cochran-Mantel-Haenszel-row mean score test with modified ridit scoring controlling for 
age group. The comparison between high-dose TEV-50717 and placebo will be tested.
5. Using the same model as described in endpoint #4 above for TS-PGII, the comparison 
between the change in the TS-PGII values from baseline to week 8 for low-dose 
TEV-50717 and placebo will be tested.
6. The change from baseline to week 8 in the C&A-GTS-QOL ADL subscale will be 
analyzed using a similar model as the primary analysis; however, instead of change in 
YGTSS TTS as the dependent variable and baseline YGTSS TTS as a covariate, the 


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corresponding C&A-GTS-QOL ADL subscale values will be used. The comparison 
between high-dose TEV-50717 and placebo will be tested.
7. Using the same model as described in endpoint #6 above for the C&A-GTS-QOL ADL 
subscale, the comparison between the change in the C&A-GTS-QOL ADL subscale 
scores from baseline to week 8 for low-dose TEV-50717 and placebo will be tested.
9.5.5.4.
Exploratory Analyses
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.6.
Multiple Comparisons and Multiplicity
The hierarchical testing method will be used to maintain the experiment-wise type I error of 5% 
level for the primary and key secondary analyses. The primary efficacy endpoint will first be 
tested at the 5% type I error level. If the p-value of the primary analysis is ≤0.05, the secondary 
hypotheses will be tested in the order listed for the analysis of key secondary endpoints until 
either an analysis produces a p-value >0.05 or all analyses result in a p-value ≤0.05. 
9.7.
Safety Analysis
Safety endpoints for this study are as follows:

adverse events and concomitant medications: from the signing of the informed 
consent/assent form through follow-up, inclusive of all visits and telephone contacts

physical examination: screening and week 8

neurological examination: screening and week 8

vital signs: screening; baseline; and weeks 2, 4, 8, and 9 
Note: orthostatic blood pressure and pulse at baseline and weeks 4 and 8

children’s C-SSRS

baseline/Screening scale: screening

since Last Visit scale: baseline, and weeks 2, 4, 8, and 9

CDI-2 (Parent and Self-report Profiles): screening; baseline; and weeks 2, 4, 8, and 9

12-Lead ECG: screening, baseline, and weeks 4 and 8

clinical laboratory tests (serum chemistry, hematology, and urinalysis): screening and 
week 8

pregnancy testing: screening, baseline, and week 8

drug screen: screening and week 8
Safety analyses will be performed on the safety analysis set (Section 9.2.3).
9.7.1.
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, adverse events 
determined by the investigator to be related to study treatment, serious adverse events, and 
adverse events causing withdrawal from the study. Summaries will be presented by treatment 
group and for all patients. Patient listings of serious adverse events and adverse events leading to 
withdrawal will be presented.
Observed values and changes from baseline 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. In addition, the number and percentage of patients with 


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on-treatment QTcF values >450, >480, or >500 msec and change from baseline >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 C-SSRS and observed values and changes from baseline in the CDI-2 
(Parent and Self-report Profiles) will be presented by treatment group for all patients. 
9.8.
Tolerability Analysis
Tolerability was not specifically defined.
9.9.
Pharmacokinetic Analysis
Blood samples will be obtained for the measurement of plasma concentrations of TEV-50717 
(deutetrabenazine), α-HTBZ, β-HTBZ, and other metabolites, as required. 
Blood sampling for pharmacokinetics will be performed at the week 8 visit. Two samples will be 
collected. The first sample will be collected upon arrival at the clinic. The second sample will be 
collected within 2 to 3 hours after the first pharmacokinetic sample collection. The time between 
samples should be maximized in order to provide the most useful information. Patients with 
early morning visits (ie, within 2 hours of their scheduled AM dosing) should take their dose in 
the clinic after the first pharmacokinetic sample is collected.
Patients will be provided with a diary to provide critical information on dosing at baseline, 
week 2, week 4, and at unscheduled visits. The date and time of the last dose of study medication 
before the week 8 visit should be recorded in the diary by the patient or caregiver/adult. The site 
will document the date and time of the sample collection. Prior to the clinic visit on week 8, 
patients will be reminded to record the start time of their last meal and the time of their last dose 
in their diary. 
Plasma samples for both α-HTBZ and β-HTBZ metabolite concentrations will be pooled with 
previous data and analyzed using population pharmacokinetics techniques. The population 
pharmacokinetics analysis will result in a final structural model that best describes the data. A 
covariate assessment will evaluate the relationship between potential covariates (ie, body weight, 
age, height, etc.) and concentrations of α-HTBZ and β-HTBZ metabolites. The final population 
pharmacokinetic analysis will be included in a separate report.
9.10.
Planned Interim Analysis
There will be no formal interim analysis.
9.11.
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.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
Refer to Appendix R for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline,
Guideline for Good Clinical Practice 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 and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials 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 IMPs as described in the IB or prescribing information.
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.
See Appendix D for the ethics expectations of informed consent or assent, competent authorities 
and independent ethics committee and institutional review board, confidentiality regarding study 
patients, and requirements for registration of the clinical study.
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix S for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents.


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13.
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.
The patients in this clinical study are 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 eg, 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 Food and Drug Administration (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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14.
REFERENCES
Bitsko RH, Holbrook JR, Visser SN, et al. A National Profile of Tourette Syndrome, J Dev 
Behav Pediatr 2014;35(5):317-22.
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.
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/.
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, Mejia N, Jankovic J. Tetrabenazine in the treatment of Tourette syndrome. 
J Pediatric Neurol 2007;5(1):9-13.
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.
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.
Mejia NI, Jankovic J. Tardive dyskinesia and withdrawal emergent syndrome in children. Expert 
Rev Neurother 2010 Jun;10(6):893-901.
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.


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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.
Posner K, Brent D, Lucas C. Columbia-Suicide Severity Rating Scale. Suicidal Behavior C-
SSRS. 2009.
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.
WHO classification of BMI: http://apps.who.int/bmi/index.jsp?introPage=intro_3.html
Xenazine: Highlights of Prescribing Information. 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf. Accessed 27 
Oct 2015.


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15.
SUMMARY OF CHANGES TO PROTOCOL
15.1.
Amendment 03 Dated 05 May 2019
The primary reason for this amendment is 
 
 
 
 
 
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
Number of Patients Planned (total): 174 (58150 (50 per 
treatment arm)
Number of Patients Planned (total): 150 (50 per 
treatment arm)
Upon further review, study 
sample size has been reverted 
back to the original sample 
size prior to Amendment 02.
1.1 Introduction
Studies have suggested that up to 7%the prevalence estimates
of schoolTS among children fulfill the diagnostic criteria for 
TS vary widely from 0.4% to 5% in community samples 
(Kurlan et al 2002Bitsko et al 2014).
Studies have suggested that the prevalence estimates 
of TS among children vary widely from 0.4% to 5% 
in community samples (Bitsko et al 2014).
Updated the prevalence 
estimates of TS among 
children upon further literature 
review for accuracy
3.2 Planned Number of Patients and Countries
The number of evaluable patients is planned to be 174150.
The number of evaluable patients is planned to be 
150. 
Enrollment number has been 
decreased back to the original 
sample size prior to 
Amendment 02.
5.10.1 Maintenance of Randomization
Patient randomization codes will be maintained in a secure 
location within Syneos Health, Biometrics. 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.
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.
Updated direction on how/who 
will maintain patient 
randomization
9.1 Sample Size and Power Considerations
It is estimated that approximately 5850 patients per arm will 
enable a power of at least 90% to detect a beneficial 
standardized effect of 6368% or more when the TEV-50717 
arm is compared to placebo (difference of 6.06.5 in the change 
from baseline to week 8 in TTS, assuming a standard deviation 
of 9.5 in each arm) in a 2-sided type I error rate of 5% after 
accounting for potential dropouts.
It is estimated that approximately 50 patients per arm 
will enable a power of at least 90% to detect a 
beneficial standardized effect of 68% or more when 
the TEV-50717 arm is compared to placebo 
(difference of 6.5 in the change from baseline to week 
8 in TTS, assuming a standard deviation of 9.5 in 
each arm) in a 2-sided type I error rate of 5% after 
Updated the sample size back 
to the expected enrollment 
number prior to Amendment 
02. The statistical 
considerations were updated 
per most current assumptions.


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Original text with changes shown
New wording
Reason/Justification for 
change
The sample size for this study has been increased from 150 
total patients (50 patients per arm) to 174 total patients (58 
patients per arm). This adjustment is based solely on external 
data (ie, valbenazine Phase 2 study results, efficacy of TEV
50717 in the treatment of HD and TD, and ABILIFY® Phase 3 
data). Data from the ongoing TEV 50717 Phase 2/3 and Phase 
3 studies, TV50717 CNS 30046 and TV50717 CNS 30060, 
are blinded and were not used to inform the sample size 
calculation.
accounting for potential dropouts.
9.5.5.2 Sensitivity Anlaysis
Sensitivity analyses for missing data, and the statistical model, 
and for the increase in sample size, will be conducted as 
detailedprovided in the statisitical analysis plan.
Sensitivity analyses for missing data and the 
statistical model will be provided in the statisitical 
analysis plan.
The definition of the 
sensitivity analysis was 
updated to remove any 
mention of increased sample 
size, now that we have 
reverted back to the original 
sample size prior to 
Amendment 02.
14 References
Bitsko RH, Holbrook JR, Visser SN, et al. A National Profile 
of Tourette Syndrome, J Dev Behav Pediatr 2014;35(5):317-
22.
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.
Bitsko RH, Holbrook JR, Visser SN, et al. A National 
Profile of Tourette Syndrome, J Dev Behav Pediatr 
2014;35(5):317-22.
Upon further literature review, 
an updated reference has been 
included to more accurately 
present the prevalence 
estimates of TS among 
children.


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15.2.
Amendment 02 Dated 25 March 2019
The primary reasons for this amendment are to increase study sample size and update 
corresponding statistical considerations; 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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Global
Informed consent/assent or assent, depending on the child’s 
age, as appropriate, is obtained
Informed consent/assent, depending on the child’s 
age, as appropriate, is obtained
Update made for clarity on 
expectations surrounding 
obtaining informed consent 
and/or assent, dependent upon 
the child’s age
Patients and their parent/legal guardiancaregiver/adult…
Patients and their caregiver/adult…
Updated terminology 
surrounding the patient’s 
caregiver/adult to encompass 
all scenarios of individuals 
caring for this population
Title Page
601 Gateway Boulevard
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South San Francisco, California 94080 
101 Main Street, 12th Floor
Cambridge, Massachusetts 02142
101 Main Street, 12th Floor
Cambridge, Massachusetts 02142
Address update
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.
© 20172019 Teva Branded Pharmaceutical Products R&D, 
Inc. and Nuvelution TS Pharma, INC. All rights reserved.
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.
© 2019 Teva Branded Pharmaceutical Products 
R&D, Inc. and Nuvelution TS Pharma, INC. All 
rights reserved.
Updates included per Teva’s 
current Confidentiality 
Statement template text
Clinical Laboratory and Other Departments and Institutions
Sponsor’s Authorized Representative
Sponsor’s Authorized Representative
 
Update to Sponsor 
representatives and points of 
contact


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Legal Representative of the Sponsor in the EU
For protocol issues, contact the following study leaders 
(right)
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
For medical issues, contact the following physicians (right)
Sponsor’s Representative of Global Patient Safety and 
Pharmacovigilance
For serious adverse events:
 
Legal Representative of the Sponsor in the EU
For protocol issues, contact the following study 
leaders (right)
Sponsor’s Medical Expert/Contact Point 
designated by the Sponsor for Further 
Information on the Study
For medical issues, contact the following 
physicians (right)
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance
For serious adverse events:
 


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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.
Central Institutional Review Board
Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Central Clinical Laboratory
Q2 Solutions
(Quest) LLC
 
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.
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


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27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Electronic Data Capture
Medidata RAVE (through Syneos Health)
Contract Research Organization
Syneos Health, LLC
1030 Sync Street
Morrisville, NC 27560
USA
Central Electrocardiogram Evaluation
ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Bioanalytical Pharmacokinetics Evaluation
Information will be included in the Trial Master File
Randomization and Trial Supply Management (RTSM) 
vendor
Endpoint
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
Electronic Data Capture
Medidata RAVE (through Syneos Health)
Contract Research Organization
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
Synopsis


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Countries Planned: North America, Latin America, 
TurkeyAustralia, Ukraine, South Korea, and Europe
Countries Planned: North America, Latin America, 
Australia, Ukraine, South Korea, and Europe
Updated list of countries for 
inclusion
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 tetrabenazinedeutetrabenazine (referred to as TEV-
50717 or, 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, developed deutetrabenazine (referred to as 
TEV-50717, previously SD-809) that is eliminated 
more slowly than tetrabenazine.
Minor updates to streamline 
background on drug product


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1.3.1.3 Toxicology
The NOAEL (no-observed-adverse-effect level) 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 NOAEL (no-observed-adverse-effect level) 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

76 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

2 ongoing Phase 2/3 and Phase 3 studies in 

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 ongoing Phase 2/3 and Phase 3 studies 
The clinical development plan 
for TEV-50717 has been 
updated to reflect the most 
current program information


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patients with TS

1 ongoing Phase 3 long-term safety study in 
patients with TS
in patients with TS

1 ongoing Phase 3 long-term safety study 
in patients with TS
2 Study Objectives and Endpoints
This is a Phase 2/3 study to evaluate the efficacy and safety of 
deutetrabenazine (TEV-50717) tablets for the reduction of 
motor and phonic tics associated with TS in children and 
adolescents 6 through 16 years of age.
This is a Phase 3 study to evaluate the efficacy and 
safety of deutetrabenazine (TEV-50717) tablets for 
the reduction of motor and phonic tics associated with 
TS in children and adolescents 6 through 16 years of 
age.
This study is a Phase 3 study, 
not a Phase 2/3 study
2.2 Exploratory Endpoints (other sections affected: 9.5.3 Exploratory Endpoints)
Exploratory Endpoints:

 
 
 
 
 
 
 
 
 
 
3.1 Study Design
Screening period (up to 31 days): 
At the discretion of the investigator, the screening visit may be 
divided into 2 visits to reduce the burden on patients. If the 
screening visit is divided into 2 visits, the blood sample should 
be obtained during the first of the 2 visits. Patients will return 
to the clinic on day 1 for baseline procedures and to re-confirm 
eligibility. Patients may be rescreened 1 time if there is a 
change in the status of the patient regarding eligibility for the 
study. (Note: Details of rescreening must be approved and 
Screening period (up to 31 days): 
At the discretion of the investigator, the screening 
visit may be divided into 2 visits to reduce the burden 
on patients. If the screening visit is divided into 2 
visits, the blood sample should be obtained during the 
first of the 2 visits. Patients will return to the clinic on 
day 1 for baseline procedures and to re-confirm 
eligibility. Patients may be rescreened 1 time if there 
is a change in the status of the patient regarding 
Updates to the study design 
included to specify screening 
procedures and to provide 
further guidance to 
investigators in the situation 
that a patient experiences 
certain types of adverse events


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documented by the medical monitor and/or Clinical 
Surveillance and Training [CST] team.)
Treatment period (8 weeks): 
As this is a fixed-dose study, patients will undergo dose 
escalation (ie, forced titration) to their target dose over the first 
4 weeks of treatment. If a patient experiences either a protocol
defined “important neuropsychiatric adverse event” or a 
serious adverse event that is related to IMP, a single dose 
reduction is permitted. An “important neuropsychiatric adverse 
event” includes the following: depression, suicidal ideation or 
behavior, anxiety, akathisia, parkinsonism, andor somnolence, 
or any other adverse event that interferes with daily activity., or 
any adverse event that is related to IMP, a single dose 
reduction is permitted. The investigator must discuss any 
further dose adjustments (eg, holding the dose or doses) with 
the medical monitor.
eligibility for the study. (Note: Details of rescreening 
must be approved and documented by the medical 
monitor and/or Clinical Surveillance and Training 
[CST] team.)
Treatment period (8 weeks): 
As this is a fixed-dose study, patients will undergo 
dose escalation (ie, forced titration) to their target
dose over the first 4 weeks of treatment. If a patient 
experiences depression, suicidal ideation or behavior, 
anxiety, akathisia, parkinsonism, or somnolence, or 
any other adverse event that interferes with daily 
activity, or any adverse event that is related to IMP, a 
single dose reduction is permitted. The investigator 
must discuss any further dose adjustments (eg, 
holding the dose or doses) with the medical monitor.
Section 3.2 Planned Number of Patients and Countries (other sections effected: Section 9.1 Sample Size and Power Considerations and 
Figure 1: Overall Study Schematic Diagram)
The number of evaluable patients is planned to be 150174.
The number of evaluable patients is planned to be 
174.
Updated enrollment numbers. 
See further justification 
provided in Section 9.1 of the 
this summary of changes.
3.4 Drug Administration (other section effected: 5.1.2 Placebo Investigational Medicinal Product [Table 3])
3.4 Dose Escalation Procedures Drug Administration

To preserve the blinding, 2 The total daily dose, as 
provided in Table 1, is divided into a twice daily 
administration. Two tablets will be taken twice daily 
starting at day 1 per Table 1…

Dose reductions, if required, should be in increments 
3.4 Drug Administration

The total daily dose, as provided in Table 1, 
is divided into a twice daily administration. 
Two tablets will be taken twice daily starting 
at day 1 per Table 1…

In the case of an adverse event, the 
Section heading updated per 
request from Regulatory 
Authorities
Dosing information and dose
reduction guidelines were 
clarified


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of 6 mg. If more than 1 dose reduction is required 
for an adverse event, the medical monitor must be 
notified. In the case of an adverse event, the 
investigator is permitted to perform a single dose 
reduction of 6 mg. The investigator must discuss any 
further dose adjustments (eg, holding the dose or 
doses) with the medical monitor.
Table 1:
Daily Dose of IMP by Baseline Body 
Weight Category, CYP2D6 Impairment, 
and Study Week
Dose group
Baseline 
weight (kg)
Daily dose (mg) at the start of 
visit/weeka
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.
investigator is permitted to perform a single 
dose reduction of 6 mg. The investigator 
must discuss any further dose adjustments 
(eg, holding the dose or doses) with the 
medical monitor.
Table 1:
Daily Dose of IMP by Baseline 
Body Weight Category, 
CYP2D6 Impairment, and 
Study Week
Dose group
Baseline 
weight (kg)
Daily dose (mg) at the start of 
visit/weeka
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.
Footnote “a” was added to 
Table 1 to provide further 
clarity on dosing expectations
Section 3.6: Table 2: Study Procedures and Assessments
Note: Week 4 assessments were previously captured 
underneath the “Maintenance Period” incorrectly. Week 4 
assessments have been moved underneath the “Escalation
Period.”
e
The screening visit may be conducted over 2 separate visits 
at the discretion of the investigator. If the screening visit is 
divided into 2 visits, the blood sample should be obtained
during the first of the 2 visits.
f
Patients will be provided with a diary at baseline, week 2, 
week 4, and at unscheduled visits, to record critical information 
on dosing.
Note: Week 4 assessments were previously captured 
underneath the “Maintenance Period” incorrectly.
Week 4 assessments have been moved underneath the 
“Escalation Period.”
e
The screening visit may be conducted over 2 
separate visits at the discretion of the investigator. If 
the screening visit is divided into 2 visits, the blood 
sample should be obtained during the first of the 2 
visits.
f
Patients will be provided with a diary at baseline, 
week 2, week 4, and at unscheduled visits, to record 
Week 4 was placed under the 
correct study period
Dose escalation is allowed 
through week 4
Updated footnotes to include
that blood samples should be 
obtained during the first 
screening visit (if 2 screening
visits are required), to include 


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g
Dose escalation will only occur during the dose escalation 
period (ie, from week 1 to week 34).
v
Contact IRT and dispense IMP and patient diary. 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 during escalation. See Table 1 for 
baseline weight-based dosing titration. At week 4, patients will 
receive doses for 4 weeks of treatment.
critical information on dosing.
g
Dose escalation will only occur during the dose 
escalation period (ie, from week 1 to week 4).
v
Contact IRT and dispense IMP and patient diary. 
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 
during escalation. See Table 1 for baseline weight-
based dosing titration. At week 4, patients will 
receive doses for 4 weeks of treatment.
specific timepoints for diary 
dispensing, to clarify the dose 
escalation period, and to 
provide guidance on 
dispensing of IMP
4.1 Patient Inclusion Criteria (other sections affected: Appendix D Ethics)
f. Patient and parent/legal guardiancaregiver/adult are willing 
to adhere to the medication regimen and to comply with all 
study procedures.
h. In the investigator’s opinion, the patient and parent/legal 
guardiancaregiver/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.
i. Patient and parent/legal guardian provided written informed 
consent/assent, depending on the child’s age, as appropriate,
according to local regulations (eg, the patient has provided 
written assent and/or co consent, as appropriate).
f. Patient and caregiver/adult are willing to adhere to 
the medication regimen and to comply with all study 
procedures.
h. 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.
i. Patient and parent/legal guardian provided written 
informed consent/assent, depending on the child’s 
age, as appropriate, according to local regulations.
Updated language in the 
inclusion criteria to encompass 
all scenarios of individuals 
caring for this population and 
for alignment across the 
protocol
4.2 Patient Exclusion Criteria (other sections affected: Appendix H Allowed and Prohibited Medications)
k. Patient has received any of the following concomitant 
medications for tics within the following specified 
exclusionary windows of screeningfirst dose:
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, dosing has been stable for at 
least 2 weeks before screening, and no changes to dose or 
k. Patient has received any of the following 
concomitant medications for tics within the following 
specified exclusionary windows of first dose:
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 
Added cannabidiol oil and 
valbenazine as concomitant 
medications
Included notes for various 
different concomitant 
medications and stipulations
Added monoamine oxidase 


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frequency are anticipated during the course of the study.
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, and no changes to dose or frequency 
are anticipated during the course of the study.
Note: Use of guanfacine or clonidine is allowed regardless of 
indication (ie, if prescribed for tics or TS) 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. If discontinuation of either medication is 
anticipated due to ineffectiveness, poor tolerability, or 
patient/caregiver preference, discontinuation should occur 4 or 
more weeks prior to the screening visit.
q. Patient has received a monoamine oxidase inhibitor within 
14 days of the baseline visit.
treatment of ADHD, dosing has been stable for at 
least 2 weeks before screening, and no changes to 
dose or frequency are anticipated during the course of 
the study.
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, and no 
changes to dose or frequency are anticipated during 
the course of the study.
Note: Use of guanfacine or clonidine is allowed 
regardless of indication (ie, if prescribed for tics or 
TS) 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. If 
discontinuation of either medication is anticipated 
due to ineffectiveness, poor tolerability, or 
patient/caregiver preference, discontinuation should 
occur 4 or more weeks prior to the screening visit.
q. Patient has received a monoamine oxidase inhibitor 
within 14 days of the baseline visit.
inhibitor as part of the 
exclusion criteria
4.3 Withdrawal Criteria and Procedures for the Patient
The investigator also has the right to withdraw a patient from 
the study in the event of 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 7.37.3), or 
d. other reasons concerning the health or well-being of the 
patient or in the event of
e. lack of cooperation. If a
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 and 
withdrawal criteria due to 
adverse event


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f. post-baseline QTcF value >500 msec or change from 
baseline >60 msec is found, the (as described in Section 7.1.7). 
The investigator should repeat the ECG assessment twice and 
compare to 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 5.10.2). 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 5.7).
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 5.10.2). 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 5.7).
4.5 Rescreening
A patient who is screened but not enrolled may be rescreened 
once1 time if there is a change in the status of the patient 
regarding eligibility for the study 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 studymedical monitor and/or 
Clinical Surveillance and Training [CST] team.) 
If the patient is rescreened, an informed consent/assent form 
(ICF) will need to be resigned.
A patient who is screened but not enrolled may be 
rescreened 1 time if there is a change in the status of 
the patient regarding eligibility for the study. (Note: 
Details of rescreening must be approved and 
documented by the medical monitor and/or Clinical 
Surveillance and Training [CST] team.) 
If the patient is rescreened, an informed 
consent/assent form (ICF) will need to be resigned.
Provided further details 
rescreening activities and 
process


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5.1.1.2 Dose Modification and Dose Stratification
As this is a fixed-dose study, patients will undergo dose 
escalation (ie, forced titration) to their target dose over the first 
4 weeks of treatment (see Section 1.1 and Table 1). If a patient 
experiences either a protocol defined “important 
neuropsychiatric adverse event” or a serious adverse event that 
is related to IMP, a single dose reduction is permitted. An 
“important neuropsychiatric adverse event” includes the 
following: depression, suicidal ideation or behavior, anxiety, 
akathisia, parkinsonism, orand somnolence, or any other 
adverse event that interferes with daily activity., or any adverse 
event that is related to IMP, a single dose reduction is 
permitted. The investigator must discuss any further dose 
adjustments (eg, holding the dose or doses) with the medical 
monitor.
As this is a fixed-dose study, patients will undergo 
dose escalation (ie, forced titration) to their target 
dose over the first 4 weeks of treatment (see Section 
1.1 and Table 1). If a patient experiences depression, 
suicidal ideation or behavior, anxiety, akathisia, 
parkinsonism, or somnolence, or any other adverse 
event that interferes with daily activity, or any 
adverse event that is related to IMP, a single dose 
reduction is permitted. The investigator must discuss 
any further dose adjustments (eg, holding the dose or 
doses) with the medical monitor.
Updated dose modification 
language to provide additional 
guidance to the investigator
5.2.1 Storage and Security (other sections affected: Appendix G HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY FOR 
IMP)
The IMP (TEV-50717 and the placebo) mustshould be stored 
protected from light, at a controlled room temperature, 1520°C 
to 3025°C (5968°F to 8677°F); however, storage between 15°C 
and 20°C (59°F and 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 and the placebo) 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 and 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 temperature range for 
storage of the IMP
5.2.3 Accountability
Empty, partially used, and unused blister packs IMP will be 
returned to the sponsor or designeedisposed of, as agreed with 
the sponsor/development partner.
Empty, partially used, and unused blister packs IMP 
will be disposed of, as agreed with the 
sponsor/development partner.
Updated guidance surrounding 
disposal practices for the IMP
5.5. Restrictions (other sectins affected: Appendix H ALLOWED AND PROHIBITED MEDICATIONS)
The use of quinidine and terbinafine are prohibited (see 
Appendix H, Table 11).
The use of quinidine and terbinafine are prohibited 
(see Appendix H, Table 11).
Added quinidine and 
terbinafine to the list of 
prohibited medications
5.8 Temporary Discontinuation of Investigational Medicinal Product


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Dose Reduction
If more than 1 dose reduction is required for an adverse 
event, the medical monitor must be notified. In the case of 
an adverse event, the investigator is permitted to perform a 
single dose reduction of 6 mg. The investigator must discuss 
any further dose adjustments (eg, holding the dose or 
doses) with the medical monitor.
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 falls below the lower limit of 
normal were tested and found to be below the lower limit of 
normal and clinically significant, the laboratory test should be 
repeated at least once. If the abnormality in the repeated 
laboratory test is consistent with the prior laboratory test, IMP 
must be suspended.
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 evaluations.
Dose Reduction
In the case of an adverse event, the investigator is 
permitted to perform a single dose reduction of 6 mg. 
The investigator must discuss any further dose 
adjustments (eg, holding the dose or doses) with 
the medical monitor.
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 significant, 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.
Updated dose reduction and 
dose suspension text to 
provide further guidance
5.10.1 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 unblinding request from Teva statistician, the service 
provider will provide the unblinded IMP assignment according 
to the processes defined in the relevant Standard Operating 
Procedure (SOP). within Syneos Health, Biometrics. At the 
time of analysis, when treatment codes are needed, the Syneos 
Patient randomization codes will be maintained in a 
secure location within Syneos Health, Biometrics. 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.
Updated guidance on the 
maintenance of randomization
and the process for requesting
unblinded codes


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Health statistician assigned to the study will make a request to 
unblind and will receive the unblinded codes.
5.10.2 Blinding and Unblinding
However, if a patient is unblinded by mistake, the investigator 
should discuss with the medical monitor whether or not the 
patient should be withdrawn.
However, if a patient is unblinded by mistake, the 
investigator should discuss with the medical monitor 
whether or not the patient should be withdrawn.
Provided further guidance to 
the investigator in the situation 
that a patient is unblinded by 
mistake
5.11 Total Blood Volume (other sections affected: 7.5.2.3 Cytochrome P450 2D6 Genotyping)
Table 4: Blood Volumes
Type of 
samples
Volume per 
sample
Total number of 
samples
Total 
volume
(maxim
um)
Clinical 
laboratory 
(chemistry/he
matology)
10 mL
2
20 mL
Pharmacokine
tic 
5 mL
1 time point (week 8) 
× 2 samples
10 mL
CYP2D6 
genotyping
53 mL
1
53 mL
Optional 
pharmacogene
tic sample
2 mL
1
2 mL
Total
35 mL
Table 4: Blood Volumes
Type of 
samples
Volume 
per 
sample
Total number of 
samples
Total 
volum
e
(maxi
mum)
Clinical 
laboratory 
(chemistry/
hematology
)
10 mL
2
20 mL
Pharmacoki
netic 
5 mL
1 time point 
(week 8) × 
2 samples
10 mL
CYP2D6 
genotyping
3 mL
1
3 mL
Optional 
pharmacoge
netic 
sample
2 mL
1
2 mL
Total
35 mL
Updated the blood draw 
volumes and included optional 
pharmacogenetic sample
6.2.5 Yale Global Tic Severity Scale
 
 
 


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7.1.2 Recording and Reporting of Adverse Events
For subjects who experience an adverse event or serious 
adverse event after signing a prescreening ICF for 
Study TV50717-CNS-30060, the event will be documented in 
the subject source documents and Electronic Data Capture 
(EDC) systems. For serious adverse events, the serious adverse 
event form must be completed in addition, and the serious 
adverse event must be reported immediately to the sponsor 
(Section 7.1.5.3.1). If the subject attends the screening visit, the 
adverse event or serious adverse event identified during the 
prescreening period will be considered medical history. For 
data entry purposes in EDC, the stop date for the prescreening 
adverse event or serious adverse event will be the date of the 
screening visit, and the start date for the associated medical 
history will be the date of the screening visit.
For subjects who experience an adverse event or 
serious adverse event after signing a prescreening 
ICF for Study TV50717-CNS-30060, the event will 
be documented in the subject source documents and 
Electronic Data Capture (EDC) systems. For serious 
adverse events, the serious adverse event form must 
be completed in addition, and the serious adverse 
event must be reported immediately to the sponsor 
(Section 7.1.5.3.1). If the subject attends the 
screening visit, the adverse event or serious adverse 
event identified during the prescreening period will 
be considered medical history. For data entry 
purposes in EDC, the stop date for the prescreening 
adverse event or serious adverse event will be the 
date of the screening visit, and the start date for the 
associated medical history will be the date of the 
screening visit. 
Added language on reporting 
of adverse events after 
subjects sign a prescreening 
ICF
7.1.5 Serious Adverse Events
An additional blood sample for the measurement of IMP 
concentration should be collected, if possible, from each 
patient experiencing a serious 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.
An additional blood sample for the measurement of 
IMP concentration should be collected, if possible, 
from each patient experiencing a serious 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.
Added language to specify that 
an additional blood sample 
should be collected, if 
possible, from each patient 
who experiences 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 to the sponsor by 
To satisfy regulatory requirements, all serious 
adverse events that occur during the study, regardless 
of judged relationship to administration of the IMP, 
Updated guidance for 
investigator reporting of 
adverse events


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the investigator according to the instructions provided on the 
serious adverse event form.
must be reported by the investigator according to the 
instructions provided on the serious adverse event 
form.


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7.2.2 Columbia-Suicide Severity Rating Scale
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 
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, 
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 
suicidality, the investigator will consult with 
the medical monitor, the consulting 
psychiatrist, and/or sponsor to determine
Added guidance on how to 
handle suicidal ideation and 
suicidal behavior descriptions
as identified by the C-SSRS


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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.
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
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 
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 subjects will be instructed 
to monitor patients for any changes in or new onset of 
depressive symptoms; unusual changes in mood, 
Added further descriptions and 
guidance on depression and 
suicidality assessed as adverse 
events


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symptoms immediately to the study investigator.
Depression and Suicidality as an Adverse Event 
Families and caregivers of 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.
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.
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.
7.11 Concomitant Medication or Treatment
The tables for allowed and prohibited medications are not 
comprehensive and may not include all possible concomitant 
The tables for allowed and prohibited medications are 
not comprehensive and may not include all possible 
Included a few more details on 
the list of concomitant 


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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 H.
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 H.
medications
8.1 Pharmacokinetic Assessment ((other sections affected: 9.9 Pharmacokinetic Analysis)
Patients will be provided with a diary to provide critical 
information on dosing at baseline, week 2, week 4, and at 
unscheduled visitsto provide critical information on dosing 
before the week 8 visit.
Patients will be provided with a diary to provide 
critical information on dosing at baseline, week 2, 
week 4, and at unscheduled visits.
Updated language to provide 
further clarity on which visits 
a diary would be dispensed 
8.3.1 CYP2D6 Genotyping/Pharmacogenetics
At the screening visit, a blood sample (5 to 63 mL) will be 
obtained for analysis of CYP2D6 genotype. The patient’s 
genotype for CYP2D6 will remain blinded during the conduct 
of the study. If the patient elects this optionfor 
pharmacogenetics (PGx) evaluation on the optional informed 
consent/assent, a PGx sample (2 mL) will be obtained and the 
remaining sample will be stored for exploratory PGx 
evaluation.
At the screening visit, a blood sample (3 mL) will be 
obtained for analysis of CYP2D6 genotype. The 
patient’s genotype for CYP2D6 will remain blinded
during the conduct of the study. If the patient elects 
for pharmacogenetics (PGx) evaluation on the 
optional informed consent/assent, a PGx sample 
(2 mL) will be obtained and stored for exploratory 
PGx evaluation.
Updated the volume of blood 
to be drawn for the analysis of 
CYP2D6 genotype at baseline 
and included additional details 
on the PGx blood sample for 
subjects who elect this option
9.1 Sample Size and Power Considerations
It is estimated that approximately 5850 patients per arm will 
enable a power of at least 90% to detect a beneficial 
standardized effect of 63% or more when the TEV-50717 arm 
is compared to placebo (difference of 6.0 of 6.5 points or more
in the change from baseline to week 8 in TTS, when the high
dose TEV 50717 arm is compared to placeboassuming a 
standard deviation of 9.5 in each arm) andin a 2-sided type I 
error rate of 5% after accounting for potential dropouts.
The sample size for this study has been increased from 150 
total patients (50 patients per arm) to 174 total patients (58 
patients per arm). This adjustment is based solely on external 
It is estimated that approximately 58 patients per arm 
will enable a power of at least 90% to detect a 
beneficial standardized effect of 63% or more when 
the TEV-50717 arm is compared to placebo 
(difference of 6.0 in the change from baseline to week 
8 in TTS, assuming a standard deviation of 9.5 in 
each arm) in a 2-sided type I error rate of 5% after 
accounting for potential dropouts.
The sample size for this study has been increased 
from 150 total patients (50 patients per arm) to 174 
total patients (58 patients per arm). This adjustment is 
Recently, a Phase 2 study 
assessing the safety and 
efficacy of valbenazine in the 
treatment of pediatric and 
adolescent TS patients 
(T-FORCE GOLD study) 
failed to meet its primary 
efficacy objective. The details 
on the results from this study 
have not yet been made public. 
Based on this negative 


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data (ie, valbenazine Phase 2 study results, efficacy of TEV-
50717 in the treatment of HD and TD, and ABILIFY® Phase 3 
data). Data from the ongoing TEV-50717 Phase 2/3 and Phase 
3 studies, TV50717-CNS-30046 and TV50717-CNS-30060, 
respectively, are blinded and were not used to inform the 
sample size calculation.
based solely on external data (ie, valbenazine Phase 2 
study results, efficacy of TEV-50717 in the treatment 
of HD and TD, and ABILIFY® Phase 3 data). Data 
from the ongoing TEV-50717 Phase 2/3 and Phase 3 
studies, TV50717-CNS-30046 and TV50717-CNS-
30060, respectively, are blinded and were not used to 
inform the sample size calculation.
efficacy outcome, the sample 
size assumptions for Study 
TV50717-CNS-30046 were 
re-evaluated using data 
external to the ongoing 
TEV-50717 Phase 3 TS 
program.
After review of the 
standardized effect in the 
TEV-50717 placebo-
controlled pivotal studies in 
HD and TD and in 
collaboration with the 
scientific advisors to the 
TEV-50717 TS program (ie, 
Dr. Jankovic, Dr. Coffey, and 
Dr. Jimenez-Shahed), a 
treatment effect of 6.0 
difference in TTS reflecting a 
63% beneficial standardized 
effect was deemed to be a 
more appropriate assumption 
to base the sample size 
calculation.
9.2.1 Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all 
randomized patients, regardless of whether or not a patient took 
any IMP. A patient is considered enrolled according to the 
status reported in the database. All efficacy analyses will be 
based on the ITT analysis setIn this population, treatment will 
be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually 
received.
The intent-to-treat (ITT) analysis set will include all 
randomized patients, regardless of whether or not a 
patient took any IMP. In this population, treatment 
will be assigned based on the treatment to which 
patients were randomized, regardless of which 
treatment they actually received.
Updated details on the intent-
to-treat analysis set
9.2.4 Per-Protocol Analysis Set


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The per-protocol analysis set will include patients who are 
compliant with study medication (80% to 105%), have a 
YGTSS assessment at baseline and at weeks 2, 4, and 8, and 
who have not taken prohibited concomitant medications as 
indicated in exclusion criterion., and who have no major 
protocol deviations that affect the validity of the efficacy 
measurements. The list of protocol deviations will be reviewed 
before unblinding, and major protocol deviations that could 
affect the primary and secondary variables will be determined.
The per-protocol analysis set will include patients 
who are compliant with study medication (80% to 
105%), have a YGTSS assessment at baseline and at 
weeks 2, 4, and 8, and who have not taken prohibited 
concomitant medications as indicated in exclusion 
criterion, and who have no major protocol deviations 
that affect the validity of the efficacy measurements. 
The list of protocol deviations will be reviewed 
before unblinding, and major protocol deviations that 
could affect the primary and secondary variables will 
be determined.
Updated the definition of the 
per-protocol analysis set
9.3 Data Handling Conventions
For all variables, only the observed data from the patients will 
be used in the statistical analyses, ie, there is no plan to 
estimate missing data, unless otherwise specified. DetailedFor 
the sensitivity analysis of the primary and key secondary 
efficacy endpoints, detailed data imputation rules will be 
described in the statistical analysis plan.
For all variables, only the observed data from the 
patients will be used in the statistical analyses, ie, 
there is no plan to estimate missing data, unless 
otherwise specified. For the sensitivity analysis of the 
primary and key secondary efficacy endpoints, 
detailed data imputation rules will be described in the 
statistical analysis plan.
Updated language pertaining 
to data imputation rules 
described in the statistical 
analysis plan
9.3.1 Handling Withdrawals and Missing Data
Missing data will not be imputed, unless otherwise specified.
Not applicable
Removed section, as it was 
determined that this subsection 
was already covered under 
existing Section 9.3
9.5.5.1 Primary Efficacy Analysis
The baseline TTS, region, and baseline age group at baseline (2 
levels: 6 to 11 years, 12 to 16 years) will be included as 
covariates.
The baseline TTS, region, and age group at baseline 
(2 levels: 6 to 11 years, 12 to 16 years) will be 
included as covariates.
Elaborated statistical analysis 
and covariates planned for the 
primary endpoint
9.5.5.2 Sensitivity Analysis
Sensitivity analyses for missing data, the statistical model, and 
for the increase in sample size, will be conducted as detailed in 
the statisitical analysis plan.
To assess the robustness of the primary efficacy analysis, the 
Sensitivity analyses for missing data, the statistical 
model, and for the increase in sample size, will be 
conducted as detailed in the statisitical analysis plan.
Removed specific analysis 
details and updated the 
protocol to state that 
sensitivity analysis will be 


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following additional analyses will include:

Using the same repeated measures model as described 
for the primary analysis, the groups will be compared 
using the per protocol population.

The primary analysis at week 8 will be repeated on a 
complete data set using multiple imputation 
methodology for imputing missing data using a 
missing not at random (MNAR) missing data 
assumption to investigate when statistical significance 
disappears.
Data will be imputed for patients missing data at week 8 using 
the predictive mean matching multiple imputation method 
(Heitjan and Little 1991, Schenker and Taylor 1996). Under a 
missing not at random data assumption, patients treated with 
TEV 50717 who discontinue the study for any reason other 
than “Lost to Follow Up” will have their missing data at 
week 8 imputed. Only placebo patients will be included in the 
imputation model, while all other patients will have data 
imputed from a model derived from their assigned treatment 
group. The imputation model will include age group at 
baseline, baseline TTS score, and TTS scores at all visits up to 
week 8 where the TTS is scheduled to be collected. The 
resulting complete, imputed datasets will each be analyzed 
using the same model as the primary analysis model, and the 
resulting statistics combined using methodology provided by 
Rubin (1987) and Little and Rubin (2002). Details on imputing 
missing data and combining inferences from the resultant 
datasets will be provided in the statistical analysis plan. 
provided in the statistical 
analysis plan


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13. FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, 
will be signed between each principal investigator and the 
sponsor (or the CRO designated by the sponsor) Syneos Health
before the IMP is delivered.
A separate clinical study agreement, including a study 
budget, will be signed between each principal 
investigator and Syneos Health before the IMP is 
delivered.
Administrative update
Appendix B STUDY PROCEDURES AND ASSESSMENTS BY VISIT
Not Applicable
The study procedures and assessments by visit have 
been updated to align with all changes as noted 
within with the Schedule of Assessments and study 
design of Protocol TV50717-CNS-30060 
Amendment 02.
Updated all study procedures 
and assessments to align with 
all changes per this 
amendment. Additional 
guidance text for the sites was 
provided.
Appendix H ALLOWED AND PROHIBITED MEDICATIONS
Table 11 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
CYP2D6=cytochrome P450 2D6.
Table 11 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
CYP2D6=cytochrome P450 2D6.
Updated Appendix H to 
include a table for other 
prohibited drugs
Appendix R Pharmacokinetic Samples
Specimen Sampling and Handling
For plasma collection, 5 mL of blood will be collected into 
Not Applicable
Removed Appendix R


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lithium heparin tubes and processed to plasma. Blood samples 
will be centrifuged (1500g, approximately 10 minutes, at 0 to 
5°C) between 5 minutes and 1 hour after sampling. If a 
refrigerated centrifuge is not available, samples should be 
chilled before centrifugation. Other measures should be taken 
as appropriate to prevent samples from heating significantly 
during centrifugation. Separated plasma will be transferred in 
approximately equal portions in 2 opaque, labeled, 
polypropylene tubes (Sets A and B).
For serum collection, samples will be collected in Vacutainer 
tubes containing no anticoagulant and allowed to set at room 
temperature for between 1 and 1.5 hours to allow for serum 
separation to occur. Samples will then be centrifuged (1500g, 
approximately 10 minutes, at 0 to 5°C). If a refrigerated 
centrifuge is not available, samples should be chilled before 
centrifugation. Other measures should be taken as appropriate 
to prevent samples from heating significantly during 
centrifugation. Separated serum will be transferred in 
approximately equal portions in 2 opaque, labeled, 
polypropylene tubes (Sets A and B).
Labels for samples should include study number, patient 
randomization number, period, nominal collection time, Set A 
or B, and indication that they are pharmacokinetic samples. 
Samples will be stored at a temperature from 20 or below in 
an upright position for a maximum of 2 weeks until they are 
shipped to the central laboratory.
Shipment and Analysis of Samples
Serum or plasma samples for all patients will be shipped from 
the investigational center to the central laboratory, where they 
will be stored until shipped to the sponsor or designee for 
analysis. Samples will be stored in an upright position at 20ºC 
until assayed. The central laboratory will be notified before the 
shipment of the samples and will be sent the shipping 


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information when the samples are shipped. An electronic file 
containing sample demographics will be emailed to the 
bioanalytical laboratory and the sponsor’s representatives from 
bioanalytical departments for each shipment.
Set A samples will be transported with a temperature data 
logger and frozen with dry ice sufficient for 4 days, by next 
day courier to the central laboratory. 
Set B samples will be sent either to the same laboratory as that 
for Set A samples on a subsequent day by next day courier, or 
be retained at the investigational center until the study is 
completed and the CSR has been issued (unless shipment to 
another facility is requested by the sponsor). Instructions as to 
the disposition of the Set B samples will be provided by the 
sponsor.
Sample shipments should be sent no later in the week than 
Wednesday morning for next day delivery. Samples are not to 
arrive on the weekend.
Samples will be analyzed using an appropriate validated 
method. Timing of the initiation of sample analysis will be 
determined by the sponsor’s representatives of bioanalytical 
departments responsible for the bioanalysis while keeping the 
study blinding, if any, intact.


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15.3.
Amendment 01 Dated 20 November 2017
The primary reason for this amendment is to change aspects of the conduct, some IMP 
administration procedures, include concomitant medications, participating countries, 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.


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change
Global
Nuvelution TS Pharma, INC.
Nuvelution TS Pharma, INC
Name update
Not applicable
Tourette Syndrome-Patient Global Impression of Impact (TS-
PGII)
Added TS-PGII to 
assessments
Gilles de la Tourette Syndrome - Quality of Life scale (GTS-QOL)
Child and Adolescent Gilles de la Tourette Syndrome – Quality of 
Life scale (C&A-GTS-QOL)
Updated to Gilles de la 
Tourette Syndrome 
children and adolescents 
scale
Screening period (up to 31 days 4 weeks ; minimum of 3 days)
Screening period (up to 31 days)
Updated to clarify the 
screening period duration
May be interviewed in conjunctionseparately or jointly
May be interviewed separately or jointly
Updated to conduct of 
interview
Baseline/day 0 1 visit
Baseline/day 1 visit
Updated to clarify visit 
day of baseline visit
Clinical Laboratory and Other Departments and Institutions
 
 
 
Update to Sponsor 
representatives and points 
of contact


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Synopsis
Not applicable
Sponsor’s Development Partner: Nuvelution TS Pharma, Inc., 601 
Gateway Boulevard Suite 1270, South San Francisco, California 
94080, United States of America
Added Sponsor 
Development Partner
Countries Planned: Approximately 10 in North America, 
SouthLatin America, Turkey, Ukraine, South Korea, and Europe
Countries Planned: North America, Latin America, Turkey, 
Ukraine, South Korea, and Europe
Updated to more 
specifically list the 
countries/regions planned
for the study
1.1 Introduction
TEV 50717 was granted breakthrough status for treatment of TD by 
the 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 and for the treatment 
of TD on 03 April 2017 and 30 August 2017, respectively.
TEV-50717 was approved for the treatment of chorea associated 
with HD and for the treatment of TD on 03 April 2017 and 30 
August 2017, respectively.
Updated to account for 
approval of TD in August 
2017.
2.1 Primary and Secondary Study Objectives and Endpoints
The secondary efficacy endpoints are as follows:
1.
change in the Tourette Syndrome Clinical Global Impression 
(TS-CGI) score from baseline to week 8 between high-dose TEV-
50717 treated patients and placebo treated patients
2.
change in the TTS of the YGTSS from baseline to week 8 for 
The secondary efficacy endpoints are as follows:
1.
change in the TS-CGI score from baseline to week 8 between 
high-dose TEV-50717 treated patients and placebo treated patients
2.
change in the TTS of the YGTSS from baseline to week 8 for 
low dose TEV-50717 and placebo will be tested
Additional secondary 
efficacy endpoints were 
included for analysis. 
Changes were made to 
existing secondary 


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low dose TEV-50717 and placebo will be tested
3.
change in the TS-CGI score from baseline to week 8 between 
low dose TEV-50717 treated patients and placebo treated patients
2.4. change in the Tourette Syndrome-Patient Global Impression of 
Impact (TS-
PGII) score from baseline to week 8 
between high-dose TEV-50717-treated patients and placebo-treated 
patients
5.
change in the TS-PGII score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated patients
6.
change in the Child and Adolescent Gilles de la Tourette 
Syndrome – Quality of Life- scale (C&A-GTS-QOL) 
physical/activities of daily living (ADL) subscale from baseline to 
week 8 between high-dose TEV-50717 treated patients and placebo 
treated patients
3.7. change in the C&A-GTS-QOL ADL subscale from baseline to 
week 8 between low-dose TEV-50717 treated patients and placebo 
treated patients
The hierarchy of testing of secondary endpoints regarding dose level 
to control type I error is specified in the section entitled “Analysis of 
Key Secondary Endpoints.”
3.
change in the TS-CGI score from baseline to week 8 between 
low dose TEV-50717 treated patients and placebo treated patients
4.
change in the Tourette Syndrome-Patient Global Impression 
of Impact (TS-PGII) score from baseline to week 8 between high-
dose TEV-50717-treated patients and placebo-treated patients
5.
change in the TS-PGII score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated patients
6.
change in the Child and Adolescent Gilles de la Tourette 
Syndrome – Quality of Life- scale (C&A-GTS-QOL) activities of 
daily living (ADL) subscale from baseline to week 8 between 
high-dose TEV-50717 treated patients and placebo treated patients
7.
change in the C&A-GTS-QOL ADL subscale from baseline to 
week 8 between low-dose TEV-50717 treated patients and placebo 
treated patients
The hierarchy of testing of secondary endpoints regarding dose 
level to control type I error is specified in the section entitled 
“Analysis of Key Secondary Endpoints.”
efficacy endpoints. (ie, 
was removed 
from secondary efficacy 
endpoints)
2.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1 Study Design
Treatment period (8 weeks): Patients who continue to remain eligible 
for participation in the study will be randomized at the baseline visit 
(day 01) and will receive blinded IMP to begin taking the next 
morning (that same day (day 1). Tablets should be taken with food 
Treatment period (8 weeks): Patients who continue to remain 
eligible for participation in the study will be randomized at the 
baseline visit (day 1) and will receive blinded IMP to begin that 
same day (day 1). Tablets should be taken with food (eg, a snack) 
Updated to align with 
Table of Assessments and 
procedures. Dosing 
information adjusted 


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(eg, a snack) and should not be taken on an empty stomach. Patients 
and their parent/legal guardian will interact regularly with the clinical 
research staff, either by telephone contact or clinic visit to assure 
adherence with study procedures and to evaluate safety and efficacy. 
To this end, clinic visits will be performed at weeks 2, 4, and 8 after 
baseline to evaluate safety; assess tic severity with the YGTSS, TS-
CGI, TS-PGII, and the 
C&A GTS-QOL; and perform safety 
rating scales to augment adverse event reporting, concomitant 
medication usage, clinical laboratory examination, and 12 lead ECGs. 
Telephone contacts will occur at the end of weeks 1, 3, 6, and 7.
and should not be taken on an empty stomach. Patients and their 
parent/legal guardian will interact regularly with the clinical 
research staff, either by telephone contact or clinic visit to assure 
adherence with study procedures and to evaluate safety and 
efficacy. To this end, clinic visits will be performed at weeks 2, 4, 
and 8 after baseline to evaluate safety; assess tic severity with the 
YGTSS, TS-CGI, TS-PGII, and the C&A-GTS-QOL; and perform 
safety rating scales to augment adverse event reporting, 
concomitant medication usage, clinical laboratory examination, 
and 12-lead ECGs. Telephone contacts will occur at the end of 
weeks 1, 3, 6, and 7.
slightly. Assessments and 
the scales to be used at 
weeks 2, 4, and 8 were 
updated per changes made 
to the endpoints.
3.4 Dose Escalation Procedures
IMP will be administered as follows:
•
IMP should be swallowed whole and taken with food (eg, a 
snack) and should not be taken on an empty stomach.
•
Daily doses will be administered twice daily in 2 divided doses, 
approximately 8 to 10 hours apart during the day. Dosing will be 
based on body weight and CYP2D6 impairment status at the baseline 
visit, as shown in Table 1.
•
To preserve blinding, 2 tablets will be taken in the morning and 
again in the evening twice daily starting at week 4 day 1 per Table 1. 
Daily doses will be administered twice daily, approximately 8 to 10 
hours apart during the day. Depending on the dose and arm assigned, 
TEV-50717 tablets and/or placebo tablets will be taken to maintain 
the blind. 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, dDose escalations may not occur more frequently 
than once every 5 days.
•
The dose of IMP will be escalated weekly during the escalation 
period, according to Table 1.
•
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 must be notified.
•
During the titration period, the dose of the IMP will be adjusted 
weekly according to Table 1. Investigators will be blinded to CYP 
status, with a dose cap for poor metabolizers prespecified by the IRT.
IMP will be packaged in blister packs and provided for patients to 
IMP will be administered as follows:
•
IMP should be swallowed whole and 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 at the baseline visit, as shown in Table 1.
•
To preserve blinding, 2 tablets will be taken twice daily 
starting at day 1 per Table 1. Daily doses will be administered 
twice daily, approximately 8 to 10 hours apart during the day. 
Depending on the dose and arm assigned, TEV-50717 tablets 
and/or placebo tablets will be taken to maintain the blind. 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 escalations may not occur more frequently 
than once every 5 days.
•
The dose of IMP will be escalated weekly during the 
escalation period, according to Table 1.
•
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 must be notified.
•
During the titration period, the dose of the IMP will be 
adjusted weekly according to Table 1. Investigators will be blinded 
to CYP status, with a dose cap for poor metabolizers prespecified 
by the IRT.
IMP will be packaged in blister packs and provided for patients to 
take at home (see Section 5.1).
Updated to account for 
the latest IMP 
administration 
instructions and guidance.


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take at home (see Section 5.1).
Section 3.6: Table 2: Study Procedures and Assessments
Not applicable
Table 2 was updated in alignment with the changes made to the 
protocol.
Study days were added to increase clarity/timing of assessments. 
The visit window was increased to ±3 days between week 1 to 
week 10. 
Assessments and footnotes were adjusted/edited
Table 2 was updated to be 
consistent and aligned 
with the changes made to 
the protocol
4.1 Patient Inclusion Criteria
j.
Females who are postmenarchal or ≥12 years of age may be 
included only if they have a negative β- HCG test at baseline or are 
sterile. Definition of sterile is given in Appendix E.
k.
Females of childbearing potentialwho 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 E.
j.
Females who are postmenarchal or ≥12 years of age may be 
included only if they have a negative β- HCG test at baseline or are 
sterile. Definition of sterile is given in Appendix E.
k.
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 E.
Update to females “of 
childbearing potential.” 
Newly defined as females 
who are postmenarchal or 
≥12 years of age (in 
alignment with updated 
Appendix E)
4.2 Patient Exclusion Criteria
m. Patient has a QTcF value >450 msec (males) or >460 msec 
(females), or >480 msec (with right bundle branch block) on a 12-
lead electrocardiogram (ECG) at screening., or requires treatment 
with drugs known to prolong the QT interval (see Appendix H Table 
10 for a complete list of prohibited QT-prolonging drugs).
t.
Patient has a history of or acknowledges alcohol or substance 
abuse-related disorder in the previous 12 months, as defined in the 
DSM-5.
m. Patient has a QTcF value >450 msec (males) or >460 msec 
(females), or >480 msec (with right bundle branch block) on a 12-
lead electrocardiogram (ECG) at screening, or requires treatment 
with drugs known to prolong the QT interval (see Appendix H 
Table 10 for a complete list of prohibited QT-prolonging drugs).
t.
Patient has a history of or acknowledges alcohol-related 
disorder in the previous 12 months, as defined in the DSM-5.
Update to include a list of 
prohibited QT prolonging 
medications.
Latest DSM-5 language 
included as well
5.1.2 Placebo Investigational Medicinal Product
(Table 3. Dosing instructions [Test IMP])
To preserve blinding, 2 tablets will be taken twice daily starting at 
day 1 per Table 1. Daily doses will be administered twice dailyin 
2 divided doses, approximately 8 to 10 hours apart during the day. In 
order to preserve blinding, 2 tablets will be taken in the morning and 
again in the evening starting at week 3Depending on the dose and 
arm assigned, TEV-50717 tablets and/or placebo tablets will be taken 
to maintain the blind. A minimum of 6 hours should elapse between 
doses. If a patient misses a dose, and it is within 6 hours of their next 
(Table 3. Dosing instructions [Test IMP])
To preserve blinding, 2 tablets will be taken twice daily starting at 
day 1 per Table 1. Daily doses will be administered twice daily, 
approximately 8 to 10 hours apart during the day. Depending on 
the dose and arm assigned, TEV-50717 tablets and/or placebo 
tablets will be taken to maintain the blind. 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. Tablets should be swallowed whole and taken with food 
Updated Table 3 to clarify 
dosing instructions for 
test and placebo IMP
Updated Table 3 to reflect 
the manufacturer of 
Placebo IMP


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dose, the missed dose should be skipped. Tablets should be 
swallowed whole and taken with food (eg, a snack) and should not be 
taken on an empty stomach.
(Table 3. Dosing instructions [Placebo IMP])
To preserve blinding, 2 tablets will be taken twice daily starting at 
day 1 per Table 1. Daily doses will be administered twice dailyin 
2 divided doses, approximately 8 to 10 hours apart during the day. In 
order to preserve blinding, 2 tablets will be taken in the morning and 
again in the evening starting at week 3Depending on the dose and 
arm assigned, TEV-50717 tablets and/or placebo tablets will be taken 
to maintain the blind. 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. Tablets should be 
swallowed whole and taken with food (eg, a snack) and should not be 
taken on an empty stomach.
(Table 3. Manufacturer [Placebo IMP])
Not applicableNorwich Pharmaceuticals, Inc.
(Referenced as NPI or Norwich)
6826 State Highway 12
Norwich, NY 13815
(eg, a snack) and should not be taken on an empty stomach.
(Table 3. Dosing instructions [Placebo IMP])
To preserve blinding, 2 tablets will be taken twice daily starting at 
day 1 per Table 1. Daily doses will be administered twice daily, 
approximately 8 to 10 hours apart during the day. Depending on 
the dose and arm assigned, TEV-50717 tablets and/or placebo 
tablets will be taken to maintain the blind. 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. Tablets should be swallowed whole and taken with food 
(eg, a snack) and should not be taken on an empty stomach.
(Table 3. Manufacturer [Placebo IMP])
Norwich Pharmaceuticals, Inc.
(Referenced as NPI or Norwich)
6826 State Highway 12
Norwich, NY 13815
5.2.3 Accountability
A record of IMP accountability (ie, IMP and other study 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 blister 
packs IMP will be disposed of per site policy, or returned to the 
sponsor or designee, as agreed with the sponsor.
A record of IMP accountability (ie, IMP and other study 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 blister packs IMP will be returned to the sponsor or 
designee, as agreed with the sponsor.
Updated to clarify 
management of unused 
blister packs IMP
5.5. Restrictions
While patients receiving strong CYP2D6 inhibitors (paroxetine, 
fluoxetine, and bupropion) at baseline 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 CYP inhibitor is prohibited.
While patients receiving strong CYP2D6 inhibitors (paroxetine, 
fluoxetine, and bupropion) at baseline 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 CYP inhibitor is prohibited.
Updated to reflect 
prohibition of the addition 
of a strong CYP inhibtor 
during treatment.
5.6 Prior and Concomitant Medication or Therapy
At each clinic visit after the screening visit, the investigator will ask 
At each clinic visit after the screening visit, the investigator will 
Updated to account for 


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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. 
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. Allowed strong CYP inhibitors at baseline are shown 
in Appendix H Table 8. Addition of a strong CYP inhibitor is 
prohibited.
Prohibited antipsychotic drugs are listed in Appendix H Table 9. 
Prohibited medications that are associated with QTc prolongation are 
listed in Appendix H Table 10.
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. 
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. Allowed strong CYP inhibitors at baseline are 
shown in Appendix H Table 8. Addition of a strong CYP inhibitor 
is prohibited.
Prohibited antipsychotic drugs are listed in Appendix H Table 9. 
Prohibited medications that are associated with QTc prolongation
are listed in Appendix H Table 10. 
the patient guidelines on 
handling additional 
prescriptions during the 
study. Added link to 
prohibited medications 
that are associated with 
QTc prolongation.
5.8 Temporary Discontinuation of Investigational Medicinal Product
If more than 1 dose reduction is required for an adverse event, the 
medical monitor shouldmust be notified.
The patients who restart IMP treatment will follow the visit schedule 
as outlined in the protocol Table 2. Patients who withdraw from the 
study will proceed as described in Section 4.3.
If more than 1 dose reduction is required for an adverse event, the 
medical monitor must be notified.
The patients who restart IMP treatment will follow the visit 
schedule as outlined in Table 2. Patients who withdraw from the 
study will proceed as described in Section 4.3.
Updated to reflect 
necessity of notifying 
medical monitor during 
dose reduction. Updated
link to visit schedule 
scheme. 
5.11 Total Blood Volume
Not applicable
Table 4 column header updated to reflect inclusion of data for 
maximum total volume. Footnotes revised to reflect update to 
definition of female subjects who are to undergo gonadotropin 
testing.
Table 4 column header 
and footnotes updated. 
Revised to account for 
update to definition of 
females “of childbearing 
potential”; newly defined 
as females who are 
postmenarchal or ≥12 
years of age (in alignment 
with updated Appendix E)
6.2.2. Tourette Syndrome-Patient Global Impression of Impact
Not applicable
Section 6.2.2 added to reflect description for the additional
assessment, Tourette Syndrome- Patient Global Impression Impact
Added section for 
additional assessment


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6.2.3 Tourette Syndrome-Patient Global Impression of Severity
 
 
 
 
6.2.4 Child and Adolescent Gilles de la Tourette Syndrome - Quality of Life Scale
The C&A-GTS-QOL is administered at baseline, week 4, and week 
8. Children 13 years of age and under mustmay be interviewed in 
conjunctionseparately or jointly with the parent/legal 
guardiancaregiver/adult as appropriate or defined by the scale. 
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 
46 subscales (cognitive, coprophenomena, psychological, physical, 
obsessionalobsessive-compulsive, and cognitiveADL) 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 
(CavannaSu et al 20082017).
The C&A-GTS-QOL is administered at baseline, week 4, and 
week 8. Children 13 years of age and under may be interviewed 
separately or jointly with the caregiver/adult as appropriate or 
defined by the scale.
The C&A-GTS-QOL is a 27-item questionnaire specific to TS 
patients that asks the patient to assess the extent to which their 
quality of life is impacted by their symptoms. The C&A-GTS-
QOL contains 6 subscales (cognitive, coprophenomena, 
psychological, physical, obsessive-compulsive, and ADL) and uses 
a 5-point Likert scale ranging from no problem to extreme 
problem. Patients will also be asked how satisfied they feel overall 
with their life at that moment by using a VAS scale between 0 and 
100 (Su et al 2017).
Updated to account for 
changes to name and 
definition of Gilles de la 
Tourette Syndrome 
children and adolescents 
scale
Subscale details were 
updated
6.2.6.
 
 
 
 
 
Updated to reflect 
changes in how the 
assessment is expected to 
be administered
6.2.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
add relevant information.
Updated to reflect 
changes in how the 
assessment is expected to 
be administered
7.1.1. Definition of an Adverse Event
In this study, any adverse event occurring after the clinical study 
(Note: Abnormal laboratory test results at the screening visit that 
Deleted statement on 


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patient has signed the informed consent form should be recorded and 
reported as an adverse event. 
(Note: Abnormal laboratory or diagnostic test results at the screening 
visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.)
preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.)
adverse event recording 
after signing of informed 
consent form
7.1.2. Recording and Reporting of Adverse Events 
For this study, there will be 1 week of washout for patients who will 
participate in the open-label safety extension study TV50717-CNS-
30047 and 2 weeks after the last dose of IMP (1 week after the end of 
the washout period) for patients who will not roll over into the open-
label safety extension study TV50717-CNS-30047.
Further details are given in the safety monitoring plan.
For this study, there will be 1 week of washout for patients who 
will participate in the open-label safety extension study TV50717-
CNS-30047 and 2 weeks after the last dose of IMP for patients 
who will not roll over into the open-label safety extension study 
TV50717-CNS-30047.
Further details are given in the safety monitoring plan.
Updated details on last 
dose of IMP. Added 
direction to safety 
monitoring plan for 
further information.
7.1.5. Serious Adverse Events
For recording of serious adverse event, the study period is defined for 
each patient as that time period from signature of the informed 
consent form to the end of the follow-up period as defined in 
Section 7.1.2. 
For recording of serious adverse event, the study period is defined 
for each patient as that time period from signature of the informed 
consent form to the end of the follow-up period as defined in 
Section 7.1.2. 
Added link to related 
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 RSI for this study is provided in
Appendix B 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.
The sponsor’s Global Patient Safety and Pharmacovigilance will 
determine the expectedness for all serious adverse events.
For the purpose of SUSAR reporting, the version of the IB at the time 
of occurrence of the SUSAR applies.
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.
For the purpose of SUSAR reporting, the version of the IB at the 
time of occurrence of the SUSAR applies.
Updated to reflect new 
definition of unexpected 
adverse events
7.1.5.3.1. Investigator Responsibility
Blinding will be maintained for the people who are involved directly 
in theall study personnel. Therefore, in case of a SUSAR, only the 
LSO/CRO will receive the unblinded report for regulatory 
submission; the others will receive a blinded report.
Blinding will be maintained for all study personnel. Therefore, in 
case of a SUSAR, only the LSO/CRO will receive the unblinded 
report for regulatory submission; the others will receive a blinded 
report.
Updated to clarify 
blinding for all study 
personnel


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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 study treatment at any time at the discretion of 
the investigator. If a patient is withdrawn from the studyIf 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 >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.
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. 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 >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.
Added guideline for IMP 
discontinuation due to 
prolonged QTcF 
7.1.8. Overdose of IMP
7.1.8.
Overdose of IMP 
Any dose of TEV 50717 (whether the investigational product or a 
placebo), whether taken intentionally or unintentionally, in excess of 
that prescribed during the given time period must be immediately 
reported to the sponsor. When the identification of the IMP must be 
known, the investigator must follow the procedures outlined in 
Section 5.10.
Section deleted
Section deleted
7.2.2. Columbia-Suicide Severity Rating Scale
The C-SSRS children’s baseline/screening scale (that collects the 
history ofassesses past and current suicidal ideation and behaviors to 
determine suicide) risk and is administered at screening. C-SSRS 
children’s SLV scale is administered at baseline and at weeks 2, 4, 
6,8, and 9, 12, and 13. Children 13 years of age and under mustmay
be interviewed in conjunctionseparately or jointly with the 
parent/legal guardian.caregiver/adult as appropriate or defined by the 
scale. For children over 13 years of age, parent/legal guardian 
involvement is strongly encouraged. Questions should be directed to 
the child, but the parent/legal guardiancaregiver/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 trials 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 ideation and behaviors to determine suicide risk 
and is administered at screening. C-SSRS children’s SLV scale is 
administered at baseline and at weeks 2, 4, 8, and 9. 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, parent/legal guardian 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 an interview by trained study personnel.
Updated to reflect 
changes to definition and 
administration of the 
C-SSRS


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7.2.3. Children’s Depression Inventory, Second Edition
The CDI-2 (parent and self-report versions) is administered at 
screening; baseline; and weeks 2, 4, 6,8, and 9, 12, 13.
The CDI-2 (parent and self-report versions) is administered at 
screening; baseline; and weeks 2, 4, 8, and 9.
Updated to reflect 
changes to definition and 
administration of the 
CDI-2
7.3. Pregnancy
Any female patient becoming pregnant during the study will 
discontinue IMP.
All pregnancies of females female patients participating in the study 
that occur during the study, or within 14 days of completion after the 
end of the study, are to be reported immediately to the individual 
identified in the clinical study personnel contact information section 
of this protocol, and the investigator must provide the sponsor
(LSO/CRO) 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 pregnant during the study will 
discontinue treatment. All patients who become pregnant will be 
monitored for the outcome of the pregnancy (including spontaneous 
or voluntary termination). 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 termination from the study will be reported as 
an adverse event or serious adverse event, as appropriate.
The investigator is not required to report patients who are found to be 
pregnant between screening and baseline, provided no protocol
related procedures were applied IMP was given. 
Since there is no evidence of teratogenicity, genotoxicity, 
fetotoxicity, or spermatotoxicity for this IMP, female partners will 
not be required to sign an ICF to monitor the outcome of the 
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 individual identified in the 
clinical study personnel contact information section of this 
protocol, and the investigator must provide the sponsor 
(LSO/CRO) 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 baseline, provided no IMP was 
given. 
Updated guidelines on 
managing pregnancies 
during the course of the 
study
7.5.2.1 Human Chorionic Gonadotropin Tests
Any female patient who becomes pregnant during the study will 
discontinue treatmentbe withdrawn. Procedures for reporting the 
pregnancy are provided in Section 7.3.
Any female patient who becomes pregnant during the study will be 
withdrawn. Procedures for reporting the pregnancy are provided in 
Section 7.3.
Updated action taken with 
IMP in case of pregnancy 
during the course of the


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study
7.6. Physical Examinations 
Any physical examination finding that is judged by the investigator 
as a 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.
Added exception to 
assessment of clinically 
signficant adverse event 
7.9. Assessment of Suicidality
Baseline assessment of suicidal ideation and behavior and treatment-
emergent suicidal ideation and behavior will be assessed during the 
study using the Columbia-Suicide Severity Rating Scale described in 
Section 7.2.2. 
Baseline assessment of suicidal ideation and behavior and 
treatment-emergent suicidal ideation and behavior will be assessed 
during the study using the Columbia-Suicide Severity Rating Scale 
described in Section 7.2.2.
Added link to related 
section
7.10. Neurological Examinations
Not applicable
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 2. 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. 
Section added to reflect 
additional assessments
7.11. Concomitant Medication or Treatment
Not applicable
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 Appendix H Table 7.
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. Prohibited medications that are associated with 
QTc prolongation are listed in Appendix H Table 10, while 
prohibited antipsychotic drugs are listed in Appendix H Table 9.
Section added to reflect 
additional assessments


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7.12. Methods and Time Points of Assessing, Recording, and, Analyzing Safety Data
Not applicable
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 
clinical project physician/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 3.6. Procedures for recording safety data are discussed in 
Appnedix T, and methods of analyses are discussed in Section 9.7.
Section added to reflect 
additional assessments
8.1. Pharmacokinetic Assessment
Not applicable
8.1. Pharmacokinetic Assessment
Subheading added to 
further specify 
assessments
8.2. Pharmacodynamic Assessment
Not applicable
8.2. Pharmacodynamics Assessment
Exposure-response (eg, pharmacodynamic [PD] and/or safety 
endpoints) may be assessed if the appropriate data are available.
Subsection added to 
reflect additional 
assessment
8.3. Pharmacogenetics
Not applicable
8.3. Pharmacogenetics
Subsection added for 
further specification of 
assessments
8.3.1. CYP2D6 Genotyping/Pharmacogenetics
8.1.1. 8.3.1. CYP2D6 GenotypeGenotyping/Pharmacogenetics
At the screening visit, a blood sample (5 to 6 mL) will be obtained for 
analysis of CYP2D6 genotype. The patient’s genotype for CYP2D6 
will remain blinded during the conduct of the study. If the patient 
elects this option on the optional informed consent, the remaining 
sample will be stored for exploratory pharmacogenetics (PGx) 
evaluation. This PGx assessment will investigate the relationship 
between subjects’ genetic variability and study outcomes. Candidate 
genes included in this assessment may be related to, or hypothesized 
to be related to, pharmacokinetics, safety features, drug mechanism of 
action, Tourette syndrome, or related diseases. The final list of genes 
to be evaluated will be determined at the time of analysis to be able to 
account for the most current research.
8.3.1. CYP2D6 Genotyping/Pharmacogenetics
At the screening visit, a blood sample (5 to 6 mL) will be obtained 
for analysis of CYP2D6 genotype. The patient’s genotype for 
CYP2D6 will remain blinded during the conduct of the study. If 
the patient elects this option on the optional informed consent, the 
remaining sample will be stored for exploratory pharmacogenetics 
(PGx) evaluation. This PGx assessment will investigate the 
relationship between subjects’ genetic variability and study 
outcomes. Candidate genes included in this assessment may be 
related to, or hypothesized to be related to, pharmacokinetics, 
safety features, drug mechanism of action, Tourette syndrome, or 
related diseases. The final list of genes to be evaluated will be 
determined at the time of analysis to be able to account for the 
most current research.
Added guidelines and 
administration of 
genotyping


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change
9.5.2. Key Secondary Endpoints
1.
Change in the TS-CGI score from baseline to week 8 between 
high-dose TEV-50717 treated patients and placebo treated patients
2.
Change in the TTS of the YGTSS from baseline to week 8 for 
low-dose TEV-50717 and placebo will be tested
23. Change in the TS
CGI score from baseline to week 8 8 
between low dose TEV-50717-treated patients and placebo-treated 
patients
4.
Change in the TS- PGII score from baseline to week 8 between 
high-dose TEV-50717-treated patients and placebo-treated patients
5.
Change in the TS-PGII score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated patients
36. Change in the C&A-GTS-QOL physical/activities of daily 
livingADL subscale from baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated patients
7.
Additional EfficacyChange in the C&A-GTS-QOL ADL 
subscale from baseline to week 8 between low-dose TEV-50717 
treated patients and placebo treated patients.
1.
Change in the TS-CGI score from baseline to week 8 between 
high-dose TEV-50717 treated patients and placebo treated patients
2.
Change in the TTS of the YGTSS from baseline to week 8 for 
low-dose TEV-50717 and placebo will be tested 
3.
Change in the TS-CGI score from baseline to week 8 between 
low dose TEV-50717-treated patients and placebo-treated patients
4.
Change in the TS- PGII score from baseline to week 8
between high-dose TEV-50717-treated patients and 
placebo-treated patients
5.
Change in the TS-PGII score from baseline to week 8 between 
low-dose TEV-50717-treated patients and placebo-treated patients
6.
Change in the C&A-GTS-QOL ADL subscale from baseline 
to week 8 between high-dose TEV-50717-treated patients and 
placebo-treated patients
7.
Change in the C&A-GTS-QOL ADL subscale from baseline 
to week 8 between low-dose TEV-50717 treated patients and 
placebo treated patients.
Additional secondary 
efficacy endpoints were 
included for analysis. 
Changes were made to 
existing secondary 
efficacy endpoints. (ie, 
 was removed 
from secondary efficacy 
endpoints)
9.5.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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patients who have a reduction of 6 or more points in the 
 
 
 
 
 
 
9.5.5.2. Sensitivity Analysis
At week 128
At week 8
Updated timepoints to be 
aligned with protocol 
guidelines
9.5.5.3. Key Secondary Efficacy Analyses
1.
The change from baseline to week 8 in TS-CGI will be 
analyzed using a similar model as the primary analysis; however, 
instead of change in YGTSS TTS as the dependent.
3.
Using the same model as described in endpoint #1 above for 
TS-CGI, the comparison between the change in the TS-CGI 
values from baseline to week 8 for low-dose TEV-50717 and 
placebo will be tested.
4.
The change from baseline to week 8 in TS-
PGII will be 
analyzed using a similar model as the primary analysis; however, 
instead of change in YGTSS TTS as the dependent variable and 
baseline YGTSS TTS as a covariate, the corresponding 
 
values will be usedCochran-Mantel Haenszel-row mean score 
test with modified ridit scoring controlling for age group. The 
comparison between high-dose TEV-50717 and placebo will be 
tested.
5.
Using the same model as described in endpoint #4 above for 
TS-
GII, the comparison between the change in the TS-
PGII values from baseline to week 8 for low-dose TEV-50717 
and placebo will be tested.
6.
The change from baseline to week 8 in the C&A-GTS-QOL
1.
The change from baseline to week 8 in TS-CGI will be 
analyzed using a similar model as the primary analysis; 
however, instead of change in YGTSS TTS as the dependent.
3.
Using the same model as described in endpoint #1 above 
for TS-CGI, the comparison between the change in the TS-
CGI values from baseline to week 8 for low-dose TEV-50717 
and placebo will be tested.
4.
The change from baseline to week 8 in TS-PGII will be 
analyzed using a Cochran-Mantel Haenszel-row mean score 
test with modified ridit scoring controlling for age group. The 
comparison between high-dose TEV-50717 and placebo will 
be tested.
5.
Using the same model as described in endpoint #4 above
for TS-PGII, the comparison between the change in the TS-
PGII values from baseline to week 8 for low-dose TEV-50717 
and placebo will be tested.
6.
The change from baseline to week 8 in the C&A-GTS-
QOL ADL subscale will be analyzed using a similar model as
the primary analysis; however, instead of change in YGTSS 
TTS as the dependent variable and baseline YGTSS TTS as a 
Additional efficacy 
analysis removed. 
Updated to account for 
changes made to existing 
secondary efficacy 
endpoints.


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ADL subscale will be analyzed using a similar model as the 
primary analysis; however, instead of change in YGTSS TTS as 
the dependent variable and baseline YGTSS TTS as a covariate, 
the corresponding C&A-GTS-QOL ADL subscale values will be 
used. The comparison between high-dose TEV-50717 and 
placebo will be tested.
7.
Using the same model as described in endpoint #6 above for 
the C&A-GTS-QOL ADL subscale, the comparison between the 
change in the C&A-GTS-QOL ADL subscale scores from 
baseline to week 8 for low-dose TEV-50717 and placebo will be 
tested.
9.5.6.4. Additional Efficacy Analysis
covariate, the corresponding C&A-GTS-QOL ADL subscale 
values will be used. The comparison between high-dose 
TEV-50717 and placebo will be tested.
7.
Using the same model as described in endpoint #6 above 
for the C&A-GTS-QOL ADL subscale, the comparison 
between the change in the C&A-GTS-QOL ADL subscale 
scores from baseline to week 8 for low-dose TEV-50717 and 
placebo will be tested.
9.5.5.4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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will be included as the covariate.
of interest will be included as the covariate.
Appendix B. Study Proecuderes and Assessments by Visit

TS-CGI

TS-PGII (Note: Input from the caregiver/adult is permitted.)

 



C&A-GTS-QOL

TS-CGI

TS-PGII (Note: Input from the caregiver/adult is 
permitted.)

 



C&A-GTS-QOL
Updated to reflect 
additional assessments
Appendix E. Females of Chilbdearing Potenial and Birth Control Method
Appendix E. 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. 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

Descriptionwho are postmenarchal or ≥12 years of 
Appendix E. 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

who are 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
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable 
Updated section for 
brevity. Clarified 
definition of “females of 
childbearing potential”. 
Updated guidelines for 
application/adminitration 
of of birth control 
methods. Updated 
information for acceptable 
and unacceptable birth 
control methods. Updated 
guidelines for pregnancy 
testing in female patients.


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differentage 
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)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 7 days (for 
IMPs without suspected teratogenicity/genotoxicity) 
and 1 month (for IMPs potentially 
teratogenic/genotoxic)1 month before the first dose of 
IMP
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, 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.
methods of contraception. Female condom and male condom 
should not be used together.


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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 women of childbearing 
potential 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 women of childbearing potential:
7.
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 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.
Pregnancy tests in women of childbearing potential:
1.
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.
2.
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 


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Original text with changes shown
New wording
Reason/Justification for 
change
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.
Appendix G. Handling, Labeling, Storage, and Accountability for IMP
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.
Empty, partially used, and unused IMP will be returned to the 
sponsor or its designee, as agreed with the sponsor.
Updated guidelines for 
management of partially 
used or unused IMP
Appnedix H. List of Allowed and Prohibited Medications
Table 10 added to reflect list of prohibited QTc prolonging drugs
Added table to provide 
list of prohibited QTc 
prolonging drugs
Appendix Q. Child and Adolescent Gilles de la Tourette Syndrome - Qualityf 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)
Appendix revised to reflect updates on questionnaire
Revised questionnaire to 
account for updates to 
assessment


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APPENDIX A.DISTRIBUTION OF AUG BY WEIGHT CATEGORIES
AND CYP2D6 STATUS
Figure 2:
Distribution of AUC of Total (α+β)-HTBZ for Selected Doses Based on 
Weight Categories


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APPENDIX B.STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for Prescreening (Up to 3 Months)
The prescreening visit will take place not more than 3 months before the baseline visit. The 
following procedure will be performed at prescreening:

obtain written informed consent/assent, depending on the child’s age, as appropriate,
before any study-related procedures are performed
2. Procedures for Screening (Up to 31 days)
The screening visit will take place up to 31 days before the baseline visit. A patient who is 
screened but not enrolled may be rescreened 1 time if there is a change in the status of the 
patient regarding eligibility for the study. (Note: Details of rescreening must be approved and 
documented by the medical monitor and/or Clinical Surveillance and Training [CST] team.)
The Yale Global Tic Severity Scale (YGTSS) questionnaire should be performed before any 
blood draws or electrocardiogram (ECG) assessments. 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 8/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. The following procedures will be performed at
screening:

obtain written informed consent/assent, depending on the child’s age, as appropriate, 
before any study-related procedures are performed

conduct clinic visit (may be conducted over 2 separate visits at the discretion of the 
investigator [Note: If the screening visit is divided into 2 visits, the blood sample 
should be obtained during the first of the 2 visits.])

review eligibility (inclusion and exclusion) criteria

review medical and psychiatric history

review demographics information

measure vital signs (pulse, blood pressure [BP], body temperature, and respiratory 
rate) and weight (Note: Weight must be measured with shoes and outerwear off.)

perform full physical and neurological examinations (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 chemical, hematological, and urine 
analyses 

perform urine drug screen (UDS)


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
obtain a blood sample (3 mL) for analysis of CYP2D6 genotype

perform a serum pregnancy (beta-human chorionic gonadotropin [β-HCG]) test (only 
in females who are postmenarchal or ≥12 years of age)

administer the following questionnaires (Note: For Mini International 
Neuropsychiatric Interview for Children and Adolescents [MINI Kid] and Columbia 
Suicide Severity Rating Scale [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])

Children’s Depression Inventory Second Edition (CDI-2), Parent and Self-
report Profiles (Note: Children 6 years of age at baseline 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.)

assess of adverse events

review medication history and concomitant medications
3. Procedures Before Administration of Investigational Medicinal Product (Baseline, 
Day 1)
Patients who meet the inclusion and exclusion criteria at screening will continue to the day 1
visit, when baseline assessments will be conducted. The YGTSS, Tourette Syndrome-
Clinical Global Impression (TS-CGI), Tourette Syndrome-Patient Global Impression of 
Impact (TS-PGII), and 
questionnaires should be performed before any blood draws or ECG assessments.
The following procedures will be performed at the day 1 visit/baseline:

randomization

conduct clinic visit 

review eligibility (inclusion and exclusion) criteria

measure vital signs (orthostatic pulse and BP [after standing for at least 3 minutes], 
body temperature, and respiratory rate) and weight (Note: Weight must be measured 
with shoes and outerwear off.)


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
perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)

perform serum pregnancy (β-HCG) test (only in females who are postmenarchal or 
≥12 years of age)

administer the following questionnaires (Note: For C-SSRS, 
 
 and Child and 
Adolescent Gilles de la Tourette Syndrome - Quality of Life scale (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-PGII, and 
 questionnaires should be 
performed before any blood draws or ECG assessments.):

CDI-2, Parent and Self-report Profiles (Note: Children 6 years of age at 
baseline will not complete the self-report version; the caregiver/adult will 
complete the parent version.)

C-SSRS (children’s Since Last Visit [SLV])

YGTSS (Input from the caregiver/adult is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)




C&A-GTS-QOL

dispense investigational medicinal product (IMP) (patients will receive doses for 2 
weeks [current dose level and next dose level] to cover the telephone contacts)

provide patients with a diary to record critical information on dosing

assess of adverse events

review concomitant medications
4. Procedures During Administration of Investigational Medicinal Product 
a.
Escalation Period (Weeks 1 and 3) and Maintenance Period (Week 6)
Patients who meet the inclusion and exclusion criteria at screening will continue to visit 1, 
when baseline assessments will be conducted. The YGTSS, TS-CGI, TS-PGII, and 
questionnaires should be performed before any blood draws or ECG assessments.


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The following procedures will be performed at weeks 1, 3, and 6:

telephone contact

dose escalation (weeks 1 and 3 only)

assess IMP accountability/compliance/supply

assess of adverse events

review concomitant medications
b. Escalation Period (Week 2)
The following procedures will be performed at week 2:

conduct clinic visit

dose escalation

measure vital signs (pulse, BP, body temperature, and respiratory rate) and weight
(Note: Weight must be measured with shoes and outerwear off.)

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, TS-PGII, and 
questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-report Profiles (Note: Children 6 years of age at 
baseline will not complete the self-report version; the caregiver/adult will 
complete the parent version.)

C-SSRS (Children’s SLV)

YGTSS (Input from the caregiver/adult is required.)

TS-CGI

TS-PGII (Note: Input from the caregiver/adult is permitted.)



dispense IMP and patient diary

collect IMP

assess IMP accountability/compliance/supply

assess of adverse events

review concomitant medications


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c.
Escalation Period (Week 4)
The following procedures will be performed at week 4:

conduct clinic visit

measure vital signs (orthostatic pulse and BP [after standing for at least 3 minutes], 
body temperature, and respiratory rate) 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.)

perform serum pregnancy (β-HCG) test (only in 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, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-report Profiles (Note: Children 6 years of age at 
baseline will not complete the self-report version; the caregiver/adult will 
complete the parent version.)

C-SSRS (Children’s SLV)

YGTSS (Note: Input from the caregiver/adult is required.)

TS-CGI

TS-PGII (Note: Input from the caregiver/adult is permitted.)


 

C&A-GTS-QOL

dispense IMP and patient diary (prior to the clinic visit on week 8, patients will be 
reminded to record the start time of their last meal and the time of their last dose of 
study medication before the week 8 visit)

collect of IMP

assess IMP accountability/compliance/supply

assess adverse events


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
review concomitant medications
d. Maintenance Period (Week 7)
The following procedures will be performed at week 7:

telephone contact 

assess IMP accountability/compliance/supply

assess adverse events

review concomitant medications
e.
Maintenance Period/Early Termination (Week 8)
Dosing requirements for the week 8 visit must be followed to ensure appropriate 
pharmacokinetic sample collection. Patients with early morning visits (ie, within 2 hours of 
their scheduled AM dosing) should take their dose in clinic after the first pharmacokinetic 
sample is collected. The date and time of the last dose of study medication before the week 8 
visit should be recorded in the diary by the patient or caregiver/adult. The site will document 
the date and time of the sample collection. Prior to the clinic visit on week 8, patients will be 
reminded to record the start time of their last meal and the time of their last dose in their 
diary. The following procedures will be performed at week 8/early termination:

conduct clinic visit

measure vital signs (orthostatic pulse and BP [after standing for at least 3 minutes], 
body temperature, and respiratory rate) and weight (Note: Weight must be measured 
with shoes and outerwear off.)

perform full physical and neurological examinations (including height)

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)

obtain pharmacokinetic blood samples (Two samples will be collected. The first 
sample will be collected upon arrival at the clinic. The second sample will be 
collected within 2 to 3 hours after the first PK sample collection. Patients with early 
morning visits (ie, within 2 hours of their scheduled AM dosing) should take their 
IMP dose in the clinic after the first PK sample is collected.)

perform clinical laboratory tests, including chemical, hematological, and urine 
analyses 

perform UDS

perform serum pregnancy (β-HCG) test (only in 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 


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be encouraged to add relevant information. The YGTSS, TS-CGI, TS-PGII, and 
questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-report Profiles (Note: Children 6 years of age at 
baseline will not complete the self-report version; the caregiver/adult will 
complete the parent version.)

C-SSRS (children’s SLV)

YGTSS (Input from the caregiver/adult is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)




C&A-GTS-QOL

collect IMP

assess IMP accountability/compliance/supply

assess adverse events

review concomitant medications
5. Follow-up (Weeks 9 and 10)
The YGTSS, TS-CGI, TS-PGII, and 
questionnaires should be performed before 
any blood draws or ECG assessments.
The following procedures and assessments will be performed at the follow-up weeks 9
and 10 (±3 days from week 8):
The following procedures will be performed at week 9:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate) and weight
(Note: Weight must be measured with shoes and outerwear off.)

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, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG 
assessments.):


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
CDI-2, Parent and Self-report Profiles (Note: Children 6 years of age at 
baseline will not complete the self-report version; the caregiver/adult will 
complete the parent version.)

C-SSRS (Children’s SLV)

YGTSS (Input from the caregiver/adult is required. 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.)

TS-CGI

TS-PGII (Note: Input from the caregiver/adult is permitted.)



(Perform the Severity Ratings of OCD symptoms [Questions 1 
through 10] only. Checklist does not need to be performed.)

assess adverse events

review concomitant medications
The following procedures will be performed at week 10:

telephone contact

assess adverse events

review concomitant medications
6. Unscheduled Visits
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 from procedures and 
assessments.
The following procedures will be performed at every unscheduled visit:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate) and weight
(Note: Weight must be measured with shoes and outerwear off.)

assess adverse events

review concomitant medications
The following procedures will be performed at the investigator’s discretion:

perform full physical and neurological examinations

perform 12-lead ECG (at the investigator’s discretion) (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 serum pregnancy (β-HCG) test (only in 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 at 
baseline 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.)

C&A-GTS-QOL

dispense IMP and patient diary, if applicable

collect IMP

assess IMP accountability/compliance/supply
Other procedures and assessments may be performed at the discretion of the investigator.


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APPENDIX C.QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations 
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.
Protocol Deviations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol deviations 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 IMP administration; 
use of prohibited medications. Protocol deviations will be identified and recorded by 
investigational center personnel in the CRF. All protocol deviations will be reported to the 
responsible IEC/IRB, as required.
When a protocol violation is reported, the sponsor will determine whether to withdraw 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.
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.


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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 Standard Operating Procedures (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(s) 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(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded.
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 during the course of these 
monitoring visits or provided in follow-up written communication.
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 Specialty 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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APPENDIX D.ETHICS
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 patient. The patient 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 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 (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. The patient’s willingness to participate in the study will be 
documented in the informed consent form, which will be signed and personally dated by the 
patient and 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 that the patient is 
free to refuse participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment.
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and each 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 each parent/legally acceptable representative and the patient. The patient and each
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 each parent/legally 
acceptable representative, and a signed and dated assent and/or co-consent form 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 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 and assent forms, and copies will be given to the patients (and each parent/legally 
acceptable representative). It will also be explained to the patients (and each 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.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 


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center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
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.
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 (GCA), or competent 
authorities. Personal medical information will always be treated as confidential.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.


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APPENDIX E.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F.
LOST TO FOLLOW-UP
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center.
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit:

The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’.


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APPENDIX G.
HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR IMP
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The IMP (TEV-50717 and the placebo) 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 
and 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.
Diversion is considered to have occurred when the legal supply chain of prescription analgesic 
medicinal products is broken, and medicinal products are transferred from a licit to an illicit 
channel of distribution or use.
Labeling
Supplies of IMPs will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on GCP and Good Manufacturing Practice and will include any 
locally required statements. If necessary, labels will be translated into the local language.
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 blister packs will be 
disposed of, as agreed with the sponsor/development partner.


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APPENDIX H.
ALLOWED AND PROHIBITED MEDICATIONS
Table 7:
Allowed Medications
Generic/Drug Class
Brand name
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
(not listed in Table 8)
-
Must be receiving stable treatment (including dose) for at least 6 weeks 
before baseline.
Benzodiazepines
-
Primary use must not be for tics; dosing must have been stable 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
INTUNIV®, TENEX®
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. If discontinuation of 
guanfacine is anticipated due to ineffectiveness, poor tolerability, or 
patient/caregiver preference, discontinuation should occur 4 or more 
weeks prior to the screening visit.
Clonidine
CATAPRES®, CLONIDINE ER®, KAPVAY®, 
CATAPRES-TTS®
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. If discontinuation of 
clonidine is anticipated due to ineffectiveness, poor tolerability, or 
patient/caregiver preference, discontinuation should occur 4 or more 
weeks prior to the screening visit.
Stimulants
Include amphetamine, methylphenidate, and lisdexamfetamine. 
Primary use is for the treatment of ADHD; dosing must have been 
stable for at least 2 weeks before screening, and no changes to dose or 
frequency are anticipated during the course of the study.
SNRIs/NRIs
Includes atomoxetine. Primary use is for the treatment of ADHD; 


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Generic/Drug Class
Brand name
Condition
Stable Medications Allowed According to Inclusion/Exclusions Criteria
dosing must have been stable for at least 4 weeks before screening, and 
no changes to dose or frequency are anticipated during the course of 
the study.
Additional Medications Allowed with Pre-Approval from Medical Monitor
Inhaled beta2 adrenergic 
agonists
-
Asthma
Guaifenesin
DURATUSS G®, GANIDIN NR®, GG 200 NR®, 
GUAIFENESIN LA®, LIQUIBID®, MUCO-FEN 
1200®, ORGANIDIN NR®, Q-BID LA®, 
ROBITUSSIN®, SCOT-TUSSIN®
Cold symptoms
Antihistamines
-
Allergies
Melatonin
Melatonin Time Release, Health Aid Melatonin, 
VesPro Melatonin, SGard
Insomnia
ADHD=Attention-deficit/hyperactivity disorder; NRI=norepinephrine reuptake inhibitor; SNRIs=serotonin-norepinephrine reuptake inhibitor.
Note: No dosing changes can be made during the study.
Table 8:
Allowed Strong CYP Inhibitors at Baseline
Generic
Brand name
Class/clinical 
use
Bupropion
APLENZIN®, BUDEPRION SR®, BUPROBAN®, FORFIVO XL®, WELLBUTRIN®, WELLBUTRIN SR®, WELLBUTRIN 
XL®, ZYBAN®, ZYBAN ADVANTAGE PACK®, BUDEPRION XL®, CARMUBINE®, CLORPRAX®, ELONTRIL®, 
QUOMEM®, VOXRA®, WELLBUTRIN®, ZYNTABAC®
Antidepressant 
(aminoketone)
Fluoxetine
PROZAC®, PROZAC WEEKLY®, SARAFEM®, RAPIFLUX®, SELFEMRA®, PROZAC PULVULES®, ADOFEN®
(BRAINPHARMA, SPAIN), AFFEX®, ANDEPIN®, APO-FLUOXETINE®, ASTRIN®, AUGORT®, AZUR®, BELLZAC®, 
BIOXETIN®, BIOZAC®, CLEXICLOR®, CLORIFLOX®, DAGRILAN®, DEFLUOX®, DEPREKS®, DEPRENON®, 
DEPREX®,DEPREXEN®, DEPREXETIN®, DEPREXIN®, DEPSET®, DIESAN®, DIGASSIM®, DINALEXIN®, 
DOCFLUOXETINE®, DOCUTRIX®, EXOSTREPT®, FEFLUZIN®, FELICIUM®, FELICIUM®, FLOCCIN®, FLONITAL®, 
FLORAK®, FLOTINA®, FLOXET®, FLUCTIN®, FLUCTINE®, FLUCTINE®, BFLUESCO®, FLUMIREX®, FLUNEURIN®, 
FLUNISAN®, FLUOCALM®, FLUOCIM®, FLUOCIM®, FLUOGAL®, FLUOX®, FLUOXA®, FLUOX-BASAN®, 
FLUOXELICH®, FLUOXEMED®, FLUOXEMERCK®, FLUOXENORM®, FLUOXE-Q®, FLUOXEREN®, FLUOXETINE 
CAPSULES® BP 2014, FLUOXETINE CAPSULES® USP 36, FLUOXETINE DELAYED-RELEASE CAPSULES® USP 36, 
FLUOXETINE ORAL SOLUTION® BP 2014, FLUOXETINE ORAL SOLUTION® USP 36, FLUOXETINE TABLETS® USP 
36, FLUOXGAMMA®, FLUOXIBENE®, FLUOXIFAR®, FLUOXIN®, FLUOXIN®, FLUOXISTAD®, FLUOXITYROL®, 
Antidepressant 
(selective 
serotonin 
reuptake 
inhibitor)


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Generic
Brand name
Class/clinical 
use
FLUOXONE®, FLUOX-PUREN®, FLUOXSTAD®, FLUSOL®, FLUSTAD®, FLUVAL®, FLUVAL®, FLUX®, FLUXADIR®, 
FLUXEMED® (PROMED, POL.), FLUXET®, FLUXIL®, FLUXOMED®, FLUXONIL®, FLUZAC®, FLUZAK®, FOKESTON®, 
FONTEX®, FOXETEVA®, FRAMEX®, FULSAC®, FYSIONORM®, GEROZAC®, GRINFLUX®, HAPILUX®, IBIXETIN®, 
IPSUMOR®, LECIMAR®, LOKSETIN®, LURAMON®, MAGRILAN®, MILEZIN®, MIZAC®, MOTIVONE®, MUTAN®, 
NODEPE®, NODEPE®, NORZAC®, NUFLUO®, OLENA®, ORTHON®, PORTAL®, PORTAL®, PORTAL®, POSITIVUM®, 
PRODEP®, PROFLUSAK®, PROSIMED®, PROZAC®, PROZAMEL®, PROZATAN®, PROZEP®, PROZIT®, PROZIT®, 
PSIPAX®, RENEURON®, SALIPAX®, SALIPAX®, SARTUZIN®, SELECTUS®, SEREZAC®, SERONIL®, SEROSCAND®, 
SOFELIN®, STEPHADILAT-S®, STRESSLESS®, TARGET®, THIRAMIL®, TUNELUZ®, XEREDIEN®, XETIRAN®, 
ZAFLUOX®, ZAXETINA®, ZEDPREX®, ZINOVAT®
Paroxetine
BRISDELLE®, PAXIL®, PAXIL CR®, PEXEVA®, ACTAPAROXETINE®, ADEPRESS®, ALLENOPAR®, APARO®, APO-
PAROX®, ARAPAXEL®, ARKETIS®, ARKETIS®, AROPAX®, AROPAX®, AS-PAROKS®, CASBOL®, DENERVAL®, 
DEROXAT®, DEXANTOL®, DROPAX®, DROPAXIN®, EUTIMIL®, FROSINOR®, LIMSA®, MOTIVAN®, NOKTURN®, 
NOPRILEX®, OXEPAR®, OXET®, PALUXETIL®, PARETIN®, PAREXAT®, PAROCETAN®, PAROGEN®, PAROLET®, 
PAROLICH®, PAROMERCK®, PARONEX®, PAROSAT®, PAROSER®, PAROTUR®, PAROX®, PAROXALON®, 
PAROXAT®, PAROXEDURA®, PAROXETINE TABLETS® BP 2014, PAROXETINE TABLETS® USP 36, PAROXETOP®, 
PAROXIA®, PAROXINOR®, PAXERA®, PAXERATIO®, PAXETIL®, PAXIL®, PAXINOL®, PAXPAR®, PAXT®, PAXTIN®, 
PREXAT®, REMOOD®, REXETIN®, RITLEMI®, SERESTILL®, SEREUPIN®, SEROXAT®, SOLBEN®, STILIDEN®, 
TABERIL®, TAGONIS®, VOLTAK®, XETANOR®, XETIN®, ZANOXINA®, ZURIA®
Antidepressant 
(selective 
serotonin 
reuptake 
inhibitor)
CYP=cytochrome P450; IMP=investigational medicinal product
Note: The use of these medications will affect the maximum daily dose of IMP, as shown in Table 1.
Table 9:
Prohibited Antipsychotic Drugs
Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Generic
Brand name
Generic
Brand name
Chlorpromazine THORAZINE®, LARGACTIL®, JUVEN TOS®, 
LARGATREX®, AMINAZIN®, CHLORACTIL®, 
CHLORAZIN®, CLONACTIL®, DIMINEX BALSAMICO®, 
FENACTIL®, HIBERNAL®, MEGAPHEN®, 
PLEGOMAZIN®, PROPAPHENIN®, PROZIN®, 
SOLIDON®, ZULEDIN®
Aripiprazole ABILIFY®, ABIZOL®, AMDOAL®, ARIFAY®, ARIPA®, 
BRISKING®, CUREXOL®, FIXMENT®, IGNIS®, MADEPZOL®, 
RIMA-FIX®, ZOLERIP®
Haloperidol
HALDOL®, SERENACE®, ALASED®, ALOPERIDIN®, 
BIOPERIDOLO®, BUTERIDOL®, DOZIC®, 
DURAPERIDOL®, ELAUBAT®, FORTUNAN®, 
HALDOL®, HALONEURAL®, HALOPER®, LEPTOL®, 
Asenapine 
maleate 
SAPHRIS®, SYCREST®


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Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Generic
Brand name
Generic
Brand name
NORODOL®, OVOCTEROL®, SEDAPERIDOL®, 
SENORM®, SERENACE®, SERENELFI®, SEVIUM®, 
SIGAPERIDOL®, VESADOL®, VESALIUM®, 
DECALDOL®, NORODOL®, SENORM®
Loxapine
LOXAPAC®, LOXITANE®, DESCONEX
Clozapine 
CLOZARIL®, AZALEPROL®, AZALEPTIN®, CLONEX®, 
CLOPIN®, CLOSASTENE®, CLOZALUX®, DENZAPINE®, 
ELCRIT®, FAZACLO®, KLOZAPOL®, LANOLEPT®, 
LEPONEX®, NEMEA®, OZAPIM®, ZAPONEX®
Molindone
MOBAN®
Iloperidone 
FANAPT® 
Perphenazine
TRILAFON®, DECENTAN®, ETAPERAZIN®, 
FENTAZIN®, LONGOPAX®, MINITRAN®, MUTABASE®, 
MUTABON®, TRIPHENAZE®, TRIPTAFEN®
Lurasidone 
LATUDA®
Pimozide 
ORAP®
ANTALON®, NOROFREN®, OPIRAN®, PIRIUM®
Olanzapine 
ZYPREXA®, AEDON®, APSICO®, APZET®, ARENBIL®, 
ARKOLAMYL®, ASTERILON®, ATYZYO®, BLOONIS®, 
CAPRILON®, CLINGOZAN®, DECOLAN®, ELYNZA®, 
FORDEP®, FREDILAN®, KOZYLEX®, LANZAFEN®, 
LANZAPIN®, LAZAPIX®, LERNUP®, MITAB®, NAKOZAP®, 
NEWZYPRA®, NIOLIB®, NORMITON®, NORPEN ORO®, 
NYKOB®, NYZOL®, OFANS®, OFERTA®, OLAFER®, OLAN®, 
OLANZARAN®, OLAPIN®, OLAZAX®, OLSTADRYN®, 
OZILORMAR®, ROLYPREXA®, TIZINA®, XAPRITX®, 
ZALASTA®, ZAPRIS®, ZERPI®, ZIPRODEC®, ZOLAFREN®, 
ZONAPIR®, ZYPADHERA®
Prochlorperazine COMPAZINE®, STEMETIL®, TEMENTIL®
Olanzapine /
fluoxetine 
SYMBYAX®
Thioridazine
MELLARIL®, MELLERETTE®, MELLERETTEN®, 
RIDERIL®, SONAPAX®, THIORIL®, TISON®, VISERGIL®, 
DETRIL®, ELPERIL®, MELERIL®, MELLERETTES®, 
MELLERIL®, MELZINE®, THIODAZINE®, THIOZINE®, 
VISERGIL®
Paliperidone INVEGA®, CILAG®, XEPLION®
Thiothixene
NAVANE®, ORBINAMON®
Quetiapine 
SEROQUEL®, ALZEN®, ATROLAK®, BIQUELLE®, DERIN®, 
EBESQUE®, GENTIAPIN®, ILUFREN®, KEFRENEX®, 
KETIRON®, KWETAPLEX®, NEURORACE®, NOTIABOLFEN®, 


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Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Generic
Brand name
Generic
Brand name
PINAPAZ®, QUENTAPIL®, QUENTIAX®, QUETATIEFI®, 
QUETEPER®, QUETEX®, QUETIAFAIR®, QUETIALAN®, 
QUETIAMYLAN®, QUETROP®, RAIKAR®, RIZMUL®, 
ROCOZ®, SEOTIAPIM®, SEQUASE®, SEROPIA®, SEROQUEL®, 
SEROQUIN®, SEROTIAPIN®, SETININ®, SONDATE®, 
TEVAQUEL®, VIKETO®, VUTIF®, XEROQUEL®, ZALURON®
Trifluoperazine
STELAZINE®, ESKAZINE®, JALONAC®, 
JATRONEURAL®, JATROSOM®, MODALINA®, 
OXYPERAZINE®, PARMODALIN®, PARSTELIN®, 
STELABID®, STELAZINE®, TERFLUZINE®
Risperidone RISPERDAL®, ALEPTAN®, ARKETIN®, ATORNIL®, 
BELIVON®, CALMAPRIDE®, DIAFORIN®, DISAPERID®, 
ITRAXEL®, LOTIN®, NECLAV®, PERDIN RIPAX®, 
RISFARMAL®, RISPAL®, RISPATAL®, RISPEMYLAN®, 
RISPEN®, RISPENON®, RISPE-Q®, RISPERDALCONSTA®, 
RISPERDALORO®, RISPERDOC®, RISPERGER®, 
RISPERIGAMMA®, RISPERSTAD®, RISPEVA®, 
RISPIMEDICA®, RISPOLIN®, RISPONE®, SMISSEN®


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Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Generic
Brand name
Generic
Brand name
Promethazine-
containing 
compounds
PHENERGAN®-CONTAINING COMPOUNDS, ATOSIL®, 
BOIPULMONALE SIMPLE®, CREMA ANITALLERGICA 
ANTIPRURIGINOSA®, FARGAN®, FENERGAN 
TOPICO®, RECTOQUINTYL-PROMETHAZINE®, 
TUSSISEDAL®, ACTITHIOL ANTIHIST®, 
ALGOTROPYL®, 
ALLERFEN®, ANTIHEMORROIDAL®, ARTU®, ATOSIL®, 
BEXOL®, BOIPULMONALE SOL®, BRONCATAR®, 
BRONCONAIT®, CHOLIGRIP NA NOC®, CIGARETTES 
ET POUDRE FUMANTERGYL®, CLOSIN®, COLDREX 
NITE®, COLDREX NITE®, DIPHERGAN®, DOBACEN 
PLUS®, DOLSOM®, DUPLAMIN®, EUSEDON MONO®, 
FARGANESSE®, FENAZIL®, FENERGAN®, FRINOVA®, 
HEMOTRIPSIN®, INSOMNYL®, JUVEPIRINE A LA 
PROMETHAZINE®, LINERVIDOL®, LYSEDIL®, 
MEDISED®, NARDYL PAMERGAN P100®, 
PAXELADINE NOCTEE®, PETIGAN MIRO®, 
PHENERGAN®, PHENHALAL®, PHENSEDYL®, 
PHENSEDYL PLUS®, PIPOLPHEN®, PIPOLZINE®, 
POLFERGAN®, PROMKIDDI®, PRONEURIN®, 
PROTHIAZINE EXPECTORANT®, PRURIDERM 
ULTRA®, PSICOSOMA®, Q-MAZINE®, QUINTOPAN 
ENFANT®, RHINATHIOL PROMETHAZINE®, RONPIRIN 
COLD REMEDY®, SAYOMOL®, SOMINEX®, SOPORIL®, 
SUGARCETON®, TACHINOTTE®, TARDYL®, THESIT 
P®, TIEUCALY®, TITANOX®, TIXYLIX®, TRANSMER®, 
ZIZ®
Tiapride 
HIPOKIN®, SEREPRILE®, TIAGER®, TIAPRID PMCS®, 
TIAPRIDAL®, TIAPRIDE PMCS®, BOINLIL®, CUCKOOL 10%®, 
DELPRAL®, GRAMALIL®, GRAMALIL 10%®, GRINOLART®, 
ITALPRID®, LUO YI®, NEURELARK®, SEREPRID®, 
SEREPRILE®, SHANG YAN®, TIALAREAD®, TIALAREAD 
10%®, TIAPRA®, TIAPRALAN®, TIAPRID-1 A PHARMA®, 
TIAPRID AbZ®, TIAPRID AL®, TIAPRID HEXAL®, TIAPRIDA 
GENERIS®, TIAPRIDAL®, TIAPRID-CT®, TIAPRIDE 10% 
SAWAI®, TIAPRIDE CT®, TIAPRIDE FUDAN FUHUA®, 
TIAPRIDE HYDROCHLORIDE AMEL®, TIAPRIDE MYLAN®,
TIAPRIDE RATIOPHARM®, TIAPRIDE SANDOZ®, TIAPRIDE 
SAWAI®, TIAPRIDEX®, TIAPID-NEURAXPHARM®, TIAPRID-
RATIOPHARM®, TIAPRIM®, TIAPRIM 10%®, TIAPRIZAL®, 
TIARYL®, TIARYL 10%®, TIAZET®
Ziprasidone GEODON®, ZELDOX®, ZYPSILAN®
Fluphenazine
PROLIXIN®, PROLIXIN DECANOATE®, PROLIXIN 
ENANTHATE®, PERMITIL®
Note: This table does not apply after the first week of the washout period for patients not rolling over to the open-label extension study (Study TV50717-CNS-
30047). 


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Table 10:
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
Droperidol
Sedative; anti-nausea/anesthesia adjunct, nausea
Erythromycinb
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.
USA=United States of America.
Table 11:
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
CYP2D6=cytochrome P450 2D6.


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APPENDIX I. 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 J.
 


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APPENDIXL.
 


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APPENDIX M.
 


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APPENDIX N.
 


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APPENDIX O.
 


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APPENDIX P.
 
 
 
 
 


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APPENDIX Q.
 


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APPENDIX R.
PRODUCT COMPLAINTS
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP 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

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 
 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 an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible.
1. Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide
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, blister pack, 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


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
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.
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s)
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.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
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).
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.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.


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APPENDIX S.
DATA MANAGEMENT AND RECORD KEEPING
Direct Access to Source Data and Documents
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory or central 
image center) the results will be sent to the investigational center, where they will be retained but 
not transcribed to the CRF, unless otherwise noted in the protocol. These data may also be sent 
electronically to the sponsor (or organization performing data management).
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. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
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 (USA) and documents of other concerned 
competent authorities. Before using the CDMS, it will be fully validated and 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.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic patient-reported outcome [ePRO] tablet), these data will be sent to the 
investigational center, where they will be retained but not transcribed to the CRF, unless 
otherwise noted in the protocol. These data may also be sent electronically to the sponsor (or 
organization performing data management). All patient data must have supportive original 
source documentation in the medical records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and considered as source data unless the 
sponsor provides written instructions specifying which data are permitted to be recorded directly 
to the CRF.
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.


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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.
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.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
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

case report forms for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the IMPs

copies of all correspondence with sponsor, the IEC/IRB, and any competent authority


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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 the CRO 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 
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.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Well-Controlled, Fixed-Dose Study of TEV 50717 (Deutetrabenazine) for the 
Treatment of Tics Associated with Tourette Syndrome 
 
 
Study Number TV50717-CNS-30060 
 
 
NCT03571256 
 
 
SAP Approval Date: 14 January 2020 


This document is confidential.
SAP Version: Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 1 of 76
Statistical Analysis Plan for Interventional Studies
Sponsor Name: Teva Branded Pharmaceutical Products R&D, Inc.
Nuvelution TS Pharma, INC.
Protocol Number: TV50717-CNS-30060
Protocol Title: A Well-Controlled, Fixed-Dose Study of TEV 50717 (Deutetrabenazine) for the Treatment 
of Tics Associated with Tourette Syndrome
Protocol Version and Date: (DD-Mmm-YYYY): 
Original Protocol Approval Date: 13 July 2017
Protocol Amendment 01 Approval Date: 20 November 2017
Protocol Amendment 02 Approval Date: 25 March 2019
Protocol Amendment 03  Approval Date: 05 May 2019
Syneos Health Project Code: 1009348A
Authors: 
, Principal Biostatistician
Notice of Confidential and Proprietary Information:
The information contained in this document is confidential belonging to Teva Branded Pharmaceutical 
Products R&D, Inc./ Nuvelution TS Pharma. Acceptance of this document constitutes agreement by the 
recipient that no information contained herein will be published or disclosed without prior written 
authorization from an official of Teva Branded Pharmaceutical Products R&D, Inc./ Nuvelution TS 
Pharma. However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the condition that 
they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, 
Syneos Health should be notified promptly.


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 2 of 76
Revision History
Version #
Date
(DD-Mmm-YYYY)
Document Owner
Revision Summary
0.1
29-May-2019
Initial Release Version
0.2
14-Jun-2019
Update per sponsor comments
1.0
28-Jun-2019
Update per sponsor comments 
1.1
10-Jan-2020

Update prior medication definition to include 
only medication stopped before first dose of IMP 
in Section 7.4.1;

Prior non-pharmacological treatment will only be 
listed in Section 7,4,2;

Correct SAS code for primary analysis of 
primary endpoint in Section 8.2.1. Maximum 
likelihood method will only be used when REML 
did not converge.

Adding that concomitant medications will be 
summarized separately for medication started 
prior to or after the first dose of IMP in Section 
9.3;

Adding SMQ of Parkinson-like events to Section 
9.4;

SAS code for imputations in Appendix 19.1 –
19.3 are updated to include situation when all 
patients completed Week 2 assessment and 
region is added to the imputation models as 
covariates and add Region1 to proc MI;

Index of tables, listings, figures are corrected.

Add CDI-2 self version item 22 to section 9.12.
2.0
14-Jan-202

To add Section 3.1 and 3.2 of primary and 
secondary estimand, and justification of the 
primary estimand in Section 8.2.2.


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 3 of 76
Approvals
I confirm that I have reviewed this document and agree with the content.


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 4 of 76
Table of Contents
Revision History..........................................................................................................................2
Approvals....................................................................................................................................3
Table of Contents........................................................................................................................4
List of Tables ..............................................................................................................................8
Glossary of Abbreviations...................................................................................................9
Purpose............................................................................................................................12
Study Objectives ..............................................................................................................13
Endpoints .........................................................................................................................22


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 5 of 76
Analysis Sets....................................................................................................................24
General Aspects for Statistical Analysis ...........................................................................26
Demographic, Other Baseline Characteristics and Prior Medications ...............................29
Efficacy ............................................................................................................................32


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 6 of 76
Safety...............................................................................................................................41
Pharmacokinetic Analysis.................................................................................................51
Interim Analyses...............................................................................................................51


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 7 of 76
Changes from Analysis Planned in Protocol.....................................................................51
Reference List..................................................................................................................52
Programming Considerations ...........................................................................................53
Quality Control .................................................................................................................58
Index of Tables.................................................................................................................59
Index of Figures................................................................................................................67
Index of Listings ...............................................................................................................69
Appendices ......................................................................................................................71


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 8 of 76
List of Tables
Table 1: Daily Dose of IMP by Baseline body Weight Category, CYP2D6 Impairment, and 
Study Week..............................................................................................................................................17
Table 2: Study Procedures and Assessments ...............................................................................18
Table 3: Some Possible Types of Major Protocol Deviations That Lead to Patient or Visit 
Exclusion from Any Analysis Set......................................................................................................25
Table 4: List of Laboratory Tests.......................................................................................................44
Table 5: Criteria for Markedly Abnormal Vital Sign Parameters by Age .................................46
Table 6: Criteria for Abnormal ECG Parameters by Age .............................................................48


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 9 of 76
Glossary of Abbreviations
Abbreviation
Description
ADHD
Attention Deficit Hyperactivity Disorder
ADL
Activities of daily living
AE
Adverse Event
α-HTBZ 
alpha-dihydrotetrabenazine
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
ANC
Absolute neutrophil count
ANCOVA 
Analysis of Covariance
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BDRM
Blinded Data Review Meeting
β-HCG 
beta human chorionic gonadotropin
β-HTBZ
beta-dihydrotetrabenazine
BP
Blood Pressure
BMI
Body Mass index
CDI-2
Children’s Depression Inventory, Second Edition
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
Cytochrome P450
CYP2D6
Cytochrome P450 2D6
ECG
Electrocardiogram
FCS
Fully Conditional Specification
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GPSP
Global Subject Safety and Pharmacovigilance
GSS
Global Severity Score


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 10 of 76
Abbreviation
Description
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
IRT 
Interactive Response Technology
ITT
Intent-to-Treat
LDH
Lactate dehydrogenase
LS
Least squares
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MINI Kid
Mini International Neuropsychiatric Interview For Children and 
Adolescents
mITT
Modified Intent-to-Treat
MNAR
Missing Not at Random
MTSS
Motor Tic Severity Score
N/A
Not Applicable
OCD
obsessive-compulsive disorder
PP
Per Protocol 
PR
Time from the beginning of the P wave to the beginning of the QRS 
complex in electrocardiogram
PT
Preferred Term
QRS
Graphical deflections corresponding to ventricular depolarization in a 
typical electrocardiogram
RBC
Red Blood Cell 
RR
Time between the start of one R wave and the start of the next R 
wave in the ECG
QC
Quality Control
QTc
Corrected QT Interval
QTcF
Fridericia’s corrected QT interval
SAB
Scientific Advisory Board
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 11 of 76
Abbreviation
Description
SD
Standard Deviation
SE
Standard Error
SI
Standard International System of Units
SLV
Since last visit
SOC
System Organ Class
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-Emergent Adverse Event
TS
Tourette syndrome
TS-CGI
Tourette Syndrome-Clinical Global Impression
TS-PGII
Tourette Syndrome-Subject Global Impression of Impact
TTS
Total Tic Score
TLF
Table, Listing and Figure
VAS
Visual Analog Scale
VTSS
Vocal Tic Severity Score
WBC
White Blood Cell
WHO
World Health Organization
YGTSS
Yale Global Tic Severity Scale


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 12 of 76
Purpose
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives.
Responsibilities
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures and listings.
Nuvelution and Teva will perform review of all tables, figures and listings before the finalization.
Timings of Analyses
The primary analysis of safety and efficacy is planned after all patients complete the week 9 follow-up 
visit and enter the open-label safety extension study TV50717-CNS-30047, or complete week 10
follow-up visit, or terminate early from the study.  Unless otherwise specified, the analysis includes all 
data collected in the database through the time of the database lock.  
An independent Data Monitoring Committee (IDMC) will review descriptive summaries of accumulating 
safety and subject disposition at a frequency recommended by the IDMC. Further description of the IDMC 
analyses can be found in the IDMC charter Version 1.0 dated 01 Feb 2018.


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14 -Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 13 of 76
Study Objectives
The purpose of the study is to determine whether TEV-50717 is effective in the treatment of tics 
associated with TS in male and female patients between 6 and 16 years of age.
Primary Estimand
The primary estimand is the difference in means between TEV-50717 high dose and placebo for the 
change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from baseline to week 
8, in the target patient population of children and adolescents with TS who receive at least 1 dose of IMP 
and have both a baseline and at least 1 post-baseline YGTSS assessment, regardless of whether or not 
dose reduction, suspension, or treatment discontinuation occurred, and regardless of treatment-related 
adverse events. For the intercurrent event of study discontinuation, all data collected until time of study
discontinuation will be included and a missing at random (MAR) assumption will be hypothesized.
The primary estimand assesses the effectiveness in the reduction of motor and phonic tics associated 
with TS, focusing on the causal effects attributable to the investigational medicinal product (IMP).
Secondary Estimands 
The secondary estimands are: 
(1) the difference in means between TEV-50717 high dose and placebo for the change in the Tourette 
Syndrome - Clinical Global Impression (TS-CGI) score from baseline to week 8;
(2) the difference in means between TEV-50717 low dose and placebo for the change in the TTS of the 
YGTSS from baseline to week 8;
(3) the difference in means between TEV-50717 low dose and placebo for the change in the TS-GCI 
score from baseline to week 8;
(4) the difference in means between TEV-50717 high dose and placebo for the change in the Tourette 
Syndrome - Patient Global Impression of Impact (TS-PGII) score from baseline to week 8;
(5) the difference in means between TEV-50717 low dose and placebo for the change in the TS-PGII 
score from baseline to week 8;
(6) the difference in means between TEV-50717 high dose and placebo for the 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 baseline to week 8;
(7) the difference in means between TEV-50717 low dose and placebo for the change in the C&A-GTS-
QOL ADL subscale score from baseline to week 8,
in the target patient population of children and adolescents with TS who receive at least 1 dose of IMP 
and have both a baseline and at least 1 post-baseline YGTSS assessment, regardless of whether or not 
dose reduction, suspension, or treatment discontinuation occurred, and regardless of treatment-related 
adverse events. For the intercurrent event of study discontinuation, all data collected until time of study
discontinuation will be included and a missing at random (MAR) assumption will be hypothesized.
The secondary estimands assess the effectiveness of TEV-50717 high dose and TEV-50717 low dose in 
the reduction of motor and phonic tics associated with TS and the impact of the reduction in tics on the 
patients’ quality of life as assessed by the clinicians and the patients, focusing on the causal effects 
attributable to the investigational medicinal product (IMP).


Statistical Analysis Plan for Interventional Studies
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Primary and Secondary Objectives
Primary Objective
The primary objective of this study is to evaluate the efficacy of fixed doses of TEV-50717 to reduce 
motor and phonic tics associated with Tourette syndrome (TS). 
Secondary Objective(s)
The secondary objective of the study is to evaluate the safety and tolerability of TEV-50717.
Brief Description
This is a Phase 3, randomized, double-blind, placebo-controlled, 8-week treatment study in which 
patients with tics associated with TS will be invited to participate. Patients will be randomized to low-dose 
TEV-50717, high-dose TEV-50717, or placebo (1:1:1). The target dose for each patient receiving 
TEV-50717 will be based on body weight and cytochrome P450 2D6 (CYP2D6) impairment status at 
baseline. 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. 
CYP2D6 status will be used by Interactive Response Technology (IRT) for randomization into the study. 
The overall treatment period will be 8 weeks in duration, including an escalation period of 4 weeks, a 
maintenance period of 4 weeks, followed by a washout period of 1 week. 
Patients who complete the study may be eligible to begin participation in an open-label safety extension 
study of TEV-50717 (Study TV50717-CNS-30047). For this study, the follow-up period is defined as 1 
week of washout for patients who will participate in the open-label safety extension study TV50717-CNS-
30047 and 2 weeks after the last dose of Investigational Medicinal Product (IMP) (1 week after the end of 
the washout period) for patients who will not roll over into the open-label safety extension study TV50717-
CNS-30047. Patients not participating in the open-label safety extension study for TEV-50717 will have a 
follow-up telephone contact for safety evaluation 1 week after the end of the treatment period (2 weeks 
after their last dose of IMP).
Patient Selection
Inclusion Criteria
Refer to Protocol Section 4.1 for inclusion criteria.
Exclusion Criteria
Refer to Protocol Section 4.2 for exclusion criteria. 
Determination of Sample Size
It is estimated that approximately 50 patients per arm will enable a power of at least 90% to detect a 
beneficial effect of 6.5 points or more in the change from baseline to week 8 in TTS when the high-dose 
TEV-50717 arm is compared to placebo, assuming a standard deviation of 9.5 and a 2-sided type I error 
rate of 5% after accounting for dropouts.
Treatment Assignment & Blinding
This is a Phase 3, randomized, double-blind, placebo-controlled, 8-week-treatment study in which 
patients with tics associated with TS will be invited to participate. Patients will be randomized to either 


Statistical Analysis Plan for Interventional Studies
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TEV-50717 (low-dose, high-dose) or matching placebo in a 1:1:1 ratio using an Interactive Response 
Technology (IRT) based on their baseline weight and CYP impairment status. The patients will be 
stratified into 2 age groups (6- to 11-years and 12- to 16-years). Patients and investigators will remain 
blinded to treatment assignment during the study.
Treatment Assignment
Patients will be centrally randomly assigned to the treatment groups by means of a computer-generated 
randomization list after confirmation of all eligibility criteria. The creation of the randomization list will be 
under the responsibility and oversight of Syneos Health.
The randomization list and treatment will be assigned to the relevant treatment groups through a qualified 
service provider, i.e., via IRT. The generation of the medication list and management of the IRT system 
will be done by a qualified service provider under the oversight of Nuvelution TS Pharma.
The staff member at the investigational center who will dispense the IMP will not know the treatment 
given to each patient.
Blinding
Patient randomization codes will be maintained in a secure access restricted folder on shared drive within 
Syneos Health, Biometrics. 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.
The sponsor’s clinical personnel and all vendors (with exception of the IRT vendor and the bioanalytical 
sample analysis vendor) involved in the study will be blinded to the IMP identity until the database is 
locked for analysis and the treatment assignment revealed. After unblinding of this study, the study site 
may remain blinded to patient treatment assignments until completion of the safety extension study 
TV50717-CNS-30047.
Pharmacokinetic data may be assessed during the study. Personnel responsible for bioanalysis will be 
provided with the randomization code in order to facilitate the analysis. However, the personnel 
responsible for bioanalysis and pharmacokinetic data analysis will not have access to clinical safety and 
efficacy data, will not have any interaction with study personnel, and will provide concentration data to 
other personnel in a manner that will not identify individual patients (i.e., a dummy patient identifier will be 
linked to an individual patient’s concentration data). 
In case of a serious adverse event or pregnancy, or in cases when knowledge of the IMP assignment is 
needed to make treatment decisions, the investigator may unblind the patient’s drug assignment as 
deemed necessary, mainly in emergency situations. Individual treatment codes, indicating the treatment 
randomization for each randomized patient, will be available to the investigator(s) and/or pharmacist(s) at 
the study center via the IRT. If possible, the sponsor should be notified of the event prior to breaking of 
the code. If this is not possible, the sponsor should be notified immediately afterwards, and the patient’s 
drug code assignment should not be revealed. Breaking of the treatment code can always be performed 
by the site without prior approval by the sponsor.
When a blind is broken, the patient will be withdrawn from the study, and the event will be recorded onto 
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. Treatment 
assignment should not be recorded in any study documents or source document.


Statistical Analysis Plan for Interventional Studies
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In blinded studies, for adverse events that are defined as: suspected unexpected serious adverse 
reactions (SUSARs), Global Patient Safety and Pharmacovigilance (GPSP) may independently request 
that the treatment code be revealed (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, analysis, and reporting 
of the data.
Syneos Health 3910.00 describes the procedures for planning and conducting unblinded analyses prior to 
database lock for IDMC. Unblinded data, including randomization codes, type of dispensed kits and all 
subsequent SDTM, ADaM datasets, and analysis results generated from the unblinding information, will 
be stored under a pre-specified secure area with restricted access. Access to the unblinded folders can 
only be requested by a manager level or higher within the associate’s department. All relevant personnel 
to receive unblinded data will be identified and their responsibilities documented on the unblinded 
personnel form. The secure area for storage of data and results (including any report and its appendices) 
will be maintained so that it can be accessed only by unblinded personnel. All staff involved in the 
conduct of the trial shall remain ignorant of the results of all unblinded analyses. 
Administration of Study Medication
Investigational medicinal product will be administered as follows:

IMP should be swallowed whole and taken with food (e.g., a snack) and should not be taken 
on an empty stomach.

Dosing will be based on body weight and CYP2D6 impairment status at the baseline visit, as 
shown in Table 1.

To preserve blinding, 2 tablets will be taken twice daily starting at day 1 per Table 1. Daily 
doses will be administered twice daily, approximately 8 to 10 hours apart during the day. 
Depending on the dose and arm assigned, TEV-50717 tablets and/or placebo tablets will be 
taken to maintain the blind. 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.

The dose of IMP will be escalated weekly during the escalation period, according to Table 1.

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 must be notified.

During the escalation period, the dose of the IMP will be adjusted weekly according to 
Table 1 to identify a dose level that optimally reduces tics and is well tolerated. Investigators 
will be blinded to CYP status, with a dose cap for poor metabolizers prespecified by the IRT.


Statistical Analysis Plan for Interventional Studies
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Table 1: Daily Dose of IMP by Baseline body Weight Category, CYP2D6 Impairment, and Study 
Week
Dose group
Baseline weight (kg)
Daily dose (mg) at the start of visit/week
Week 1
(Days 1-7)
Week 2
(Days 8-14)
Week 3
(Days 15-21)
Week 4 main dose 
(Days 22-28) to 
Week 8 main dose 
(Days 50-56)
Low dose
≥40 
12
24
30
36
≥40, CYP impaired
6
12
18
18
30 to <40
6
12
18
24
30 to <40, CYP impaired
6
12
12
12
20 to <30
6
12
18
18
20 to <30, CYP impaired
6
6
6
6
High dose
≥40 
12
24
36
48
≥40, CYP impaired
6
15
24
30
30 to <40
12
24
30
36
30 to <40, CYP impaired
6
12
18
18
20 to <30
12
18
24
30
20 to <30, CYP impaired
6
12
12
12
CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor metabolizer.
Study Procedures and Flowchart
Study procedures and assessments with their time points are presented in Table 2. During a visit, study 
procedures and assessments should be performed in the order specified in the study manual.


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Table 2: Study Procedures and Assessments
Pre-
screening
Screening
BLa
Escalation period 
(weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unsche-
duled
Study weekb
Up to 
3 months
Up to 
31 days
Day
1
1
(Da
y 7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 
42)
7
(Day 
49)
8/
ETc
(Day 
56)
9
(Day 
63)
10d
(Day
70)
Visit window 
(days)
0
±3 days
±3 days from 
week 8
Informed 
consent/assent
X
X
Randomization 
X
Clinic visit
Xe
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
Dose escalationf
X
X
X
Xg
Eligibility criteria
X
X
Medical and 
psychiatric history
X
Demographics
X
Vital signs and 
weighth
X
Xi
X
Xi
Xi
X
X
Physical 
examination
X
X
Xj
Neurological 
examination
X
X
Xj
Height
X
X
12-Lead ECGk
X
X
X
X
Xj
PK blood sampling
Xl


Statistical Analysis Plan for Interventional Studies
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Pre-
screening
Screening
BLa
Escalation period 
(weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unsche-
duled
Study weekb
Up to 
3 months
Up to 
31 days
Day
1
1
(Da
y 7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 
42)
7
(Day 
49)
8/
ETc
(Day 
56)
9
(Day 
63)
10d
(Day
70)
Visit window 
(days)
0
±3 days
±3 days from 
week 8
Chemistry/hematol
ogy/
urinalysis
X
X
Xj
Urine drug screen
X
X
Xj
CYP2D6 genotypem
X
β-HCG testn
X
X
X
X
Xj
MINI Kido
X
CDI-2 (Parent and 
Self-report 
versions)p
X
X
X
X
X
X
Xj
C-SSRS (Children’s 
Baseline/Screening
)q
X
C-SSRS (Children’s 
Since Last Visit) q
X
X
X
X
X
Xj
YGTSSr s
X
X
Xt
X
X
Xt
TS-CGIs
X
X
X
X
X
TS-PGIIs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xu
X
Xu


Statistical Analysis Plan for Interventional Studies
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Pre-
screening
Screening
BLa
Escalation period 
(weeks)
Maintenance period (weeks)
Follow-up 
(weeks)
Unsche-
duled
Study weekb
Up to 
3 months
Up to 
31 days
Day
1
1
(Da
y 7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
6
(Day 
42)
7
(Day 
49)
8/
ETc
(Day 
56)
9
(Day 
63)
10d
(Day
70)
Visit window 
(days)
0
±3 days
±3 days from 
week 8
C&A-GTS-QOLq
X
X
X
Xj
Dispense IMPv
X
X
X
Xj
Collect IMP
X
X
X
Xj
Assess IMP 
accountability/comp
liance/
supply
Xw
X
Xw
X
Xw
Xw
X
Xj
Assess AEs
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
a The baseline visit (day 1) will occur the same day as the scheduled first dose of the IMP (day 1).
b Assessment will be performed at the end of study week (±3 days). 
c For patients who withdraw prematurely, an early termination visit should be conducted as soon as possible after the last dose of IMP. In addition, 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 10. 
d This visit is a telephone contact for safety evaluation, required only for patients who will not roll over into the open-label safety extension study for TEV-50717. 
e The screening visit may be conducted over 2 separate visits at the discretion of the investigator.
f Patients will be provided with a diary to record critical information on dosing. The date and time of the last dose of study medication before the week 8 visit 
should be recorded in the diary by the patient or parent/legal guardian. The site will document the date and time of the sample collection. Prior to the clinic visit 
on week 8, patients will be reminded to record the start time of their last meal and the time of their last dose in their diary.
g Dose escalation will only occur during the dose escalation period (i.e., from week 1 to week 3).
h Weight must be measured with shoes and outerwear off.
i Orthostatic blood pressure and pulse will be measured after patient is in standing position for at least 3 minutes.
j Assessment will be completed at investigator’s discretion.
k All ECGs will be performed after at least 5 minutes of rest in a supine or semi-supine position.
l Two samples will be collected. The first sample will be collected upon arrival at the clinic. The second sample will be collected within 2 to 3 hours after the first 
PK sample collection. Patients with early morning visits (ie, within 2 hours of their scheduled AM dosing) should take their IMP dose in the clinic after the first PK 
sample is collected.


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m The patient’s genotype for CYP2D6 will be blinded during the conduct of the study, except for the sample analysis and IRT vendor.
n For females who are postmenarchal or ≥12 years of age, a urine test will be administered at baseline and at week 4, while a serum test will be administered at 
screening, week 8, and if clinically indicated.
o MINI Kid (children and adolescents) modules to be used are 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 Children 6 years of age at baseline will not complete the self-report version; the parent/legal guardian will complete the parent version.
q 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.
r Input from the caregiver/adult is required.
s The YGTSS, TS-CGI, TS-PGII, and TS-PGIS questionnaires should be performed before any blood draws or ECG assessments.
t 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).
u Perform the Severity Ratings of OCD symptoms (Questions 1 through 10) only. Checklist does not need to be performed.
v 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 during 
escalation. See Table 1 for baseline weight-based dosing titration. At week 4, patients will receive doses for 4 weeks of treatment.
w The site needs to discuss the drug status during the telephone contacts to ensure that the patient has adequate tablets, inform the patient if they should 
escalate, and remind them to bring completed blister packs to the next in-clinic visit.
Abbreviations: AE=adverse event; ADHD=Attention Deficit Hyperactivity Disorder; β-HCG=beta human chorionic gonadotropin; BL=baseline visit; CDI-
2=Children’s Depression Inventory Second Edition; 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- scale; IMP=Investigational Medicinal Product; IRT=Interactive Response Technology; MINI Kid=Mini International Neuropsychiatric 
Interview For Children and Adolescents; OCD=obsessive-compulsive disorder; PK=pharmacokinetic; TS-CGI=Tourette Syndrome-Clinical Global Impression; 
TS-PGII=Tourette Syndrome-Patient Global Impression of Impact; 
; YGTSS=Yale Global Tic 
Severity Scale.


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Endpoints
Primary Efficacy Endpoint
The primary efficacy endpoint is the change in the Total Tic Score (TTS) of the Yale Global Tic Severity 
Scale (YGTSS) from baseline to week 8 between high-dose TEV-50717-treated patients and 
placebo-treated patients.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:
1.
Change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from baseline to 
week 8 between high-dose TEV-50717-treated patients and placebo-treated patients;
2.
Change in the TTS of YGTSS from baseline to week 8 between low-dose TEV-50717-treated 
patients and placebo-treated patients;
3.
Change in the TS-CGI score from baseline to week 8 between low-dose TEV-50717-treated 
patients and placebo-treated patients;
4.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from 
baseline to week 8 between high-dose TEV-50717-treated patients and placebo-treated patients;
5.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from 
baseline to week 8 between low-dose TEV-50717-treated patients and placebo-treated patients;
6.
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 baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated patients;
7.
Change in the C&A-GTS-QOL ADL subscale from baseline to week 8 between low-dose 
TEV-50717-treated patients and placebo-treated patients.
Exploratory Endpoints
Exploratory endpoints are as follows:
 
 
 


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Pharmacokinetic Endpoints
The pharmacokinetics of the alpha dihydrotetrabenazine (α HTBZ) and beta dihydrotetrabenazine (β 
HTBZ) metabolites of TEV-50717, and other metabolites (as needed), will be explored based on sparse 
sampling at Week 8.
Safety Endpoints
The safety endpoints for this study are as follows:

Incidence of adverse events;

Observed values and changes from baseline in vital signs;

Observed values and change from baseline in the Children’s Depression Inventory, Second 
Edition (CDI-2), Parent and Self-report Profiles;

Observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS);

Observed values in electrocardiogram (ECG) parameters and shifts from screening for clinically 
significant abnormal findings;

Observed values and changes from screening in clinical laboratory parameters (hematology, 
chemistry, and urinalysis).


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Analysis Sets
Screened Analysis Set
The screened analysis set will include all patients who are screened and have informed consent. This set 
will be used for patient listing and summary of patient disposition.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients, regardless of whether or not a 
patient took any IMP. In this population, treatment will be assigned based on the treatment to which 
patients were randomized, regardless of which treatment they actually received. 
The ITT analysis set will be used for all study population summaries, unless otherwise noted.  Summaries 
will be presented by treatment group and for all patients. Patients listing on efficacy data will be based on 
ITT analysis set.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP. In this the 
safety analysis set, treatment will be assigned based upon the treatment patients actually receive, 
regardless of the treatment to which they were randomized, unless otherwise specifed.
All safety analyses and listings will be based on the safety analysis set.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set will include a subset of the ITT analysis set including only 
patients who receive at least 1 dose of IMP and who have both a baseline and at least 1 post-baseline 
YGTSS assessment. In the mITT analysis set, treatment will be assigned based on the treatment to which 
patients were randomized, regardless of which treatment they actually received. 
All efficacy analyses will be based on the mITT analysis set.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set will include patients who are compliant with study medication (80% to 
105%), have a YGTSS assessment at baseline and at weeks 2, 4, and 8, and who have not taken 
prohibited concomitant medications as indicated in exclusion criterion, and who have no major protocol 
deviations that affect the validity of the efficacy measurements. Protocol deviations will be captured 
during the study conduct. Protocol deviations will be classified as major or minor prior to database lock. 
The list of protocol deviations will be reviewed before unblinding and major protocol deviations that could 
affect the primary and secondary variables will be determined. All exclusion from PP analysis set will be 
reviewed in the blinded data review meeting (BDRM) before database lock.
Major Protocol Deviations Results in Exclusion from Analysis Set
Some of the examples of major deviations that may result in patient or visit exclusion from any analysis 
set are given in Table 3.


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Statistical Analysis Plan for Interventional Studies
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General Aspects for Statistical Analysis
General Methods
Statistical methodology and analyses are in accordance with the principles outlined by the ICH E9 
guidelines.  All statistical analyses will be conducted using SAS statistical software version 9.3 or above. 
Tables, listings and figures (TLFs) will be produced in accordance with the principles outlined by the ICH 
E3 guidelines. For most summary statistics, data will be analyzed by the following treatment groups:  
TEV-50717 High-Dose; TEV-50717 Low-Dose; Placebo. Total column will be included in all non-efficacy 
tables.
Data summaries will use descriptive statistics (number of patients [n], mean, standard deviation [SD], 
standard error [SE], median, minimum, and maximum) for continuous variables, and frequency and 
percentage of patients for categorical and ordinal variables, unless otherwise specified. For continuous 
variables, if n<5 then only median, min and max will be presented. 
Unless otherwise specified, all statistical tests will be two-tailed using a 0.05 level of significance. All 
confidence intervals (CIs) will be two sided 95% CIs.
Only visits mapped to scheduled visits will be included in by-visit summaries.  All visit assessment data 
will be included in shift tables and will appear in the patient listings.
Key Definitions
Baseline Values
Baseline is defined as the last non-missing measurement on or prior to the first dose of double-blind IMP.  
First Dose Date
The first dose date will be the date that the first dose of randomized, double-blind IMP is administered. 
Dose starting and stopping dates are collected on CRF per blister per week. The first dose date will be 
derived as the earliest date obtained from CRF. 
Last Dose Date
Last dose date is defined as the last dose stopping date. It will be derived as the latest dose stopping 
date obtained from CRF.
Study Day
Study Day is the number of days starting from the first administration of IMP, which is counted as Study 
Day 1.  If the assessment date is after the date of the first double-blind medication, the study day is 
calculated as date of assessment - date of the first dose administration+1.  If the assessment date is prior 
to the date of the first double-blind medication, the study day is calculated as date of assessment - date of 
the first dose administration.
Duration
Duration of double-blind treatment will be determined as: 
Duration = last dose date - first dose date + 1.  


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Missing Data
The handling of missing or incomplete data is described for each endpoint and data type (as needed) in 
Sections 8 to 9. In general, no data imputation will be applied for missing values in safety analysis. Data 
imputation method for efficacy analysis will be described in Section 8.
Visit Windows
 
 
 
  
 
 
  
 
 
 
 
 
After mapping the data to the analysis visits of unscheduled and early termination visits, the following 
rules will apply unless other handling is specified for a particular analysis. 

If there is scheduled visit in the analysis window, scheduled visit will be selected.

If there is no scheduled visit, but early termination visit, early termination visit will be selected. 

If there are no scheduled or early termination visits, the unscheduled visit will be selected. If there are 
multiple unscheduled visits, the following rules will be used in sequential order:
o
The record closest to the planned assessment day will be selected for analysis. 


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o
If 2 records are equidistant from the scheduled day, then the later record will be selected. 

If a patient has no scheduled record or early termination/unscheduled visits in an analysis window, 
the patient will be considered missing at that visit.
For these analyses performed by time period, e.g. adverse events, the following definitions will be used:

Escalation Period - from the first dose of treatment until the day before the week 4 visit. For patients 
discontinued before the week 4 visit, the Escalation Period is until the later of the last dose of 
treatment and the early termination visit. 

Maintenance Period - from the day of the week 4 visit until the day of the week 8 visit. If a patient
enters the Maintenance Period but discontinues treatment early, the Maintenance Period is until the 
later of the last dose of treatment and the early termination visit. 

Follow-up Period - from the end of the Maintenance Period through the end of the study.

Overall Period - includes the Escalation Period, the Maintenance Periods, and the Follow-up Period, if 
applicable.
If the AE onset date is partial and can be potentially counted in multiple periods, AE will be included with 
the earliest period. 
Pooling of Centres
Patients will not be pooled based on site size, but rather by region, to ensure a sufficient number of 
patients per treatment arm in the ITT, mITT and PP sets for analysis that contain region as a model effect. 
The tables below show which countries comprise each of the regions to be used in analysis.  
Region
Country
Europe
France
Hungary
Italy
Netherland
Poland
Romania
Sweden
Ukraine
North America
United States
Canada
Latin America
Argentina
Columbia
Mexico
Asia Pacific
Australia
Korea


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Demographic, Other Baseline Characteristics and Prior Medications
Patient Disposition and Withdrawals
Patient screened and patients screened but not in the ITT analysis set will be summarized only for all 
patients in screened analysis set using patient counts. Patients in the ITT analysis set, patients in the ITT 
analysis set but not treated, patients in safety, mITT, and PP analysis sets, patients who complete 
titration period, complete maintenance period, complete the study, complete the follow-up, and patients 
who withdraw from the study (and reason for withdrawing) during each treatment period will be 
summarized using descriptive statistics. The ITT analysis set will be used as the denominator for 
calculating percentages. 
If more than 15% of the patients withdraw from the study during the treatment period, the number of days 
until study discontinuation will be plotted using Kaplan-Meier methodology using the ITT analysis set 
(defined in section 5.3). Patients who complete the study treatment period will be censored on the study 
day of the last dose. 
A listing of study completion will be provided for all screened patients. A listing for analysis dataset with 
reason patient is excluded from the analysis set will also be provided for all patients in ITT analysis set.
In addition, the major protocol deviations will be summarized for ITT analysis set.
Demographic and Other Baseline Characteristics
Patient demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups. BMI will be computed as:
BMI (kg/m2) = Weight at baseline (kg)/[Height at screening (m)2].
In addition, normal age and sex-based z-scores and percentiles for BMI will be determined using the 
WHO growth charts. Age and sex-based BMI categories includes: Underweight (< 5 percentile), Normal 
(≥ 5 - < 85 percentile), Overweight (≥ 85 - < 95 percentile), Obese (≥ 95 percentile).
The continuous variables of patient age, weight, height, body mass index (BMI), BMI World Health 
Organization (WHO) adjusted z-scores and percentile, will be summarized using descriptive statistics. 
The categorical variables of patient sex, race, ethnicity, and BMI categories will be summarized using 
descriptive statistics for each category. Missing categories will be presented if necessary. For randomized 
patients, age at baseline will be used. 
The continuous variables of time since Tourette syndrome diagnosis in years and baseline TTS of the 
YGTSS will be summarized using descriptive statistics. The categorical variables of age group at baseline 
(6 to 11 years, 12 to 16 years), use of a strong CYP2D6 inhibitor (Yes/No), CYP2D6 genotype (Poor 
CYP2D6 metabolizer/ Non-poor CYP2D6 metabolizer), and CYP2D6 impairment status (Impaired/Not 
impaired) will be summarized using descriptive statistics for each category.
Strong CYP2D6 inhibitor status is determined by classifying patients as taking versus not taking a strong 
CYP2D6 inhibitor (i.e. paroxetine, fluoxetine, or bupropion), collected at screening from site. Impaired 
CYP2D6 function is defined as use of a strong CYP2D6 inhibitor at baseline or a poor CYP2D6 
metabolizer. Both CYP2D6 genotype and impairment status will be blinded during the study.


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Summaries for demographics and baseline characteristics will also be presented for the ITT, safety, mITT 
and PP analysis sets.
Medical History and Concomitant Diseases
Significant medical and psychiatric history, including dates of diagnoses and procedures and whether the 
condition is ongoing, if applicable, will be collected. Each condition will be recorded as a verbatim term, 
date of onset, date resolved, and a checkbox that indicates ongoing conditions. Significant surgical and 
medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
20.1.
Medical and surgical history will be summarized for the safety analysis set by treatment group, system 
organ class (SOC), and MedDRA preferred term (PT). Patient data will be listed.
Medication
Any prior therapy, medication, or procedure a patient has had within 3 months before study drug 
administration will be recorded on the case report form (CRF). Medications will be coded according to the 
WHO Drug Version: June 2017. Preferred drug name, Anatomical/ Therapeutic/ Chemical (ATC) class will 
be reported for inclusion in the database.  
Medication summaries based on ATC level 3 and the preferred drug names will be produced for the 
safety analysis set. The summaries will present, by treatment group, the frequency and percentage of 
patients who used any medication in an ATC class, or any medication based on a single preferred drug 
name. Medication summaries will be sorted by descending total frequency of ATC class and by PT within 
ATC class. Patients will be counted only once for each medication class and each preferred drug name.
Prior Medication
Prior medications and therapies will include all medications and therapies stopped before the first day of 
study drug administration. Prior medication will be summarized by the ATC level 3 and preferred name. 
Prior medication will be summarized. The same summary will be repeated for prior antidepressant and 
ADHD medication use. These medications are identified by the ATC codes of: 
ADHD medications:
N-NERVOUS SYSTEM
  N06-PSYCHOANALEPTICS
    N06B-PSYCHOSTIMULANTS, AGENTS USED FOR ADHD AND NOOTROPICS
      N06BA-Centrally acting sympathomimetics
      N06BC-Xanthine derivatives
      N06BX-Other psychostimulants and nootropics.
Antidepressant:
N-NERVOUS SYSTEM
  N06-PSYCHOANALEPTICS
    N06A-ANTIDEPRESSANTS
      N06AA-Non-selective monoamine reuptake inhibitors
      N06AB-Selective serotonin reuptake inhibitors
      N06AF-Monoamine oxidase inhibitors, non-selective
      N06AG-Monoamine oxidase A inhibitors
      N06AX-Other antidepressants.


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Other Therapies 
Prior non-pharmacological treatment will be collected in CRF. Type of treatment/procedure and indication 
will be listed.
Prior treatment given for TS will be summarized. The table will include number of patients with previous 
treatment given for TS, total duration of treatment, and best response to treatment. For an ongoing 
treatment, date of informed consent will be used to compute duration. If the start date is partial with year 
and month, 1st will be imputed. If the start date has only year, Jan, 1st will be imputed. If the end date is 
partial, the latest possible date on or before informed consent date will be imputed. If there are multiple 
prior treatments, the duration will be computed as the sum of all non-overlapping treatments. For 
overlapping treatments, the duration will be from the earliest treatment start date to the latest treatment 
end date.


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Efficacy
The mITT analysis set will be used for all efficacy analyses, unless otherwise noted. Analyses and 
summaries will be presented by treatment group.
Week 9 efficacy data will be summarized but will not be included in any statistical analyses.
Efficacy Assessment and Time Points
Yale Global Tic Severity Scale (YGTSS)
The YGTSS rating scale is a semi-structured clinician rating instrument that provides an evaluation of the 
number, frequency, intensity, complexity, and interference of motor and phonic tics (Leckman et al 1989). 
The YGTSS is composed of 11 items: 5 items for motor tic severity, 5 items for vocal tic severity, and 1 
item for impairment. Each item for motor tic severity and vocal is rated on a 6-point scale (0 for none to 5 
to severe). The MTSS is the sum of the 5 items for motor tic severity and the VTSS is the sum of the 5 
items for vocal tic severity. The TTS is the sum of the MTSS and the VTSS. The impairment score ranges 
from 0 (none) to 50 (severe). The GSS is the sum of the TTS and the impairment score.  
YGTSS is administered at screening; baseline; and weeks 2, 4, 8, and 9. 
For YGTSS, if a response to 1 item is missing within the MTSS or VTSS subscale, the missing response 
will be replaced with the average of the remaining responses within the subscale; if responses to 2 or 
more items within a subscale are missing, the missing responses will not be replaced and the subscale 
score will be set to missing; if at least 1 subscale is missing then the TTS will be set to missing. If the TTS 
or impairment score are missing, then the GSS will be set to missing. 
Tourette Syndrome-Clinical Global Impression (TS-CGI) 
The TS-CGI is administered at baseline and at weeks 2, 4, 8, and 9. 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).
Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) 
The TS-PGII is administered at baseline and weeks 2, 4, 8, and 9. 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.
Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS QOL) 
The C&A-GTS-QOL is administered at baseline, week 4, and week 8. 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. 


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The C&A-GTS-QOL is a 27-item questionnaire specific to TS patients that asks the patient to assess the 
extent to which their quality of life is impacted by their symptoms. The C&A-GTS-QOL contains 
6 subscales (cognitive, coprophenomena, psychological, physical, obsessive-compulsive, and ADL) and 
uses a 5-point Likert scale ranging from no problem to extreme problem. Patients will also be asked how 
satisfied they feel overall with their life at that moment by using a VAS scale between 0 and 100 (Su et al 
2017). Following are the questions assessed in each C&A-GTS-QOL subscale:

Cognitive (questions 11, 12, 13, 14, 18, 20, 21, 23) (range: 0- 32)

Psychological (questions 15, 16, 17, 19, 25, 27) (range: 0 – 24)

Obsessive-compulsive (questions 7, 8, 9, 10) (range: 0 – 16)

Physical (questions 1, 3, 4) (range: 0 – 12)

Coprophenomena (questions 5, 6, 22) (range: 0 -12)

ADL (questions 2, 24, 26) (range: 0-12)
Scores for the six subscales are generated by summing items and, for ease of interpretation, 
transformation to a range of 0 to 100 (100x [(observed score - min possible score)/(max possible score -
min possible score)]). The total score, resulting from the sum of the subscale scores, is also normalized to 
a 0–100 range. For C&A-GTS-QOL, if a response to 1 question is missing within the subscale, the 
missing response will be replaced with the average of the remaining responses within the subscale; if 
responses to 2 or more questions within a subscale are missing, the missing responses will not be 
replaced and the subscale score will be set to missing; if at least 1 subscale is missing then the total 
score will be set to missing. For all analysis and summary, transformed scores will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Primary Efficacy Endpoint and Analysis
Primary Efficacy Analysis
The primary analysis will be a mixed-model, repeated-measures with the change in the TTS as the 
dependent variable. The model will include fixed effects for treatment group, week (3 levels: weeks 2, 4, 
and 8), and the treatment group by week interaction. The baseline TTS, region, and age group at 
baseline (2 levels: 6-11 year, 12-16 years) will be included as covariates. The unstructured covariance 
matrix for repeated observations within patients will be used. In case that the model does not converge, 
the Maximum-Likelihood estimation method will be used instead of the default Restricted Maximum-
Likelihood. If the model still does not converge, then a simpler covariance structure with fewer parameters 
will be used, according to the following order: Heterogeneous Autoregressive (1), Heterogeneous 
Compound Symmetry, Autoregressive (1), and Compound Symmetry. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.
The least squares means of the change in TTS from baseline at week 8 will be compared (primary: 
TEV-50717 high-dose arm vs. the placebo arm; secondary: TEV-50717 low-dose arm vs. the placebo 
arm) using 2-sided tests at the alpha=0.05 level of significance. The SAS code for this test is as follows:
 
   
   
   
   
 
The least square (LS) mean and standard error for the treatment groups, and the LS mean difference, 
95% confidence interval (CI), and p-value for each comparison (TEV-50717 high-dose vs. placebo at 
week 8; TEV-50717 low-dose vs. placebo at week 8) will be presented.
Cohen’s d effect size will also be computed for each comparison (Kelley, 2007). Cohen’s d is calculated 
as:
d = (μt – μp) / (pooled SD),
where µt represents the least-square (LS) mean of the specified TEV-50717 group (High- or Low-dose, 
µp is the LS mean of the placebo group, and the pooled SD is based on the adjusted LS means and 
adjusted standard errors from the mixed-effect model for MMRM, specifically: 
 	
 = 	  (	)
 1
 + 1

and nt=number of patients in specified TEV-50717 group and np=number of patients in placebo group.
The utility of Cohen’s d is to help judge the clinical importance of a measured treatment difference.
Sensitivity Analysis
The primary efficacy analysis on change in the TTS at Week 8 is to use MMRM model, described in 
Section 8.2.1 (the primary analysis model), using all observed data in the mITT anlaysis set. Data from 
patients that had dose reduction, suspension, treatment discontinuation, or treatment-related adverse 
events were collected in the study and will be included in the analyses, as these patients are generally 


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not excluded from the mITT analysis set. This model is appropriate when data isMAR. This approach is 
considered reasonable under the assumption that the percent of early terminations will be low. As of 12 
Dec 2019 the overall early termination rate from study 30060 was 8%, which is regarded to be in line with 
this assumption. Therefore, the proposed analysis is suitable for the primary estimand.
To assess the robustness of the primary efficacy analysis, the following additional analyses will include:
 
 
Details of sensitivity analysis for missing data and the statistical model are explained in the next 2 
sections.
8.2.2.1.
Sensitivity analyses for missing data
 
 
 
 
 
 
 
 
 


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The complete multiple imputation methodology, along with SAS code, is detailed in Appendix C 
(Section 19.3).
8.2.2.2.
Sensitivity analysis for the statistical model
 
 
 
Subgroup Analysis
Data summary of TSS of YGTSS by subgroup below will be conducted using the mITT population. In 
addition, 95% CI for the change from baseline will be provided:

Gender: Male and Female 

Race Group: White, Black or African American, and Other

Baseline Age Group (6-11 years, 12-16 years)

CYP2D6 impairment status (Yes/No)
In addition, TTS of YGTSS will be analyzed in the same fashion as the primary analysis in Section 8.2.1
by baseline age group, with the exception that age group will not be included as the fixed effect. 
Secondary Efficacy Endpoint(s) and Analyses
The secondary endpoints for this study are as follows: 
1.
Change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from baseline to 
week 8 between high-dose TEV-50717-treated patients and placebo-treated patients;
2.
Change in the TTS of YGTSS from baseline to week 8 between low-dose TEV-50717-treated 
patients and placebo-treated patients;
3.
Change in the TS-CGI score from baseline to week 8 between low-dose TEV-50717-treated 
patients and placebo-treated patients;
4.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from 
baseline to week 8 between high-dose TEV-50717-treated patients and placebo-treated patients;
5.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from 
baseline to week 8 between low-dose TEV-50717-treated patients and placebo-treated patients;
6.
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 baseline to week 8 between high-dose 
TEV-50717-treated patients and placebo-treated patients;


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7.
Change in the C&A-GTS-QOL ADL subscale from baseline to week 8 between low-dose 
TEV-50717-treated patients and placebo-treated patients.
A hierarchical (fixed-sequence) testing approach will be used for the analysis of the primary and key 
secondary endpoints to maintain the experiment-wise type I error rate of 5%. If an endpoint is not 
statistically significant, confirmatory hypothesis testing will not be carried out on the remaining 
hypotheses, and remaining hypotheses will be considered exploratory rather than confirmatory. 
Secondary efficacy analyses will be based on mITT analysis set. 
Secondary Efficacy Analysis
8.3.1.1.
Analysis of the change in the TS-CGI from baseline to Week 8
The change in the TS-CGI score from baseline to Week 8 (1st and 3rd secondary endpoints) will be 
analyzed in the same fashion as the primary analysis in Section 8.2.1, with the exception that the 
baseline value of the given endpoint will be included as the covariate.
8.3.1.2.
Analysis of the change in the TTS of YGTSS between low-dose TEV-50717-treated patients
and placebo-treated patients
The change in the TTS of YGTSS from baseline to Week 8 between low-dose TEV-50717 treated 
patients and placebo-treated patients (2nd secondary endpoint) will be analyzed as part of Section 8.2.1.
8.3.1.3.
Analysis of the change in TS-PGII
The change in the TS-PGII score from baseline to Week 8 (4th and 5th secondary endpoints) will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) row mean score test with modified ridit scoring, 
controlling for baseline TS-PGII. The TS-PGII will be summarized as shifts from baseline score to each 
visit that it is measured using descriptive statistics. 
The SAS code for the analysis at week 8 for each pair of high-dose TEV-50717 and placebo, or low-dose 
TEV-50717 and placebo is as follows:
   
   
8.3.1.4.
Analysis of the change in C&A-GTS-QOL ADL subscale
The change in the C&A-GTS-QOL ADL subscale score from baseline to week 8 (6th and 7th secondary 
endpoints) will be analyzed in the same fashion as the primary analysis in Section 8.2.1, with the 
exception that the baseline value of the given endpoint will be included as the covariate. 
Sensitivity Analysis
 
 


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Exploratory Endpoints and Analysis
Exploratory endpoints for this study are as follows: 
 
 
 
 
 


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. 
 
 
 
 
 
 
 
 
   
 
 
 
 


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Safety
The safety endpoints for this study are as follows:
•
Incidence of adverse events 
•
Observed values and changes from baseline in vital signs
•
Observed values and change from baseline in the Children’s Depression Inventory, Second 
Edition (CDI-2), Parent and Self-report Profiles
•
Observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS)
•
Observed values in electrocardiogram (ECG) parameters and shifts from screening for clinically 
significant abnormal findings
•
Observed values and changes from screening in clinical laboratory parameters (hematology, 
chemistry, and urinalysis)
The safety analysis set will be used for all safety analyses. Summaries will be presented by treatment 
group and for all patients.
Extent of Exposure
Duration of exposure to study drug (days) for individual patients is the number of days patient received 
drug (last day of study drug – first day of study drug + 1).  Duration of treatment (days) will be 
summarized using descriptive statistics. Weeks on treatment using the categories ≤2 weeks, >2 to ≤4 
weeks, >4 to ≤6 weeks, >6 to ≤8 weeks, and >8 weeks will also be summarized using descriptive 
statistics.  
Treatment Compliance 
Study drug administration will be included in the CRF. In the form, med ID (ID for blister pack), week 
range, dosing start and stop date, and number of pills taken from the blister pack are collected. Treatment 
compliance (%) is calculated as 100*(total number of pills taken / number of tablets expected to be used). 
The total number of pills taken is the sum of pills taken from all bottles dispensed, identified by med ID. If 
a patient does not return a pill bottle, it will be assumed that the patient took no study drug from that bottle 
for the purposes of calculating compliance. The number of pills expected to be used is based on the 
number of morning and evening dosing times during the treatment period (2 pills are used for each dosing 
time point).  A patient will be deemed compliant over the treatment period if the patient has taken 80% to 
105% of the expected tablets of study drug. 
Treatment compliance (%) will be summarized as continuous data using descriptive statistics. In addition, 
treatment compliance will be summarized as categorical data using descriptive statistics for the following 
categories:  <80%, 80% to 105%, >105%.
Concomitant Medication
A concomitant medication is 1)any medication that starts prior to first day of study drug administration and 
continues into treatment period; or 2) any medication that starts on or after the first dose of IMP and 
before the last dose of IMP. Concomitant medication will be summarized separately for 1) and 2). In the 


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case of completely missing stop date and medication is not ongoing, medication will be assumed to be 
concomitant. Medication cannot be considered as both prior and concomitant.
Concomitant medication summaries based on ATC level 3 and the preferred drug names will be produced 
for the safety analysis set. The summaries will present, by treatment group, the frequency and 
percentage of patients who used any medication in an ATC class, or any medication based on a single 
preferred drug name. Medication summaries will be sorted by descending total frequency of ATC class 
and by PT within ATC class. Patients will be counted only once for each medication class and each 
preferred drug name.
In addition, ADHD and antidepressant (see Section 7.4.1 for ATC code list) change will be summarized 
for:

Proportion of patients requiring new medication; 

Proportion of patients requiring increased medication; 

Proportion of patients requiring decreased medication; 

Proportion of patients discontinued medication;

Proportion of patients with medication switch.
Adverse Events 
Adverse events will be collected and recorded from the time a patient signs the informed consent to the 
end of follow-up period. For this study, the follow-up period for recording of adverse events is defined as 1 
week of washout for patients who will participate in the open-label safety extension study TV50717-CNS-
30047 and 2 weeks after the last dose of IMP for patients who will not roll over into Study 
TV50717-CNS-30047. 
For all AEs, preferred AE terms and system organ class (SOC) will be coded using terminology from the 
Medical Dictionary for Regulatory Activities (MedDRA), version 20.1 or higher.
A treatment emergent adverse event (TEAE) is defined as an AE that begins after the first administration 
of study medication or existing AEs that worsen after the first dose of study medication.  All reported AEs 
will be listed, but only TEAEs will be summarized in tables. 
Drug related AEs will be considered those to be reasonable possibility based on the investigators 
assessment.  Missing relationship will considered as “Related”.  
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs within SOCs 
presented in descending order of patient incidence. 
AE summary tables are listed below:

An overall summary of the number and percentage of patients reporting any TEAEs, serious 
TEAEs, treatment-related TEAEs, serious treatment-related TEAE, any TEAEs leading to study 
drug discontinuation, any TEAEs leading to patient study drug interruption, and TEAEs leading to 
death. The overall summary will also be prepared by age group (6-11 years, or 12-16 years);

TEAEs overall and by SOC and PT;

TEAEs by severity, overall and by SOC and PT. Missing severity, if any, will be assumed as 
“severe”;

Serious TEAEs, overall and by SOC and PT;


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
Serious treatment-related TEAEs, overall and by SOC and PT ;

TEAEs by relationship to study treatment, overall and by SOC and PT;

TEAEs leading to study drug discontinuation, overall and by SOC and PT;

TEAEs leading to study drug interruption, overall and by SOC and PT;

TEAEs leading to dose reduction overall and by SOC and PT;

Most common TEAEs, overall and by PT.  Most common TEAEs are defined as TEAEs that occur 
in > 4% of the patients in either of the treatment groups. ;

SMQs for suicide/self-injury, depression (exclude suicide and self-injury), and Parkinson-like 
events. 
For summary tables, patients having more than 1 event with the same PT will be counted once for that 
term.  Patients having more than 1 event with the same SOC will be counted once for each event and
once for that SOC. For tabulations by severity, only a patient’s most severe event within the category 
(e.g. overall, SOC, PT) will be counted; similarly, for tabulations by relationship, only a patient’s most 
related event within a category will be counted.  Summaries will be presented by treatment group and for 
all patients. The denominator for percentages will be the number of patients in safety analysis set for the 
given treatment group (i.e., the N’s for the columns). Summary of all TEAEs will be presented in the 
overall period (escalation plus maintenance phase plus follow-up period) and for the escalation period, 
maintenance period, and follow-up period. By period summary will be based on the period the AE 
occurred (Section 6.4). Same type of AE may be counted in multiple periods in cases below:

AE resolved in the same period and reoccurred in a new period.

AE increased severity in another period.
Same AE will be counted only once in summary in the overall period. 
All adverse events in the overall treatment period will be summarized by CYP2D6 impairment status 
(Impaired/Not impaired). In addition, serious AEs and AEs by severity will be summarized by CYP2D6 
impairment status.
Listings will be provided for all AEs and the following subsets:

All AEs

Serious AEs

AEs leading to study drug discontinuation

AE leading to dose interruption

AEs leading to death.
Laboratory Evaluations
Laboratory tests will include chemistry panel, hematology panel, and urinalysis testing. Laboratory tests 
will be performed at the following time points: at the screening visit, and at week 8. If clinically significant 
laboratory abnormalities have been noticed at week 8 visit, those laboratory evaluations will be repeated 
at the week 9 visit. A list of laboratory tests is included in Table 4.


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Observed values (in SI units) and change from baseline to Week 8 will be summarized by treatment 
group.  For hematology and chemistry panel, result will also be categorized as “Normal”, “Low”, or “High” 
based on their normal ranges. For urinalysis results, tests will be classified as “Normal” or “Abnormal”. 
Shift tables comparing laboratory test results from baseline to Week 8 will be presented. 
All laboratory data will be listed.  For hematology, chemistry, columns will be included for normal ranges 
and individual abnormal laboratory values will be flagged.  Listing for urinalysis will include the 
microscopic examination provided for patients who have a positive result from the urinalysis dipstick 
evaluation.  
Table 4: List of 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 
Pregnancy
Pregnancy tests will be performed for females who are postmenarchal or ≥12 years of age. Urine test will 
be administered at baseline, and serum test will be administered at screening and Week 8. The 
pregnancy data will be presented in a data listing. 
Urine Drug Screening 
Urine drug screening tests are collected at screening and week 8. The urine drug screening data will be 
presented in a data listing.


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Vital Signs 
Vital signs will be measured at screening, baseline, and weeks 2, 4, 8, and 9. Measurements of vital signs 
will include measurement of pulse, blood pressure (BP), weight, body temperature, and respiratory rate. 
Pulse and BP in supine or semi-erect/seated position will be measured in each scheduled or unscheduled 
visits. In addition, standing BP and pulse will be taken at baseline, weeks 4, and 8. BMI will be computed 
similarly as in Section 7.2 at Week 8 and early termination visits. Weight and height at the visit will be 
used. Normal age and sex-based z-scores, percentiles for BMI, and BMI categories will also be 
determined using the WHO growth charts similarly as in Section 7.2. 
Orthostatic systolic and diastolic BP and pulse will be calculated as supine or semi-erect/seated 
measurement – standing measurement. Orthostatic hypotension (determined by blood pressure 
measurements only) is defined as having either a ≥ 20 mmHg reduction from supine to standing position 
in systolic blood pressure (SBP) or ≥ 10 mmHg reduction from supine to standing position in diastolic 
blood pressure (DBP) or both. Orthostatic tachycardia is defined as pulse increase ≥20 bpm from supine 
to standing position.
Observed values, change from baseline, for each vital sign parameter and position will be summarized at 
each visit by treatment and overall. 
In addition, orthostatic hypotension or orthostatic tachycardia occurrences, and the markedly abnormal 
post-baseline vital signs results will also be summarized for patients with at least one markedly abnormal 
value during the treatment period according to criteria specified in Table 5. A listing will be provided for all
markedly abnormal vital signs. A shift table for BMI age and sex adjusted categories will be presented 
comparing shifts from the baseline visit to week 8. Percentages will be based on the number of safety 
patients with a non-missing value for both the baseline and post-baseline visit for the given vital sign. 


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Table 5: Criteria for Markedly Abnormal Vital Sign Parameters by Age
Parameter
(unit)
Age
(years old)
Markedly Low
Markedly High
SBP (supine, 
standing) (mmHg)
6-12
Value ≤ 70 and≥ 20 
decrease from baseline
Value ≥ 120 and
≥ 20 increase from 
baseline
13-18
Value ≤ 90 and
≥ 20 decrease from 
baseline
Value ≥ 135 and
≥ 20 increase from 
baseline
DBP (supine, 
standing) (mmHg)
6-12
Value ≤ 40 and
≥ 15 decrease from 
baseline
Value ≥ 80 and
≥ 15 increase from 
baseline
13-18
Value ≤ 50 and
≥ 15 decrease from 
baseline
Value ≥ 90 and
≥ 15 increase from 
baseline
Pulse rate (supine, 
standing) (bpm)
6-10
Value ≤ 60 and
≥ 15 decrease from 
baseline
Value ≥ 135 and
≥ 15 increase from 
baseline
11-18
Value ≤ 50 and
≥ 15 decrease from 
baseline
Value ≥ 120 and
≥ 15 increase from 
baseline
SBP orthostatic 
criteria (mmHg)
~
≥ 20 decrease from supine 
to standing position
NA
DBP orthostatic 
criteria (mmHg)
~
≥ 10 decrease from supine 
to standing position
NA
Pulse rate 
orthostatic criteria 
(bpm)
~
NA
≥ 20 increase from 
supine to standing 
position
Temperature (˚C)
~
NA
Value ≥ 38.3°C and 
≥0.8°C increase from 
baseline
Note: ~ means that the abnormal range is applicable for all patients within age group: 6 to 17 years 
old.
Vital signs data will be provided in a data listing.
ECG
Assessment of Standard 12-lead ECG are obtained at screening, baseline, weeks 4 and 8.  A central 
ECG Standard 12-lead ECG will record heart rate (HR), PR interval, RR interval, QT interval, Frederica’s 
corrected QT interval (QTcF), and QRS duration. The overall ECG assessment will be centrally reported 
as “Normal” or “Abnormal” with respect to relevant abnormalities. If a post-baseline QTcF value 
>500 msec or change from baseline >60 msec is found, the investigator should repeat the ECG 
assessment twice. In this case, the confirmed QTcF, defined as the average of all 3 ECG values at the 
visit, will be used for summary. If ECG tests are repeated on the same day for any other reason per 
investigators discretion, the average of all ECG values on that day will be used for summary.


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Observed results of each ECG parameter and change from baseline will be summarized by treatment and 
overall, and by visit using descriptive statistics. 
In addition, for QTcF, average baseline confirmed QTcF (the average of the screening and Day 1 QTcF), 
and the change from average baseline will be summarized by treatment and overall, and by visit using 
descriptive statistics.
QTcF values will be classified as having QTc prolongation according to the following conditions.
QTc Prolongation
Confirmed QTcF >450 msec
Confirmed QTcF>480 msec
Confirmed QTcF>500 msec
Increase from baseline QTcF ≥ 60 msec 
Increase from average baseline confirmed QTcF ≥ 60 
msec
Increase from baseline QTcF ≥ 30 msec
Increase from average baseline confirmed QTcF ≥ 30 
msec
The number and percentage of patients with QTc prolongation will be summarized by treatment and 
overall, and by visit.  
A shift table comparing the overall ECG assessment from baseline to each visit will be presented. 
In addition, the abnormal post-baseline ECG results will also be summarized for patients with at least one 
abnormal value during the treatment period. The summary will be completed by treatment and overall, 
and age groups (6 - < 8 years, 8 - < 12 years, and 12 - < 16 years), and overall using the age at the time 
of the individual assessment. 
Criteria for abnormal values used in the study are presented in Table 6.


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Table 6: Criteria for Abnormal ECG Parameters by Age
ECG parameter 
(unit)
Age (years old)
Abnormally Low
Abnormally High
HR (bpm)
6 to <8
< 65
> 115
8 to <12
< 55
> 110
12 to <16
< 50
> 105
≥16
< 50
> 100
PR interval (msec)
6 to <8
--
> 160
8 to <12
--
> 175
12 to <16
--
> 180
≥16
--
> 200
QRS interval (msec)
6 to <8
--
> 100
8 to <12
--
> 105
12 to <16
--
> 110
≥16
--
> 120
Physical Examinations
Physical examinations are performed obtained at screening and Week 8. Physical examinations will not 
be summarized. Physical examinations will be listed.
Neurological Examinations
Neurological examinations will be performed at screening and Week 8. Each assessment (i.e. Mental 
Status, Cranial Nerves, Motor System, Gait and Balance, Tendon Reflexes, Sensation and Other) will 
include category of normal/abnormal and not clinical significant (NCS)/abnormal and clinical significant 
(CS). Neurological examinations will be listed.
ADHD Symptoms
Based on input from the TEV-50717 Tourettes Syndrome Scientific Advisory Board (SAB) , which 
contains  experts in the area of child psychiatric, and in the attempt to identify possible symptoms 
consistent with ADHD symptomatology, the items below from C&A-GTS-QOL were chosen:
 


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Summary statistics will be provided to the observed values and change from baseline.  This analyses are 
only exploratory and for signal detection purpose.
Children’s Depression Inventory, Second Edition (CDI-2)
The CDI-2 (parent and self-report versions) is administered at screening, baseline, and weeks 2, 4, 8, and 
9. As the CDI-2 is designed for children 7 to 17 years of age, children 6 years of age at baseline 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 CDI-2 
Self-report version contains 6 subscales (emotional problem, negative mood/physical symptoms, negative 
self-esteem, functional problems, ineffectiveness, interpersonal problems). The raw score is the sum of all 
subscales scores, ranging from 0 to 56, with higher score indicating more severe depressive symptoms. 
The raw score is normalized to T-score (range: 40-90) based on patient’s age and gender.
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 CDI-2 
parent version contains 2 subscales (emotional problems and functional problem). The raw score is the 
sum of the 2 subscales, ranging from 0 to 51, with higher score indicating more depression-related 
behaviors observed in their children.
The CDI-2 parent version and self-report versions subscale scores, raw scores, and self-report version T 
scores will be presented at baseline and each visit each is measured.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS children’s baseline/screening scale assesses past and current suicidal ideation and 
behaviors to determine suicide risk and is administered at screening. The C-SSRS children’s since last 
visit (SLV) scale is administered at baseline and at weeks 2, 4, 8, and 9. Patients will be placed into 
categories for suicidal ideation and for suicidal behavior based on their responses to various questions.
The suicidal ideation categories will be determined as follows by examining the response to the 5 
questions under Suicidal Ideation. 


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Type
Section
Suicidal ideation
(0) None – if response is No to Questions 1 and 2 
(1) Wish to be Dead – if response to Question 1 is Yes and 
responses to Questions 2-5 are No. 
(2) Non-Specific Active Suicidal Thoughts – if response to Question 2 
is Yes and response to Questions 3-5 are No.
(3) Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act – if response to question 3 is Yes and response to 
questions 4 and 5 are No. 
(4) Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan – if response to Question 4 is Yes and response to Question 5 
is No. 
(5) Active Suicidal Ideation with Specific Plan and Intent – if response 
to Question 5 is Yes.
For suicidal behavior, the following categories will be used. The categories will be determined based on 
the response to the questions under suicidal behavior. 
Type
Section
Suicidal behavior
(6) Preparatory Acts or Behavior – if response to Preparatory Acts 
and Behavior is Yes and responses to Actual Attempt, Interrupted 
Attempt, Aborted Attempt, and Completed Suicide are No
(7) Aborted Attempt – if response to Aborted Attempt is Yes and 
responses to Actual Attempt, Aborted Attempt, and Completed 
Suicide are No.
(8) Interrupted Attempt – if response to Interrupted Attempt is Yes 
and response to Aborted Attempt, and Completed Suicide are No.
(9) Actual Attempt – if response to Actual Attempt is Yes and 
Completed Suicide is No.
(10) Completed Suicide - if response to Completed Suicide is Yes
(0) None – if responses to all the above 4 questions are No. 
Suicidal ideation or behavior will be derived as the highest suicidal ideation or behavior score at the visit. 
Score of 0 represent “No Suicidal Ideation/Behavior”.
The frequency and percentage of suicidal ideation, suicidal behavior, suicidal ideation or behavior, and 
self-injurious behavior without suicidal intent will be summarized by treatment and overall, and visit. For 
baseline/screening version at baseline, past 2 years scores will be summarized.
Frequency and severity of suicidal ideation or behavior will also be summarized, using a shift table to 
examine changes in above C-SSRS scores from baseline compared to the worst (highest) category 
during the treatment period, by treatment and overall.


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Pharmacokinetic Analysis
Samples collected for PK analysis will be quantified for α-HTBZ and β-HTBZ of TEV-50717, and other 
metabolites (as required), may be analyzed using population PK techniques. Analysis methods will be 
detailed in a separate exploratory population PK analysis plan. 
Interim Analyses
No interim analysis is planned.
Changes from Analysis Planned in Protocol
A new exploratory endpoint is added:


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Reference List
Heitjan DF and Little RJA. Multiple Imputation for the Fatal Accident Reporting System. Applied Statistics
1991; 40:13–29.
Schenker N and Taylor JMG. Partially Parametric Techniques for Multiple Imputation. Computational 
Statistics and Data Analysis 1996;22:425-446.
Little RJA, Rubin DB. Statistical Analysis with Missing Data, Second Edition. 2002, New York: John Wiley 
& Sons.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & Sons.
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.
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.
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.
Ratitch B, Lipkovich I, O’Kelly M. Combining Analysis Results from Multiply Imputed Categorical Data. 
PharmaSUG 2013 – Paper SP 03


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Programming Considerations
 
 
  
 
 
 
 
 
 
     
        
 
 
 


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Quality Control
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses. An overview of the development of programs is detailed in Syneos 
Health SOP Developing Statistical Programs (3907).
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting
the Transfer of 
Biostatistical Deliverables (3908) describes the quality control procedures that are performed for all SAS 
programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the output by checking for their logic, efficiency and 
commenting and by review of the produced output.


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 59 of 76
Index of Tables
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 60 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 61 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 62 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 63 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 64 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 65 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 66 of 76
Summary 
number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 67 of 76
Index of Figures
Graph 
Number
Title
Population
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 68 of 76
Graph 
Number
Title
Population
 
 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 69 of 76
Index of Listings
Listing 
Number
Title
Population
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 70 of 76
Listing 
Number
Title
Population
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 71 of 76
Appendices
 
 
 
 
 
 
  
    
  
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 72 of 76
 
   
   
   
   
   
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 73 of 76
 
   
 
   
   
   
   
   
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 74 of 76
 
 
 
 
 
   
 
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 75 of 76
 
   
   
   
   
   
   
 
 
 


Statistical Analysis Plan for Interventional Studies
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc./Nuvelution TS Pharma, INC.;
Protocol No.: TV50717-CNS-30060
This document is confidential.
SAP Version:  Version 2.0 14-Jan-2020
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018
Filing requirements: TMF
Page 76 of 76