Clinical trial NCT03452943
Conditions: Tourette Syndrome
Keywords: Tourette Syndrome adolescents children
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2018-02-05; Completion date: 2019-11-12
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 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.

Detailed description:

Arms: arm 1: TEV-50717 tablets twice daily (BID) up to 48 milligrams (mg)/day orally for a total of 12 weeks arm 2: Placebo matched to TEV-50717 BID for a total of 12 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 for 12 weeks.

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and 
Adolescents 
 
 
Study Number TV50717-CNS-30046 
 
 
NCT03452943 
 
 
Protocol Approval Date: 25 March 2019 


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
Study TV50717-CNS-30046
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Clinical Study Protocol with Amendment 05
Study Number TV50717-CNS-30046
A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 (Deutetrabenazine) 
for the Treatment of Tourette Syndrome in Children and Adolescents
Phase 2/3
IND number: 127692;
NDA number: NA;
EudraCT number: 2016-000622-19
Original Protocol Approval Date: 26 February 2016
Protocol Amendment 05 Approval Date: 25 March 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/or its affiliates and Nuvelution TS Pharma, INC. 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 05
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AMENDMENT HISTORY
The protocol for Study TV50717-CNS-30046 (original protocol dated 26 February 2016) has 
been amended and reissued as follows:
Amendment 05
25 March 2019
86 patients randomized/enrolled to date
Amendment 04
13 September 2018
35 patients randomized/enrolled to date
Amendment 03
06 November 2017
No patients randomized/enrolled to date
Amendment 02
03 October 2017
No patients randomized/enrolled to date
Amendment 01
22 June 2017
No patients randomized/enrolled to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 17.


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INVESTIGATOR AGREEMENT
Original Protocol Dated 26 February 2016
Amendment 05 Dated 25 March 2019
IND number: 127692;
EudraCT number: 2016-000622-19
Article 45 or 46 of 1901/2006 does not apply
A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 (Deutetrabenazine) 
for the Treatment of Tourette Syndrome in Children and Adolescents
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with amendment 05 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations.
Principal Investigator
Signature
Date


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Placebo-Controlled Study–Tourette Syndrome
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COORDINATING INVESTIGATOR AGREEMENT


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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COORDINATING INVESTIGATOR AGREEMENT


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


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CLINICAL STUDY PERSONNEL CONTACT INFORMATION
Sponsor’s Authorized Representative:
 Teva Branded Pharmaceutical Products R&D, Inc.
 
Legal Representative of the Sponsor in the EU
For medical issues, contact the physician listed below: 


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


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CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV50717-CNS-30046
Title of Study: A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 (Deutetrabenazine) for the 
Treatment of Tourette Syndrome in Children and Adolescents
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc., 41 Moores Road, Frazer, Pennsylvania 19355, United 
States of America
Sponsor’s Development Partner: Nuvelution TS Pharma, Inc., 101 Main Street, 12th Floor, Cambridge, 
Massachusetts 02142, United States of America
Investigational New Drug (IND) Number: 127692 New Drug Application (NDA) Number: Not available
EudraCT Number: 2016-000622-19
Name of Active Ingredient: Deutetrabenazine
Name of Investigational Medicinal Product (IMP): TEV-50717 (previously SD-809)
Type of the Study: Efficacy and Safety (Phase 2/3)
Number of Investigational Centers Planned: Approximately 50
Countries Planned: North America, Russia, and Europe 
Planned Study Period: Planned start in January 2018 with a duration of approximately 15 months
Number of Patients Planned: Approximately 116 (58 per treatment arm; TEV-50717 versus placebo randomized 
in a 1:1 ratio stratified by age at baseline [6 to 11 years, 12 to 16 years]) 
Study Population: Male and female patients between 6 and 16 years of age (inclusive) with tics associated with 
Tourette syndrome (TS)
Primary Objective: The primary objective of this study is to evaluate the efficacy of TEV-50717 to reduce motor 
and phonic tics associated with TS.
Secondary Objectives: The secondary objective of the study is to evaluate the safety and tolerability of titration and 
maintenance therapy with TEV-50717.
Study Endpoints: 
Primary Efficacy Endpoint: 

Change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from baseline to 
week 12 
Key Secondary Efficacy Endpoints:
1.
Change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from baseline to week 12
2.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from baseline to 
week 12
3.
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 12
Exploratory Endpoints: 
 


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Safety Endpoints: 

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)
Pharmacokinetic Endpoint:

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 12.
General Design and Methodology: 
This is a Phase 2/3, randomized, double-blind, placebo-controlled, parallel group study in which patients with tics 
associated with TS will be invited to participate. Patients who qualify for the study will be centrally randomized in a 
1:1 ratio (stratified by age at baseline [6 to 11 years, 12 to 16 years]) to receive either TEV-50717 or placebo. 
Throughout the study, patients will interact regularly with investigative site personnel, in clinic and by telephone, for 
the evaluation of safety, tic severity, and behavioral status (in clinic only). 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 dose of IMP for each patient will be 
titrated to an optimal level followed by maintenance therapy at that dose. Investigators will be blinded to CYP 
status, with a dose cap for poor metabolizers prespecified by the IRT. The overall treatment period will be 12 weeks 
in duration, including a titration period of 7 weeks, a maintenance period of 5 weeks, followed by a washout period 
of 1 week
 
. For the YGTSS, input from the caregiver/adult is required. 
For both the TS-PGII and
, input from the caregiver/adult is permitted. For all other scales, 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. 


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Questions should be directed to the child, but the caregiver/adult should be encouraged to add relevant information. 
It should be noted that the CDI-2 has individual parent and child questionnaires.
Patients who complete the study may be eligible to begin participation in an open-label safety extension study 
TV50717-CNS-30047 after the end of the washout period. At the week 13 visit, patients may choose to enter 
Study TV50717-CNS-30047 (on that day), or they will have an additional week to make a decision and return for 
day 1. Patients not participating in Study TV50717-CNS-30047 will have a follow-up telephone contact to evaluate 
safety 1 week after the end of the washout period (2 weeks after their last dose of IMP). 
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. 
At the discretion of the investigator, the screening visit may be divided into 2 visits if the visit length is felt to be too 
burdensome for the patient. If the screening visit is divided into 2 visits, the blood sample should be obtained during 
the first of the 2 visits. Patients who have received comprehensive behavioral intervention for tics (CBIT) for TS or 
cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) may participate in this study as long 
as therapy was completed at least 4 weeks prior to screening. 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 subinvestigators who will be administering the YGTSS from 
screening through the end of study visit must undergo and pass a Rater Certification Program which will be 
provided separately from this protocol. Every effort must be made to ensure that the same certified rater administers 
the YGTSS to a specific patient at all visits, especially at the baseline and week 12/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.
Titration period (7 weeks): Patients who remain eligible for participation in the study will be randomized at the 
baseline visit (day 1), and that evening (ie, after the study visit) will receive 6 mg of blinded IMP with food. Tablets 
should be taken with food (eg, a snack) and should not be taken on an empty stomach. The titration scheme and 
maximum dose will be determined by body weight and CYP2D6 impairment status at baseline, as shown in the 
tables below. Patients and their caregiver/adult will interact weekly with the clinical research staff, either by 
telephone contact or clinic visit from week 1 through week 7 of the titration period, in order to evaluate safety and 
establish a dose of IMP that optimally reduces tics and is well tolerated (optimal dose). Safety evaluations during 
titration include assessment of vital signs, monitoring for adverse events and concomitant medications, 12-lead 
ECGs, and rating scales for depression and suicidality.
In-person (in-clinic) study visits will be scheduled at weeks 2, 4, and 6, and telephone contacts will be scheduled for 
weeks 1, 3, 5, and 7 in order to assess tic severity and adverse events. The dose of the IMP should be increased on a 
weekly basis until one of the following criteria is met:

The investigator determines there has been a clinically meaningful reduction in tics as indicated by a 
sustained reduction in the TS-CGI.

The patient experiences a protocol-defined “clinically significant” adverse event (defined as an adverse 
event that is related to study medication and is either moderate or severe in intensity or meets the 
criteria for a serious adverse event).

The maximum allowable dose is reached based on the patient’s weight and CYP2D6 impairment status 
at baseline.


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Although dose adjustments can be made up to and including the week 7 telephone call, if a stable dose is reached 
before then, the patient should continue on that dose (ie, the dose should not be increased further) for the remainder 
of the titration period and throughout maintenance dosing, unless there is a change in symptoms during the titration 
period. If a patient experiences a “clinically significant” adverse event attributable to the IMP, the investigator will 
determine if a dose reduction or suspension is necessary. 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 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. At the end of the titration period, the patient’s dose will be established for the 
maintenance period.
Maintenance period (5 weeks): Patients will continue to receive their maintenance dose over the next 5 weeks, 
although dose reductions for adverse events are allowed. Patients will return to the clinic at weeks 9 and 12 for 
assessments of safety and efficacy. At week 12, patients will undergo a complete evaluation, including physical and 
neurological examination, safety laboratory testing, and 12-lead ECG, CDI-2, and C-SSRS assessments, as well as 
the YGTSS, TS-CGI, TS-PGII, 
, 
, 
 and C&A-GTS-QOL. In addition, patients 
will undergo pharmacokinetic sampling at week 12.
Washout period and follow-up: All patients will discontinue IMP at the week 12 visit and will return 1 week later 
for evaluation of safety and tic reduction (week 13). Patients who complete the study may be eligible to begin 
participation in the open-label safety extension study, TV50717-CNS-30047, at that time. 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. At the week 13 
visit, patients may choose to enter Study TV50717-CNS-30047 (on that day), or they will have an additional week 
to make a decision and return for day 1. Patients not participating in Study TV50717-CNS-30047 will have a 
follow-up telephone contact for safety evaluation 1 week after the end of the washout period (2 weeks after their last 
dose of IMP [week 14]).
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 (Study TV50717-CNS-30047) may begin/resume tic therapy 
medication after the first week of the washout period. 
Method of Blinding and Randomization:
Patients will be randomly assigned to receive treatment with TEV-50717 or matching placebo in a 1:1 ratio using an 
IRT. Patients will be stratified by age at baseline (6 to 11 years, 12 to 16 years). 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. 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.
IMP Dose, Mode of Administration, and Administration Rate: 
IMP will be administered as oral tablets at a starting dose of 6 mg. Titration schemes based on body weight at 
baseline are shown in the tables below. The maximum daily dose is determined by body weight and CYP2D6 
impairment status at baseline (see the table below). Although dose adjustments can be made up to and including the 


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week 7 telephone call, if a stable dose is reached before then, the patient should continue taking that dose for the 
remainder of the titration period and throughout maintenance dosing. If a patient experiences a “clinically 
significant” adverse event that is attributed to the IMP, the investigator will determine if a dose reduction or 
suspension is necessary. At the end of the titration period, the patient’s dose will be established for the maintenance 
period. If a patient experiences an adverse event during the maintenance period and the investigator believes a dose 
reduction in warranted, the dose may be reduced.
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 blister packs. The placebo tablets and 
packaging will match those for TEV-50717. 
IMP will be administered as follows:

IMP should be swallowed whole and taken with food. Tablets should be taken with food (eg, a snack) 
and should not be taken on an empty stomach.

Dosing will be based on body weight and CYP2D6 impairment status at the baseline visit, as shown in 
the tables below.

The starting dose is 6 mg in all patients. Daily doses will be administered twice daily, approximately 
8 to 10 hours apart during the day. A minimum of 6 hours should elapse between doses. If a patient 
misses a dose, and it is within 6 hours of their next dose, the missed dose should be skipped.

After week 1, dose increases may not occur more frequently than every 5 days.

Dose reductions, if required, should be in increments of 6 mg. If more than 1 dose reduction is 
required for an adverse event, the medical monitor must be notified.

During the titration period, the dose of IMP should be adjusted weekly according to the table below 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.
Maximum Daily Dose of IMP by Study Day and Weight Category at Baseline
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP 
impairment 
status
Not 
impaired
Impaired
Not 
impaired
Impaired
Not impaired
Impaired
Day 1-7
6 mg
6 mg
6 mg
6 mg
6 mg (Days 1 
and 2)
12 mgb
6 mg (Days 1 
and 2)
12 mgb
Day 8-14
12 mg
12 mg
12 mg
12 mg
18 mg
18 mg
Day 15-21
18 mg
18 mg
18 mg
18 mg
24 mg
24 mg
Day 22-28
18 mg
18 mg
24 mg
24 mg
30 mg
30 mg
Day 29-35
24 mg
18 mg
30 mg
24 mg
36 mg
36 mg
Day 36-42
24 mg
18 mg
36 mg
24 mg
42 mg
36 mg
Day 43-49
30 mg
18 mg
42 mg
24 mg
48 mg
36 mg
a Administration of a given dose will take place throughout the days indicated. The new dose starts the morning 
after the telephone contact or the morning after the clinic visit (ie, Days 8, 15, 22, 29, 36, and 43), as applicable.
b Patients will receive 6 mg on days 1 and 2, and 12 mg starting on day 3.


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bid=twice a day; CYP=cytochrome P450; IMP=investigational medicinal product.
Note: CYP impaired=patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 poor 
metabolizer. The investigator, in consultation with the patient and caregiver/adult, will determine if a dose increase 
is warranted to achieve optimal tic reduction.
IMP: TEV-50717 
Reference Therapy: Placebo
Duration of Patient Participation: This study will consist of up to a 31-day screening period, a 12-week 
double-blind treatment period, and a 1-week washout period. Patients who complete the study may be eligible to 
begin participation in an open-label safety extension study TV50717-CNS-30047 after the end of the washout 
period. Patients not participating in Study TV50717-CNS-30047 will have a follow-up telephone contact to evaluate 
safety 1 week after the end of the washout period (2 weeks after their last dose of IMP). Patients are expected to 
participate in this study for its entire duration, which is a minimum of 14 weeks.
Inclusion Criteria: Patients may be enrolled in the study 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 provide 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 L.
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 L.
Exclusion Criteria: Patients will not be 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. 


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c.
Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
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 screening.
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 clinically significant OCD at baseline that, in the opinion of the investigator, is the primary 
cause of impairment.
i.
Patient has received CBIT for TS or CBT for OCD within 4 weeks of screening.
j.
Patient has received any of the following concomitant medications for tics within the 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 A), 
metoclopramide, levodopa, and dopamine agonists 
Note: Use of stimulant medications, including amphetamine, methylphenidate, and 
lisdexamfetamine, is allowed if primary use is for the treatment of ADHD, dosing has been stable 
for at least 2 weeks before screening, 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 Tourette syndrome) if the dosing has been stable for at least 4 weeks before screening and no 
changes to dose or frequency are anticipated during the course of the study. 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. 
k.
Patient has received treatment with deep brain stimulation, or transmagnetic stimulation, or 
transcranial direct current stimulation for reduction of tics within 4 weeks of the screening visit. 
l.
Patient has an unstable or serious medical illness at screening or baseline


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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 >480msec (with right bundle branch block) on 12-lead 
ECG at screening, OR requires treatment with drugs known to prolong the QT interval (see 
Appendix A, Table 6 for a complete list of prohibited QT-prolonging drugs).
n.
Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or 
uncompensated heart failure.
o.
Patient has evidence of hepatic impairment, as indicated by:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of 
the normal range (ULN) at screening

alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
Note: Patients with Gilbert’s Syndrome are eligible to participate if approved by the medical 
monitor. 
Note: Patients with abnormalities in 2 or more of the following clinical laboratory parameters 
must be approved for enrollment by the medical monitor: AST, ALT, ALP, and Tbil. 
p.
Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine 
>1.5 × ULN at screening. 
q.
Patient has received a monoamine oxidase inhibitor within 14 days of the baseline visit.
r.
Patient has a known allergy to any of the components of the IMP.
s.
Patient has participated in an investigational drug or device study and received IMP/intervention 
within 30 days or 5 drug half-lives of baseline, whichever is longer.
t.
The patient is a pregnant or lactating female or plans to become pregnant during the study.
u.
Patient has a history of or acknowledges alcohol-related disorder in the previous 12 months, as defined 
in the DSM-V™.
v.
Patient has a positive urine drug screen test result or is unable to refrain from substance abuse 
throughout the study.
w.
Patient has a DSM diagnosis based on the MINI Kid Inventory modules performed at screening that, in 
the opinion of the investigator, makes the patient unsuitable for the study.
Measures and Time Points: 
Primary Efficacy Measures and Time Points: YGTSS (to calculate TTS): Screening; baseline; and weeks 2, 
4, 6, 9, 12, and 13
Key Secondary Efficacy Measures and Time Points: 
1.
TS-CGI: baseline and weeks 2, 4, 6, 9, 12, and 13
2.
TS-PGII: baseline and weeks 2, 4, 6, 9, 12, and 13
3.
C&A-GTS-QOL ADL subscale: baseline, week 6, and week 12
Exploratory Measures and Time Points: 
 
 


Placebo-Controlled Study–Tourette Syndrome
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Safety Measures and Time Points: 

adverse events and concomitant medications: from the signing of the informed consent/assent, 
depending on the child’s age, as appropriate, through follow-up, inclusive of all visits and telephone 
contacts

physical examination: screening and week 12

neurological examination: screening and week 12

vital signs: screening; baseline; and weeks 2, 4, 6, 9, 12, and 13 
Note: orthostatic blood pressure and pulse at baseline and weeks 4 and 12

MINI Kid: screening

Children’s C-SSRS

Baseline/screening scale: screening

Since Last Visit scale: baseline and weeks 2, 4, 6, 9, 12, and 13

CDI-2 (Parent and Self-Report versions): screening; baseline; and weeks 2, 4, 6, 9, 12, and 13

12-lead ECG: screening; baseline; and weeks 4, 6, and 12

clinical laboratory tests (serum chemistry, hematology, and urinalysis): screening and week 12

pregnancy testing: screening, baseline, and weeks 4 and 12

drug screen: Screening and week 12
Pharmacokinetic Measures and Time Points:
Blood samples will be obtained for the measurement of plasma concentrations of TEV-50717 
(deutetrabenazine), α-HTBZ, β-HTBZ, and other metabolites, as needed. Blood sampling for pharmacokinetic 
analysis will be performed at the week 12 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 before the week 12 visit. The 
date and time of the last dose of study medication before the week 12 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 12, 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 metabolites will be pooled with previous data and incorporated 
into a population pharmacokinetic analysis. The population pharmacokinetic 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. Exposure-response (eg, 
pharmacodynamic [PD] and/or safety endpoints) may be assessed if the appropriate data are available.
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.


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Allowed and Disallowed Medications Before and During the Study: 
See Appendix A for details of allowed and disallowed medications. 
Statistical Considerations:
Sample Size Rationale: 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 12 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 12. 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
(5 levels: Weeks 2, 4, 6, 9, and 12), and the treatment group by week interaction. The baseline TTS, region, and age 
group at baseline 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 12 will be 
compared (the active 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 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. The change in the 
TS-CGI (1) and C&A-GTS-QOL ADL subscale (3) scores from baseline to week 12 will be summarized and 
analyzed in the same fashion as the primary analysis, with the exception that the baseline value of the given 
endpoint will be included as the covariate. TS-PGII (2) will be analyzed using a Cochran-Mantel-Haenszel row 
mean score test with a modified ridit score that controls for age group.
Exploratory Analyses: 
 
 
 
 
 
 
 
 
 


Placebo-Controlled Study–Tourette Syndrome
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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 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 active metabolites and will be analyzed using population pharmacokinetic techniques. 
Analysis methods will be detailed in a separate population pharmacokinetic analysis plan. Exploratory 
pharmacokinetic/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.
Observed values in the C-SSRS and observed values and changes from baseline in the CDI-2 (Parent and Self-report
versions) will be presented by treatment group for all patients.


Placebo-Controlled Study–Tourette Syndrome
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..................................7
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................8
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................30
1.
BACKGROUND INFORMATION...........................................................................33
1.1.
Introduction.................................................................................................................33
1.2.
Name and Description of IMP....................................................................................34
1.3.
Findings from Nonclinical and Clinical Studies.........................................................34
1.3.1.
Nonclinical Studies.....................................................................................................34
1.3.1.1.
Nonclinical Pharmacology..........................................................................................34
1.3.1.2.
Nonclinical Pharmacokinetics and Drug Metabolism................................................35
1.3.1.3.
Toxicology..................................................................................................................35
1.3.2.
Clinical Studies...........................................................................................................36
1.3.2.1.
Clinical Pharmacology Studies...................................................................................36
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................37
1.3.2.3.
Pharmacometrics Analysis of TEV-50717 Active Metabolites to Support 
Dose Selection and Pharmacokinetic Characterization in a Pediatric 
Population...................................................................................................................37
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................38
1.5.
Selection of Drugs and Dosages.................................................................................38
1.5.1.
Justification for Dosage of Active Drug.....................................................................38
1.5.2.
Justification for Use of Placebo..................................................................................38
1.6.
Compliance Statement................................................................................................39
1.7.
Study Population and Justification .............................................................................39
1.8.
Location and Study Duration......................................................................................39
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................40
2.1.
Purpose of the Study...................................................................................................40


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2.2.
Study Objectives.........................................................................................................40
2.2.1.
Primary Objective.......................................................................................................40
2.2.2.
Secondary Objective...................................................................................................40
2.3.
Study Endpoints..........................................................................................................40
2.3.1.
Primary Efficacy Endpoint .........................................................................................40
2.3.2.
Key Secondary Efficacy Endpoints............................................................................40
2.3.3.
Exploratory Endpoints................................................................................................40
2.3.4.
Safety Endpoints.........................................................................................................41
2.3.5.
Pharmacokinetic Endpoint..........................................................................................41
3.
STUDY DESIGN .......................................................................................................42
3.1.
General Design and Study Schema.............................................................................42
3.1.1.
Overall Design and Screening Period.........................................................................42
3.1.2.
Screening Period.........................................................................................................42
3.1.3.
Titration Period...........................................................................................................43
3.1.4.
Maintenance Period ....................................................................................................44
3.1.5.
Washout Period and Follow-up ..................................................................................44
3.2.
Justification for Study Design ....................................................................................45
3.3.
Primary and Secondary Efficacy Measures and Time Points.....................................46
3.3.1.
Primary Efficacy Measure and Time Points...............................................................46
3.3.2.
Key Secondary Efficacy Measures and Time Points..................................................46
3.3.3.
Exploratory Measures and Time Points......................................................................46
3.4.
Safety Measures and Time Points...............................................................................46
3.5.
Pharmacokinetic Measures and Time Points..............................................................47
3.6.
Randomization and Blinding......................................................................................47
3.7.
Maintenance of Randomization and Blinding............................................................48
3.7.1.
Randomization............................................................................................................48
3.7.2.
Blinding/Unblinding...................................................................................................48
3.7.3.
Independent Data Monitoring Committee..................................................................49
3.8.
Drugs Used in the Study.............................................................................................49
3.8.1.
IMP .............................................................................................................................49
3.8.2.
Placebo........................................................................................................................50
3.9.
Drug Supply and Accountability ................................................................................50
3.9.1.
Drug Storage and Security..........................................................................................50


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3.9.2.
Drug Accountability ...................................................................................................50
3.10.
Duration of Patient Participation and Justification.....................................................50
3.11.
Stopping Rules and Discontinuation Criteria .............................................................50
3.12.
Source Data Recorded on the Case Report Form.......................................................51
3.13.
Study Procedures ........................................................................................................51
3.13.1.
Procedures for Screening and Enrollment..................................................................56
3.13.1.1.
YGTSS Rater Certification.........................................................................................57
3.13.2.
Procedures Before IMP Treatment (Baseline/Day 1).................................................57
3.13.3.
Procedures During IMP Treatment.............................................................................59
3.13.3.1.
Titration Period (Baseline/ Day 1 Through 7)............................................................59
3.13.3.2.
Maintenance Period ....................................................................................................60
3.13.4.
Procedures After IMP Treatment................................................................................62
3.13.4.1.
Week 13......................................................................................................................63
3.13.4.2.
Week 14......................................................................................................................64
3.13.5.
Unscheduled Visits .....................................................................................................64
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................66
4.1.
Patient Inclusion Criteria ............................................................................................66
4.2.
Patient Exclusion Criteria...........................................................................................66
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................69
4.4.
Withdrawal Criteria and Procedures...........................................................................69
5.
TREATMENT OF PATIENTS..................................................................................71
5.1.
Drugs Administered During the Study .......................................................................71
5.2.
Restrictions .................................................................................................................72
5.3.
Prior and Concomitant Therapy or Medication..........................................................73
5.4.
Procedures for Monitoring Patient Compliance .........................................................73
5.5.
Dose Reduction and Temporary IMP Discontinuation ..............................................74
5.6.
Total Blood Volume ...................................................................................................74
6.
ASSESSMENT OF EFFICACY ................................................................................76
6.1.
Primary Efficacy Measure and Justification...............................................................76
6.2.
Key Secondary Efficacy and Exploratory Measures..................................................76
6.2.1.
Tourette Syndrome–Clinical Global Impression........................................................76
6.2.2.
Tourette Syndrome-Patient Global Impression of Impact..........................................76
6.2.3.
Tourette Syndrome-Patient Global Impression of Severity........................................77


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6.2.4.
Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Scale ...........77
6.2.5.
Yale Global Tic Severity Scale...................................................................................77
6.2.6.
.....................................................................................77
6.2.7.
Children’s Yale-Brown Obsessive-Compulsive Scale...............................................78
7.
ASSESSMENT OF SAFETY.....................................................................................79
7.1.
Adverse Events ...........................................................................................................79
7.1.1.
Definition of an Adverse Event ..................................................................................79
7.1.2.
Recording and Reporting Adverse Events..................................................................80
7.1.3.
Severity of an Adverse Event .....................................................................................80
7.1.4.
Relationship of an Adverse Event to the IMP ............................................................81
7.1.5.
Serious Adverse Events..............................................................................................81
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................82
7.1.5.2.
Expectedness...............................................................................................................82
7.1.5.3.
Reporting a Serious Adverse Event............................................................................83
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................85
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................85
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................85
7.2.
Psychometric Rating Scales........................................................................................85
7.2.1.
Mini International Neuropsychiatric Interview for Children and Adolescents ..........86
7.2.2.
Columbia-Suicide Severity Rating Scale....................................................................86
7.2.3.
Children’s Depression Inventory, Second Edition .....................................................87
7.3.
Pregnancy ...................................................................................................................87
7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Product.......................................................................................................88
7.5.
Clinical Laboratory Tests ...........................................................................................89
7.5.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................89
7.5.2.
Other Clinical Laboratory Tests .................................................................................90
7.5.2.1.
Human Chorionic Gonadotrophin Test ......................................................................90
7.5.2.2.
Urine Drug Screen ......................................................................................................90
7.5.3.
Cytochrome P450 2D6 Genotyping............................................................................91
7.6.
Vital Signs ..................................................................................................................91
7.7.
Electrocardiography....................................................................................................91
7.8.
Physical Examinations................................................................................................92


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7.9.
Assessment of Suicidality...........................................................................................92
7.10.
Neurological Examinations ........................................................................................93
7.11.
Concomitant Therapy or Medication..........................................................................93
7.12.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............93
8.
ASSESSMENT OF PHARMACOKINETICS AND SCREENING 
ASSESSMENTS.........................................................................................................94
8.1.
Pharmacokinetic Assessment......................................................................................94
8.2.
Pharmacodynamics Assessment.................................................................................94
8.3.
Pharmacogenetics .......................................................................................................94
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics....................................................................94
9.
STATISTICS ..............................................................................................................96
9.1.
Sample Size and Power Considerations .....................................................................96
9.2.
Analysis Sets...............................................................................................................96
9.2.1.
Intent-to-Treat Analysis Set........................................................................................96
9.2.2.
Safety Analysis Set.....................................................................................................96
9.2.3.
Modified Intent-to-Treat Analysis Set........................................................................96
9.2.4.
Per-Protocol Analysis Set...........................................................................................96
9.3.
Data Handling Conventions........................................................................................97
9.4.
Study Population.........................................................................................................97
9.4.1.
Patient Disposition......................................................................................................97
9.4.2.
Demographic and Baseline Characteristics ................................................................97
9.5.
Efficacy Analysis........................................................................................................97
9.5.1.
Primary Endpoint........................................................................................................97
9.5.2.
Key Secondary Endpoints...........................................................................................97
9.5.3.
Exploratory Endpoints................................................................................................98
9.5.4.
Planned Method of Analysis.......................................................................................98
9.5.4.1.
Primary Efficacy Analysis..........................................................................................98
9.5.4.2.
Sensitivity Analysis ....................................................................................................99
9.5.4.3.
Key Secondary Efficacy Analyses..............................................................................99
9.5.4.4.
Exploratory Analyses..................................................................................................99
9.6.
Multiple Comparisons and Multiplicity....................................................................100
9.7.
Safety Endpoints and Analysis .................................................................................100
9.7.1.
Safety Endpoints.......................................................................................................100


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9.7.2.
Safety Analysis .........................................................................................................100
9.8.
Pharmacokinetic Analysis ........................................................................................101
9.9.
Planned Interim Analysis..........................................................................................101
9.10.
Reporting Deviations from the Statistical Plan ........................................................101
10.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS.............................102
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................103
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................103
11.1.1.
Protocol Amendments ..............................................................................................103
11.1.2.
Protocol Violations...................................................................................................103
11.2.
Information to Study Personnel................................................................................103
11.3.
Study Monitoring......................................................................................................104
11.4.
Clinical Product Complaints.....................................................................................104
11.4.1.
Product Complaint Information Needed from the Investigational Center................105
11.4.2.
Handling of IMP at the Investigational Center.........................................................105
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................106
11.4.4.
Documenting a Product Complaint ..........................................................................106
11.5.
Audit and Inspection.................................................................................................106
12.
ETHICS ....................................................................................................................107
12.1.
Informed Consent/Assent .........................................................................................107
12.2.
Competent Authorities and Independent Ethics Committees/Institutional 
Review Boards..........................................................................................................107
12.3.
Confidentiality Regarding Study Patients ................................................................107
12.4.
Declaration of the End of Clinical Study..................................................................108
12.5.
Registration of the Clinical Study.............................................................................108
13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING .................................................................................................................109
13.1.
Data Collection.........................................................................................................109
13.2.
Data Quality Control.................................................................................................109
13.3.
Archiving of Case Report Forms and Source Documents........................................110
13.3.1.
Sponsor Responsibilities...........................................................................................110
13.3.2.
Investigator Responsibilities.....................................................................................110
14.
FINANCING AND INSURANCE...........................................................................112


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15.
REPORTING AND PUBLICATION OF RESULTS..............................................113
16.
REFERENCES .........................................................................................................114
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................116
17.1.
Amendment 01 Dated 22 June 2017.........................................................................116
17.2.
Amendment 02 Dated 03 October 2017 ...................................................................136
17.3.
Amendment 03 Dated 06 November 2017 ...............................................................164
17.4.
Amendment 04 Dated 13 September 2018...............................................................173
17.5.
Amendment 05 Dated 25 March 2019......................................................................195
APPENDIX A.
ALLOWED AND DISALLOWED MEDICATIONS....................................205
APPENDIX B.
DISTRIBUTION OF AUC BY WEIGHT CATEGORIES AND 
CYP2D6 STATUS....................................................................................................209
APPENDIX C.
MINI INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW 
FOR CHILDREN AND ADOLESCENTS ..............................................................210
APPENDIX D.
CHILDREN’S DEPRESSION INVENTORY, SECOND EDITION, 
PARENT AND SELF-REPORT PROFILES...........................................................228
APPENDIX E.
CHILDREN’S COLUMBIA-SUICIDE SEVERITY RATING SCALE ........236
APPENDIX F.
CHILDREN’S YALE-BROWN OBSESSIVE-COMPULSIVE SCALE .......242
APPENDIX G.
YALE GLOBAL TIC SEVERITY SCALE....................................................255
APPENDIX H.
...............264
APPENDIX I.
 
.....................................................................................265
APPENDIX J.
.........................................................267
APPENDIX K.
 
 
..............................................................................................................268
APPENDIX L.
 
...................................................................................


Placebo-Controlled Study–Tourette Syndrome
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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................52
Table 2:
Maximum Daily Dose of IMP by Study Day and Weight Category at 
Baseline.......................................................................................................................72
Table 3:
Blood Volumes...........................................................................................................75
Table 4:
Clinical Laboratory Tests ...........................................................................................90
Table 5:
Allowed Medications................................................................................................205
Table 6:
Prohibited QTc-Prolonging Drugs............................................................................207
Table 7:
Prohibited Antipsychotic Drugs ...............................................................................207
Table 8:
Other Prohibited Drugs.............................................................................................208


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LIST OF FIGURES
Figure 1:
Overall Study Schema ................................................................................................45
Figure 2:
Distribution of AUC of Total (α+β)-HTBZ for Selected Doses Based on 
Weight Categories ....................................................................................................209


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
21CFR
Title 21 Code of Federal Regulations
ADHD
Attention Deficit Hyperactivity Disorder
α-HTBZ
alpha-dihydrotetrabenazine
ADL
activities of daily living
ALP
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
AST
aspartate aminotransferase (SGOT)
AUC
area under the curve
β-HCG
beta-human chorionic gonadotropin
β-HTBZ
beta-dihydrotetrabenazine
bid
twice a day
BL
baseline visit
BP
blood pressure
BUN
blood urea nitrogen
CBIT
comprehensive behavioral intervention for tics
CBT
cognitive behavioral therapy
CDI-2
Children’s Depression Inventory, Second Edition
CDMS
clinical data management system
CNS
central nervous system
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
CST
Clinical Surveillance and Training
CYP
cytochrome P450
CYP2D6
cytochrome P450 2D6
DSM-V™
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition


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Abbreviation or 
Specialist Term
Explanation
ECG
electrocardiogram
ePRO
electronic patient-reported outcome
ET
early termination visit
FDA
Food and Drug Administration [United States]
GCP
Good Clinical Practice
GPSP
Global Patient Safety and Pharmacovigilance
C&A-GTS-QOL
Child and Adolescent Gilles de la Tourette Syndrome–Quality of Life
HD
Huntington disease
IB
Investigator’s Brochure
ICH
International Council for Harmonisation (of Technical Requirements for 
Registration of Pharmaceuticals for Human Use)
IDMC
Independent Data Monitoring Committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IMP
investigational medicinal product
IND
Investigational New Drug [Application]
IRT
Interactive Response Technology
ITT
intent-to-treat
LDH
lactate dehydrogenase
LSO
local safety officer
MA
Marketing Authorization
MAOI
monoamine oxidase inhibitor
MINI Kid
Mini International Neuropsychiatric Interview For Children and Adolescents 
(version 6.0)
mITT
Modified Intent-to-Treat
NA
not available
NDA
New Drug Application
NOAEL
no-observed-adverse-effect level
OCD
obsessive-compulsive disorder
PD
pharmacodynamic
PGx
pharmacogenetics


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Abbreviation or 
Specialist Term
Explanation
PND
postnatal day
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RBC
red blood cell
SD-809/TEV-50717
deutetrabenazine
SLV
Since Last Visit
SOP
Standard Operating Procedure
SUSAR
suspected unexpected serious adverse reaction
Tbil
total bilirubin
TD
tardive dyskinesia
TEAE
treatment-emergent adverse event
TS
Tourette syndrome
TS-CGI
Tourette Syndrome-Clinical Global Impression
TS-PGII
Tourette Syndrome-Patient Global Impression of Impact
TTS
Total Tic Score
U
unscheduled visit
UDS
urine drug screen
ULN
upper limit of the normal range
USA
United States of America
VAS
visual analog scale
VMAT2
vesicular monoamine transporter 2
WBC
white blood cell
YGTSS
Yale Global Tic Severity Scale


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1.
BACKGROUND INFORMATION
1.1.
Introduction 
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and 
phonic tics that frequently co-occurs with a variety of behavioral and psychiatric problems 
(Jankovic 2001, Jankovic and Kurlan 2011). Studies have suggested that up to 7% of school 
children fulfill the diagnostic criteria for TS (Kurlan et al 2002). Tics are classified as either 
simple or complex; simple motor tics include eye blinks, shoulder shrugs, while simple vocal tics 
include grunting, coughing and sniffing. Complex motor tics include touching/tapping and 
walking in patterns, while complex vocal tics include echolalia (repeating another’s speech) and 
coprolalia (shouting obscenities or profanities) (Jankovic 2001, Shaw and Coffey 2014). TS was 
thought to be a psychogenic disorder until improvement with neuroleptics was first observed in 
the 1960s, leading to the theory of central dopaminergic hyperactivity as a possible mechanism 
of tics associated with TS. When the symptoms impair function, most physicians utilize alpha 
adrenergic drugs (guanfacine, clonidine), typical neuroleptics (haloperidol, pimozide, 
fluphenazine), or atypical neuroleptics (olanzapine, ziprasidone, aripiprazole) to control tics 
(Gilbert and Jankovic 2014, Wijemanne et al 2014). In the United States of America (USA), 
haloperidol and pimozide are approved for the treatment of tics associated with TS, while
aripiprazole carries a broader indication of “for the treatment of TS”. Neuroleptics have the 
potential for serious adverse effects, including tardive dyskinesia (TD), which typically 
manifests as an irreversible orofacial stereotypy, and other forms of hyperkinetic movement 
disorder (Waln and Jankovic 2013). Up to 25% of adults chronically treated with dopamine 
receptor antagonists (neuroleptics; including the so-called “atypical” neuroleptics, such as 
aripiprazole) eventually develop TD (Jankovic 1995, Pasricha et al 2006, Peña et al 2011). 
Although elderly individuals, especially women, are particularly susceptible to developing TD, 
this iatrogenic condition may also rarely occur in children (Mejia and Jankovic 2010). 
Tetrabenazine, which depletes dopamine presynaptically, has been shown to be effective in 
treating the tics associated with TS (Jain et al 2006, Jankovic 2015, Jankovic and Beach 1997,
Kenney et al 2007, Paleacu et al 2004, Porta et al 2008), but has not been documented to cause 
TD in clinical use.
While generally effective in reducing the tics of TS, tetrabenazine is associated with frequent 
adverse events, including somnolence, nausea, depression, insomnia, and parkinsonism, that may 
limit its utility. Moreover, tetrabenazine is an immediate-release formulation with the following 
limitations: (1) adverse events of tetrabenazine, such as somnolence, akathisia, and anxiety, are 
often associated with peak concentration after dosing; (2) the active metabolites have short 
half-lives, with the attendant requirement to dose the immediate-release formulation frequently; 
and (3) the active metabolites alpha-dihydrotetrabenazine (α-HTBZ) and beta-
dihydrotetrabenazine (β-HTBZ) are either primarily (α) or exclusively (β) metabolized by 
cytochrome P450 2D6 (CYP2D6). Polymorphisms in the CYP2D6 gene necessitate genotyping 
to prevent poor metabolizers from experiencing significantly greater exposure to the active drug 
moiety than extensive metabolizers (Mehanna et al 2013).
To address the limitations of commercial tetrabenazine (Xenazine®), Auspex, a wholly owned 
subsidiary of Teva Pharmaceutical Products R&D, Inc, 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 can 
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 (SD-809-C-17). Results of this study are 
summarized in Section 1.3.2.2 and support further development of TEV-50717 for treatment of 
tics associated with TS.
TEV-50717 was granted breakthrough status for treatment of TD by the Food and Drug 
Administration (FDA) based on the results of Study SD-809-C-18, and NDA 209885 was 
granted priority review status. TEV-50717 was approved for the treatment of chorea associated 
with HD on 03 April 2017 and for the treatment of chorea associated with TD on 
30 August 2017.
1.2.
Name and Description of IMP
TEV-50717 (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor with 
the chemical name (RR, SS)-1,3,4,6,7,11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-
2H-benzo[a]quinolizin-2-one. TEV-50717 is provided for this study as 6-mg, 9-mg, 12-mg, 
15-mg, and 18-mg oral tablets, all of which are identical in size, shape, and color (white). The 
investigational medicinal product (IMP) will be supplied in 40-count blister packs.
A more detailed description of the product is given in Section 3.8. 
1.3.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the current Investigator’s Brochure (IB).
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 to 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 (CNS) pharmacological effects. In particular, the adverse event of 
catalepsy, a known response in rats to drugs which reduce CNS 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 were assessed in male and female 
juvenile rats from PND 25 to PND 70 with a recovery phase and postdosing reproductive 
assessment.
TEV-50717 produced no test-article-related effects on learning and memory functions, on 
histopathology assessments, on reproductive capacity (male and female fertility, estrus cyclicity), 
or on intrauterine survival of embryos from matings during recovery from test article 
administration. Adversely reduced body weight gain and adverse clinical observation of tremors 
and in-cage hyperactivity were all noted in previous studies with adult rats; these effects have not 
predicted adult clinical intolerance to TEV-50717. The highest dose level of M1 (50 mg/kg/day) 
produced no test article-related toxicities (clinical observations, changes in body weight gain, 
clinical pathology, histopathology, ophthalmology, and performance in learning and memory 
tests).


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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




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 
patients where population pharmacokinetic analyses were performed to extensively evaluate 
the pharmacokinetics and pharmacokinetics/pharmacodynamics relationship of TEV-50717. A 
summary of the clinical pharmacology findings is provided in the IB.
Pharmacometric analyses of the active metabolites of TEV-50717 based on the Phase 1 clinical 
pharmacology in healthy adult subjects 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 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 sequential 
pharmacokinetic sampling data obtained in healthy subjects 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 B). Population model parameters were re-estimated 
for the combined Phase 1 and adolescent data obtained from patients in Study SD-809-C-17. The 
model was used to simulate total (+β)-HTBZ exposures across a range of body weights 
corresponding to a pediatric and adolescent population according to the Centers for Disease 
Control growth charts. 
 
 
 
This analysis provides the basis for the dosing recommendations in Section 5.1. 
1.4.
Known and Potential Risks and Benefits to Human Patients 
Additional information regarding benefits and risks to patients may be found in the current IB 
and in the United States prescribing information for AUSTEDO™(deutetrabenazine).
1.5.
Selection of Drugs and Dosages 
A detailed description of IMP administration is presented in Section 5.1.
1.5.1.
Justification for Dosage of Active Drug
The dose ranges to be evaluated in this study, based on body weight and CYP2D6 impairment 
status at baseline, were selected on the basis of the safety, preliminary efficacy, and population 
pharmacokinetic data generated from Study SD-809-C-17 (Table 2). In this study, TEV-50717 
up to 18 mg twice daily (36 mg/day) was well tolerated and demonstrated clinically meaningful 
benefit in adolescents with TS-associated tics. The dosages proposed in the present study aim to 
match the exposure achieved in adults receiving up to 48 mg/day (24 mg twice daily), a level 
previously demonstrated to be efficacious, safe, and well tolerated in patients with 
HD-associated chorea. 
IMP will be titrated on a weekly basis for 7 weeks, based on investigator, patient, and 
parent/guardian assessments of tic reduction and adverse events. This dosing strategy is practical 
in a clinical setting and affords sufficient time between dose steps for efficacy and safety to be 
assessed. It is also consistent with the clinical application of tetrabenazine, another VMAT2 
inhibitor with accepted efficacy in this population. A 5-week maintenance period is sufficient for 
stable treatment to allow evaluation of safety and efficacy at the target dose.
1.5.2.
Justification for Use of Placebo
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. 


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Moreover, a placebo control is ideal for characterizing the efficacy and safety of an experimental 
agent in a new study population.
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Council for Harmonisation 
(ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6 and any applicable 
national and local laws and regulations (eg, Title 21 Code of Federal Regulations [21CFR] 
Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament and of the 
Council on the approximation of the laws, regulations, and administrative provisions of the 
Member States relating to the implementation of GCP in the conduct of clinical studies on 
medicinal products for human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMP as described in the IB.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the Independent Ethics Committee/Institutional Review Board 
(IEC/IRB), and with competent authorities.
1.7.
Study Population and Justification
The population to be studied includes children and adolescents, 6 through 16 years of age, with 
TS. Per selection 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.
1.8.
Location and Study Duration
This study is planned to be conducted in North America, Russia, and Europe, at approximately 
50 centers. It is expected to start in January 2018 and have a duration of approximately 
15 months. Additional centers will be added, if needed. Expected duration of the study may also 
be extended dependent on enrollment and other factors.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
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.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of this study is to evaluate the efficacy of TEV-50717 to reduce motor and 
phonic tics associated with TS.
2.2.2.
Secondary Objective
The secondary objective of the study is to evaluate the safety and tolerability of titration and 
maintenance therapy with TEV-50717.
2.3.
Study Endpoints 
2.3.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the change in the TTS of the YGTSS from baseline to week 12.
2.3.2.
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are as follows:
1.
Change in the TS-CGI score from baseline to week 12
2.
Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score 
from baseline to week 12
3.
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 12
2.3.3.
Exploratory Endpoints
Exploratory endpoints are as follows:
 
 


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2.3.4.
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)
2.3.5.
Pharmacokinetic Endpoint
The pharmacokinetics of the α- and β-HTBZ metabolites of TEV-50717, and other metabolites 
(as needed), will be explored based on sparse sampling at week 12.


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
3.1.1.
Overall Design and Screening Period
This is a Phase 2/3, randomized, double-blind, placebo-controlled, parallel group study in which 
patients with tics associated with TS will be invited to participate. Patients who qualify for the 
study will be centrally randomized in a 1:1 ratio (stratified by age at baseline [6 to 11 years, 12 to 
16 years]) to receive either TEV-50717 or placebo. Throughout the study, patients will interact 
regularly with investigative site personnel, in clinic and by telephone, for the evaluation of 
safety, tic severity, and behavioral status (in clinic only). The target dose for each patient 
receiving TEV-50717 will be based on body weight and 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 dose of IMP for each patient will be titrated to an optimal level 
followed by maintenance therapy at that dose. Investigators will be blinded to CYP status, with a 
dose cap for poor metabolizers prespecified by the IRT (Table 2). The overall treatment period 
will be 12 weeks in duration, including a titration period of 7 weeks, a maintenance period of 5 
weeks, followed by a washout period of 1 week.
 
 
 For the YGTSS, input from the caregiver/adult is 
required. For both the TS-PGII and 
 input from the caregiver/adult is permitted. For all 
other scales, 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. It should be 
noted that the CDI-2 has individual parent and child questionnaires.
Patients who complete the study may be eligible to begin participation in an open-label safety 
extension study (TV50717-CNS-30047) after the end of the washout period. At the week 13 
visit, patients may choose to enter Study TV50717-CNS-30047 (on that day), or they will have 
an additional week to make a decision and return for day 1. Patients not participating in 
Study TV50717-CNS-30047 will have a follow-up telephone contact to evaluate safety 1 week 
after the end of the washout period (2 weeks after their last dose of IMP).
3.1.2.
Screening Period
The screening period in this study is 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. 


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At the discretion of the investigator, the screening visit may be divided into 2 visits if the visit 
length is felt to be too burdensome for the patient. If the screening visit is divided into 2 visits, 
the blood sample should be obtained during the first of the 2 visits. Patients who have received 
comprehensive behavioral intervention for tics (CBIT) for TS or cognitive behavioral therapy 
(CBT) for obsessive-compulsive disorder (OCD) may participate in this study as long as therapy 
was completed at least 4 weeks prior to screening. Patients will return to the clinic on day 1 to 
perform baseline procedures and to reconfirm 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.)
3.1.3.
Titration Period
During the titration period (7 weeks), patients who remain eligible for participation in the study 
will be randomized in a 1:1 ratio stratified by age (6 to 11 years, 12 to 16 years) at the baseline 
visit (day 1), and that evening (ie, after the study visit) will receive 6 mg of blinded IMP with 
food. Tablets should be taken with food (eg, a snack) and should not be taken on an empty 
stomach. The titration scheme and maximum dose will be determined by body weight and 
CYP2D6 impairment status at baseline, as shown in Table 2. Patients and their caregiver/adult 
will interact weekly with the clinical research staff, either by telephone contact or clinic visit 
from week 1 through week 7 of the titration period, in order to evaluate safety and establish a 
dose of IMP that optimally reduces tics and is well tolerated (optimal dose). Safety evaluations 
during titration include assessment of vital signs, monitoring for adverse events and concomitant 
medications, 12-lead ECGs, and rating scales for depression and suicidality.
In-person (in-clinic) study visits will be scheduled at weeks 2, 4, and 6, and telephone contacts 
will be scheduled for weeks 1, 3, 5, and 7 in order to assess tic severity and adverse events. The
dose of the IMP should be increased on a weekly basis until one of the following criteria is met:

The investigator determines that there has been a clinically meaningful reduction in 
tics, as indicated by a sustained reduction in the TS-CGI

The patient experiences a protocol-defined “clinically significant” adverse event
(defined as an adverse event that is related to study medication and is either moderate 
or severe in intensity or meets the criteria for a serious adverse event).

The maximum allowable dose is reached, based on the patient’s weight and CYP2D6 
impairment status at baseline.
Although dose adjustments can be made up to and including the week 7 telephone call, if a stable 
dose is reached before then, the patient should continue on that dose (ie, the dose should not be 
increased further) for the remainder of the titration period and throughout maintenance dosing, 
unless there is a change in symptoms during the titration period. If a patient experiences a 
“clinically significant” adverse event attributable to the IMP, the investigator will determine if a 
dose reduction or suspension is necessary. 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 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 


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efficacy by the investigator, and information from rating scales. At the end of the titration period, 
the patient’s dose will be established for the maintenance period. 
3.1.4.
Maintenance Period
During the maintenance period (5 weeks), patients will continue to receive their maintenance 
dose, although dose reductions for adverse events are allowed. Patients will return to the clinic at 
weeks 9 and 12 for assessments of safety and efficacy. At week 12, patients will undergo a 
complete evaluation, including physical and neurological examination, safety laboratory testing, 
12-lead ECG, CDI-2, and C-SSRS assessments, as well as the YGTSS, TS-CGI, TS-PGII, 
, 
, and C&A-GTS-QOL. 
In addition, patients will undergo pharmacokinetic sampling at week 12. 
3.1.5.
Washout Period and Follow-up
All patients will discontinue IMP at the week 12 visit and will return 1 week later for evaluation 
of safety and tic reduction (week 13). Patients who complete the study may be eligible to begin 
participation in the open-label safety extension 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. At the week 13 visit, patients may 
choose to enter Study TV50717-CNS-30047 (on that day), or they will have an additional week 
to make a decision and return for day 1. Patients not participating in Study TV50717-CNS-30047 
will have a follow-up telephone contact to evaluate safety 1 week after the end of the washout 
period (2 weeks after their last dose of IMP).
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 (Study TV50717-CNS-30047) may 
begin/resume tic therapy medication after the first week of the washout period.
See Table 1 for study procedures and assessments.
See Figure 1 for study schema.


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Figure 1:
Overall Study Schema
a Maximum total daily dose for patients ≥40 kg is 48 mg/day (24 mg bid), 30 to <40 kg is 42 mg/day (21 mg bid), 
and 20 to <30 kg is 30 mg/day (15 mg bid). For those considered CYP2D6 impaired, maximum daily dose for 
patients ≥40 kg is 36 mg/day, 30 to <40 kg is 24 mg/day, and 20 to <30 kg is 18 mg/day (Table 2).
b If a stable dose is reached before the indicated time, the patient should continue taking that dose for the remainder 
of the titration period and throughout the maintenance therapy dosing.
c This is a telephone contact for safety evaluation, required only for patients who will not roll over into the 
open-label safety extension study TV50717-CNS-30047.
bid=twice a day; CYP=cytochrome P450; ET=early termination visit.
3.2.
Justification for Study Design
At the present time, effective treatment options for TS are suboptimal and limited. As a chronic 
condition impairing major life activities during childhood, such as occupational, social, and 
educational activities, TS presents an area of significant unmet medical need in the pediatric 
population.
Preliminary efficacy and safety data for TEV-50717 as a treatment for TS have been generated in 
an open-label, Phase 1b pilot study (Study SD-809-C-17). Results of Study SD-809-C-17 
supported further development of TEV-50717 as a treatment of TS.
Consequently, the standard placebo-controlled, double-blind study design (TEV-50717 versus 
placebo in a 1:1 ratio) was chosen for the next study (ie, this Phase 2/3 study) to determine 
whether IMP treatment results in a statistically significant effect on tics in patients with TS.
The justification for the choice of the comparator (placebo) is provided in Section 1.5.2, the 
choice of dosage is discussed in Section 1.5.1, while the justifications for the choice of the 
population and the inclusion and exclusion criteria for the study are provided in Section 1.7 and 
Section 4.3, respectively.


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3.3.
Primary and Secondary Efficacy Measures and Time Points
A description of the efficacy measures is provided in Section 6.
3.3.1.
Primary Efficacy Measure and Time Points
YGTSS (to calculate TTS): Screening; baseline; and weeks 2, 4, 6, 9, 12, and 13.
3.3.2.
Key Secondary Efficacy Measures and Time Points
1.
TS-CGI: baseline and weeks 2, 4, 6, 9, 12, and 13
2.
TS-PGII: baseline and weeks 2, 4, 6, 9, 12, and 13
3.
C&A-GTS-QOL ADL subscale: baseline, week 6, and week 12
3.3.3.
Exploratory Measures and Time Points
 
 
 
 
 
3.4.
Safety Measures and Time Points

adverse events and concomitant medications: from the signing of the informed 
consent/assent, depending on the child’s age, as appropriate, through follow-up, 
inclusive of all visits and telephone contacts

physical examination: screening and week 12

neurological examination: screening and week 12

vital signs: screening; baseline; and weeks 2, 4, 6, 9, 12, and 13
Note: orthostatic blood pressure (BP) and pulse at baseline and weeks 4 and 12

MINI Kid: screening 


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
Children’s C-SSRS

Baseline/screening scale: screening

Since Last Visit [SLV] scale: baseline and weeks 2, 4, 6, 9, 12, and 13

CDI-2 (Parent and Self-Report versions): screening; baseline; and weeks 2, 4, 6, 9, 
12, and 13

12-lead ECG: screening; baseline; and weeks 4, 6, and 12

clinical laboratory tests (serum chemistry, hematology, and urinalysis): screening and 
week 12

pregnancy testing: screening, baseline, and weeks 4 and 12

drug screen: screening and week 12
A description of the safety measures is provided in Section 7.
3.5.
Pharmacokinetic Measures and Time Points
Blood samples will be obtained for the measurement of plasma concentrations of TEV-50717 
(deutetrabenazine), α-HTBZ, β-HTBZ, and other metabolites, as needed. Blood sampling for 
pharmacokinetic analysis will be performed at the week 12 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.
A description of the pharmacokinetic measures is provided in Section 8.
3.6.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. Patients will be randomly assigned 
to receive treatment with TEV-50717 or matching placebo in a 1:1 ratio stratified by age at 
baseline (6 to 11 years, 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.
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. 


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The staff member at the investigational center who will dispense the IMP will not know the 
treatment given to each patient.
3.7.
Maintenance of Randomization and Blinding
3.7.1.
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.
3.7.2.
Blinding/Unblinding
Pharmacokinetic data may be assessed during the study. For patients who have pharmacokinetic 
sample bioanalysis and/or data analysis conducted, the individuals responsible for sample 
bioanalysis and other responsible personnel will know who received IMP and who received 
placebo during the study (of those patients only). 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 (ie, a 
dummy patient identifier will be linked to an individual patient’s concentration data). 
For information about personnel who may be aware of treatment assignments, see Section 3.6. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events.
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 
IMP 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 system. 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). 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. Treatment assignment 
should not be recorded in any study documents or source document.
In blinded studies, for adverse events that are defined as: suspected unexpected serious adverse 
reactions (SUSARs) (ie, reasonable possibility; see Section 7.1.4), 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 


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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.
3.7.3.
Independent Data Monitoring Committee
During the conduct of this study, an IDMC will review accumulating safety data on a regular 
basis to ensure the continuing safety of the study patients and review of any study conduct 
issues. 
The IDMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician. The IDMC will receive safety data 
periodically which will be presented by masked treatment groups. They will have the right to 
recommend modification of the study for safety reasons. 
IDMC sessions can be open or closed. During open sessions, representatives of the sponsor 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.
The conduct and specific details regarding the IDMC sessions and requests to unblind any 
blinded treatment assignment are outlined in the IDMC charter.
3.8.
Drugs Used in the Study
3.8.1.
IMP
The IMP is a matrix formulation and is designed as a gastro-erosional tablet to be administered 
with food and should not be taken on an empty stomach. The IMP is coated with a white 
polymer coating to aid in swallowing. TEV-50717 tablets have been manufactured according to 
current Good Manufacturing Practice regulations. TEV-50717 tablets are available in the 
following 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 blister packs. The placebo tablets and packaging 
will match those for TEV-50717. 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. 
A more detailed description of administration procedures is given in Section 5.1.


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3.8.2.
Placebo 
Placebo tablets match TEV-50717 tablets. The packaging will be the same as described for
TEV-50717 above.
A more detailed description of administration procedures is given in Section 5.1.
3.9.
Drug Supply and Accountability
3.9.1.
Drug Storage and Security
The IMP (TEV-50717 and 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.
3.9.2.
Drug Accountability
Each IMP shipment to the site will include a packing slip listing the contents of the shipment, 
drug return instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMP and other study materials from 
the sponsor are correctly received, recorded, handled and stored safely and properly in 
accordance with the local regulations, and used in accordance with this protocol. 
A record of IMP accountability (ie, IMP and other materials received, used, retained, returned, or 
destroyed) must be prepared and signed by the principal investigator or designee, with an 
account given for any discrepancies. Empty, partially used, and unused IMP will be disposed of, 
as agreed with the sponsor/development partner.
3.10.
Duration of Patient Participation and Justification
This study will consist of up to a 31-day screening period, a 12-week double-blind treatment 
period, and a 1-week washout period. Patients who complete the study may be eligible to begin 
participation in an open-label safety extension study TV50717-CNS-30047 after the end of the 
washout period. Patients not participating in Study TV50717-CNS-30047 will have a follow-up 
telephone contact to evaluate safety 1 week after the end of the washout period (2 weeks after 
their last dose of IMP).
Patients are expected to participate in this study for its entire duration, which is a minimum of 
14 weeks. See Section 12.4 for the definition of the end of the study.
3.11.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational center to identify safety concerns. The study may be terminated by the sponsor at 
any time. 
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 


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51
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, or adverse event). 
Please see Section 4.4 for the withdrawal criteria and procedures.
3.12.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the sponsor provides written instructions specifying 
which data are permitted to be recorded directly onto the CRF, such as eScales. 
If patient data are processed from other vendors (eg, clinical laboratory, central ECG, diary data), 
the results will be sent to the investigational center, where they will be retained but not entered 
into the CRF. These data may also be sent electronically to the sponsor (or organization 
performing data management) for direct use with the clinical database (see Section 13.1). All 
clinical patient data from other vendors will be available to the investigator.
The CRFs are filed in the sponsor’s central file after study completion. 
3.13.
Study Procedures
Study procedures and assessments with their time points are presented in Table 1. During a visit, 
study procedures and assessments should be performed in the order specified in the study 
manual.
Detailed by-visit information is provided in the sections following the table. Detailed 
descriptions of each assessment are provided in Section 6 (efficacy assessments), Section 7
(safety assessments), and Section 8 (pharmacokinetic and other assessments).


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Table 1:
Study Procedures and Assessments
Screening
BLa
Titration
Maintenance
Follow-up
U
Study weekb
Up to 
31 days
Day
1c
1
(Day 
7)
2
(Day 
14)
3
(Day 
21)
4
(Day 
28)
5
(Day 
35)
6
(Day 
42)
7
(Day 
49)
9
(Day 
63)
12/ETd
(Day 
84)
13
(Day 
91
14e
(Day 
98)
Visit window (days)
0
days
±3 days
±3 days from 
Week 12
In-clinic visit
Xf
X
X
X
X
X
X
X
X
Telephone contact
X
X
X
X
X
Evaluate/Adjust IMP
Xg
X
Xg
X
Xg
X
X
X
Informed consent/assent 
X
Eligibility criteria
X
X
Medical history and psychiatric 
history
X
Demographics
X
Vital signs and weighth
X
Xi
X
Xi
X
X
Xi
X
X
Physical examination
X
X
Xj
Neurological examination
X
X
Xj
Height
X
X
Xj
12-lead ECGk
X
X
X
X
X
Xj
Pharmacokinetic blood sampling
Xl
Chemistry/Hematology/Urinalysis
X
X
Xm
Xj
Urine drug screen
X
X
Randomization 
X
CYP2D6 genotypen
X
β-HCG testo
X
X
X
X
Xj


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Table 1:
Study Procedures and Assessments (Continued)
Screening
BLa
Titration
Maintenance
Follow-up
U
Study weekb
Up to 
31 days
Day
1c
1
(Day 
7)
2
(Day
14)
3
(Day 
21)
4
(Day 
28)
5
(Day 
35)
6
(Day 
42)
7
(Day 
49)
9
(Day 
63)
12/ETd
(Day 
84)
13
(Day 
91
14e
(Day 
98)
Visit window (days)
0
days
±3 days
±3 days from 
Week 12
MINI Kidp,q
X
CDI-2 (Parent and Self-report)r
X
X
X
X
X
X
X
X
Xj
C-SSRS (Children’s 
Baseline/Screen)q
X
C-SSRS (Children’s Since Last 
Visit)q
X
X
X
X
X
X
X
Xj
YGTSSs,t
X
X
Xu
X
Xu
Xu
X
Xu
TS-CGIt
X
X
X
X
X
X
X
TS-PGIIt
X
X
X
X
X
X
X
t
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xv
X
Xv
C&A-GTS-QOLq
X
X
X
Dispense IMPw
Xx
Xx
Xx
Xy
Xy
Xj
Collect IMP
X
X
X
X
X
Xj
Assess IMP 
accountability/compliance/supply
Xz
X
Xz
X
Xz
X
Xz
X
X
Xj
Assess adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationsaa
X
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
a The baseline visit will occur on the same day as the scheduled first dose of the IMP (day 1).


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b Assessment to occur at the end of the study week.
c 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 12 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 12, patients will be reminded to record the start time of their last meal and the time of their last dose in their diary.
d For patients who withdraw prematurely, an early termination visit should be conducted as soon as possible after the last dose of IMP. All patients who 
discontinue early will have a follow-up telephone contact for safety evaluation 2 weeks after their last dose of IMP; evaluations will be as described for 
week 14 (Section 3.13.4.2).
e 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 TV50717-
CNS-30047.
f The screening visit may be conducted over 2 separate visits at the discretion of the investigator.
g Dose adjustment will be made by the investigator after telephone contact with the patient and caregiver/adult to evaluate tic reduction and adverse events.
h Weight must be measured with shoes and outerwear off. Before pulse and BP are measured, the patient must be in a supine or semi-erect/seated position and 
resting for at least 5 minutes (the same position and arm should be used each time vital signs are measured for a given patient).
i Orthostatic BP and pulse will be measured after patient is in a standing position for at least 3 minutes.
j Assessment to be completed at investigator’s discretion.
k All ECGs will be performed after at least 5 minutes 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 2 to 3 hours after the first 
pharmacokinetic sample collection. Patients with early morning visits (ie, within 2 hours of their scheduled AM dosing) should take their IMP dose in clinic 
after the first pharmacokinetic sample is collected.
m Patients with clinically significant laboratory abnormalities at week 12 will have those laboratory evaluations repeated at the week 13 visit.
n The patient’s genotype for CYP2D6 will be blinded during the conduct of the study. 
o For females who are postmenarchal or ≥12 years of age, a urine test will be administered at baseline and week 4, while a serum test will be administered at 
screening and week 12, and if clinically indicated.
p 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).
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 Children 6 years of age at baseline will not complete the Self-report version; the caregiver/adult will complete the Parent version.
s Input from the caregiver/adult is required.
t The YGTSS, TS-CGI, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG assessments.
u Perform assessment of “Severity Ratings” of the questionnaire. Inventory portions, ie, “Motor Tic Symptom Checklist” and “Phonic Tic Symptom Checklist” 
do not need to be performed.
v Perform the Severity Ratings of OCD symptoms (Questions 1 through 10) only. Checklist does not need to be performed.
w Contact IRT and dispense IMP and patient diary.
x IMP will be dispensed in the clinic; patients will receive doses for 2 weeks (current dose level and next dose level) to cover the telephone contacts. The site will 
determine titration (ie, starting the next dose) for the patient by telephone. See Table 2 for baseline weight-based dosing titration.


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y Patients will receive doses for 3 weeks of treatment.
z The site needs to discuss the drug status during the telephone contacts to ensure the patient has adequate tablets, inform the patient if they should titrate, and 
remind them to bring used and unused IMP blister packs to the next in-clinic visit.
aaParents/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.
ADHD=Attention Deficit Hyperactivity Disorder; β-HCG=beta-human chorionic gonadotropin; BL=baseline visit; BP=blood pressure; CDI-2=Children’s 
Depression Inventory, Second Edition, Parent and Self-report Profiles; C-SSRS=Columbia-Suicide Severity Rating Scale; 
 
 CYP2D6=cytochrome P450 2D6; ECG=electrocardiogram; ET=early termination visit; C&A-GTS-QOL=Child and Adolescent 
Gilles de la Tourette Syndrome – Quality of Life; IMP=investigational medicinal product; IRT= Interactive Response Technology; MINI Kid=Mini International 
Neuropsychiatric Interview For Children and Adolescents; OCD=obsessive-compulsive disorder; TS-CGI=Tourette Syndrome-Clinical Global Impression; TS-
PGII=Tourette Syndrome-Patient Global Impression of Impact; 
; U=unscheduled visit; 
YGTSS=Yale Global Tic Severity Scale.


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3.13.1.
Procedures for Screening and Enrollment
A signed and dated informed consent form will be obtained from the parent/legally acceptable 
representative, and a signed and dated assent, depending on the child’s age, as appropriate, will 
be obtained from each patient before screening procedures commence, according to national 
laws and local IEC/IRB requirements. Parents/legally acceptable representatives will 
acknowledge and agree to the possible use of this information for the study by giving informed 
consent.
A patient who is screened but not enrolled may be rescreened 1 time if there is a change in the 
status of the patient regarding eligibility for the study. (Note: Details of rescreening must be 
approved and documented by the medical monitor and/or CST team.) 
The screening visit will take place not more than 31 days before the baseline visit. The screening 
visit may be conducted over 2 separate visits at the discretion of the investigator. The following 
procedures will be performed at screening:

obtain written informed consent/assent, depending on the child’s age, as appropriate, 
before any other study-related procedures are performed

conduct clinic visit

review eligibility (inclusion and exclusion) criteria

inform patients of study restrictions and compliance requirements

review medical and psychiatric history

review demographics information

measure vital signs (pulse, BP, body temperature, and respiratory rate) 

perform full physical and neurological examinations (including height and weight. 
Note: Weight must be measured with shoes and outerwear off)

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position)

perform clinical laboratory tests, including chemical, hematological, and urine 
analyses

obtain a blood sample (3 mL) for analysis of CYP2D6 genotype

perform urine drug screen (UDS)

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 Kid and C-SSRS, children 
13 years of age and under may be interviewed separately or jointly with the 
caregiver/adult as appropriate or defined by the scale. For children over 13 years of 
age, caregiver/adult involvement is strongly encouraged. Questions should be 
directed to the child, but the caregiver/adult should be encouraged to add relevant 


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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], OCD [Module J], 
Alcohol Dependence/Abuse [Module L], Substance Dependence/Abuse [Non-
alcohol; Module M], Attention Deficit Hyperactivity Disorder [ADHD; 
Module O], Conduct Disorder [Module P], and Psychotic Disorders and Mood 
Disorders with Psychotic Features [Module R])

CDI-2, Parent and Self-report (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.)

review medication history and concomitant medications

inquire about adverse events
3.13.1.1.
YGTSS Rater Certification
All investigators and subinvestigators who will be administering the YGTSS from screening 
through the end of study visit must undergo and pass a Rater Certification Program which will be 
provided separately from this protocol. Every effort must be made to ensure that the same 
certified rater administers the YGTSS to a specific patient at all visits, especially at the baseline 
and week 12/early termination visits. However, if due to unforeseen circumstances the same rater 
is absolutely unavailable to complete a visit rating, the YGTSS can be administered only by 
another certified individual from that study site.
3.13.2.
Procedures Before IMP Treatment (Baseline/Day 1)
Patients who meet the inclusion/exclusion criteria at screening will continue to the baseline visit, 
when baseline evaluations will be conducted.
The following procedures will be performed at baseline:

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)

measure 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 urine pregnancy (β-HCG) test (only in females who are postmenarchal or 
≥12 years of age)

randomization with stratification by age at baseline (6 to 11 years, 12 to 16 years)


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
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 (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

dispense IMP (patients will receive doses for 2 weeks [current dose level and next 
dose level] to cover the telephone contacts) and patient diary

provide patients with a diary to record critical information on dosing 

review concomitant medications

inquire about adverse events
A patient who is not enrolled in the study on the basis of results of baseline assessments (eg, 
because inclusion and exclusion criteria were not met or enrollment did not occur within the 
specified time) may be screened again 1 more time if there is a change in the patient’s medical 
background, a modification of study entry criteria, or other relevant change. (Note: Details of 
rescreening must be approved.)
Patients will be assigned a permanent unique number at screening (see Section 3.13.1). Patients 
who continue to meet the inclusion/exclusion criteria at baseline will be randomized to a 
treatment (active or placebo) using an IRT, and the appropriate IMP will be dispensed.


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3.13.3.
Procedures During IMP Treatment
3.13.3.1.
Titration Period (Baseline/ Day 1 Through 7)
3.13.3.1.1. Telephone Contacts (Weeks 1, 3, 5, and 7)
The following procedures/assessments will be performed via telephone contact at weeks 1, 3, 5, 
and 7:

assess IMP accountability/compliance/supply status to ensure the patient has adequate 
tablets, inform the patient if they should titrate, and remind them to bring used and 
unused IMP blister packs to the next in-clinic visit

inquire about adverse events

review concomitant medications
If a patient experiences an adverse event that is reported during a telephone contact and is 
probably related to the IMP, he or she will be brought to the clinic for evaluation (see 
Section 3.13.5). Based on the telephone evaluation, the investigator will determine whether, with 
the medication already provided, the patient should continue titration or reduce the dose. If 
additional IMP is required, it would be ordered from the distributor and provided to the patient at 
an unscheduled visit.
3.13.3.1.2. Clinic Visits (Weeks 2, 4, and 6)
The following procedures/assessments will be performed at in-person clinic visits at weeks 2, 4, 
and 6:

conduct clinic visit

evaluate and, if required, adjust IMP dose (see Section 5.1)

measure vital signs (pulse, BP, body temperature, and respiratory rate); at week 4 
only, orthostatic BP and pulse should be measured after the patient is in standing 
position for at least 3 minutes

measure weight (Note: Weight must be measured with shoes and outerwear off)

perform 12-lead ECG (weeks 4 and 6 only [Note: ECG will be performed after at 
least 5 minutes rest in a supine or semi-supine position.])

perform urine pregnancy (β-HCG) test at week 4 (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.):


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
CDI-2, Parent and Self-report (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: At weeks 2 and 6, perform assessment of “Severity Ratings” of 
the questionnaire only. Inventory portions, ie, “Motor Tic Symptom Checklist” 
and “Phonic Tic Symptom Checklist” do not need to be performed. Input from 
caregiver/adult is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)



 

C&A-GTS-QOL (week 6 only)

dispense IMP (patients will receive doses for 2 weeks at week 2 and week 4 visits 
[current dose level and next dose level] and for 3 weeks at week 6 visit to cover the 
telephone contacts) and patient diary

assess drug accountability and compliance

collect used and unused IMP blister packs

inquire about adverse events

review concomitant medications
3.13.3.2.
Maintenance Period
3.13.3.2.1. Week 9
The following procedures/assessments will be performed at the in-person clinic visit during the 
maintenance period of the study at week 9:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate)

measure weight (Note: weight must be measured with shoes and outerwear off)

administer the following questionnaires (Note: For C-SSRS and 
, 
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 


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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 (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: Perform assessment of “Severity Ratings” of the questionnaire. 
Inventory portions, ie, “Motor Tic Symptom Checklist” and “Phonic Tic 
Symptom Checklist” do not need to be performed. Input from caregiver/adult 
is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)


 

dispense IMP (patients will receive doses for 3 weeks) and patient diary

assess drug accountability and compliance

collect used and unused IMP blister packs

inquire about adverse events

review concomitant medications 
3.13.3.2.2. Week 12/Early Termination
Dosing requirements for the week 12 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 12 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 12, 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/assessments will be performed at the in-person clinic visit at week 12/early 
termination:

conduct clinic visit

if a patient is withdrawn due to an adverse event, a blood sample for IMP 
measurement should be taken, if possible. For week 12 visit only: Collect 2 blood 
samples (5 mL each) for pharmacokinetic analysis (initial and 2 to 3 hours thereafter 
as specified in Table 1) 

measure vital signs (orthostatic pulse and BP [after standing for at least 3 minutes], 
body temperature, and respiratory rate)


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
perform full physical and neurological examinations (including height and weight; 
note: weight must be measured with shoes and outerwear off)

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)

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 
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 (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

assess drug accountability and compliance

collect used and unused IMP blister packs

inquire about adverse events

review concomitant medications
3.13.4.
Procedures After IMP Treatment
Patients who participate in the study in compliance with the protocol for at least 12 weeks of 
double-blind treatment will be considered to have completed the study. See Section 12.4 for the 
definition of the end of the study.


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All patients will discontinue IMP at the week 12 visit and will return 1 week later for evaluation 
of safety and tic reduction (week 13 visit; see Section 3.13.4.1). Patients who complete the study 
may be eligible to begin participation in an open-label safety extension study TV50717-CNS-
30047. Patients not participating in Study TV50717-CNS-30047 will have a follow-up telephone 
contact for safety evaluation 1 week after the end of the washout period (2 weeks after their last 
dose of IMP [week 14 visit]; see Section 3.13.4.2). 
For patients who withdraw prematurely an early termination visit (see Section 3.13.3.2.2 for 
applicable procedures) should be conducted as soon as possible after the last dose of IMP. All 
patients who discontinue early will have a follow-up telephone contact for safety evaluation 
2 weeks after their last dose of IMP; evaluations will be as described for week 14 
(Section 3.13.4.2). Additional details for patients who withdraw prematurely from the study are 
described in Section 4.4. 
As appropriate, patients should be treated with standard of care following termination of the 
study.
Data from any efficacy evaluations performed after the specified time will not be collected on 
the CRF; in the event, however, that such data are collected, these data will not be analyzed. 
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 4.4 and Section 7.1.2.
3.13.4.1.
Week 13
The following procedures/assessments will be performed at the in-person clinic visit at week 13:

conduct clinic visit

measure vital signs (pulse, BP, body temperature, and respiratory rate)

measure weight (Note: weight must be measured with shoes and outerwear off)

for patients with clinically significant laboratory abnormalities at week 12, repeat 
those laboratory evaluations at this visit

administer the following questionnaires (The YGTSS, TS-CGI, TS-PGII, and 
 questionnaires should be performed before any blood draws or ECG 
assessments.):

CDI-2, Parent and Self-report (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.)

YGTSS (Note: Perform assessment of “Severity Ratings” of the questionnaire. 
Inventory portions, ie, “Motor Tic Symptom Checklist” and “Phonic Tic 


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Symptom Checklist” do not need to be performed. Input from the 
caregiver/adult is required.)

TS-CGI

TS-PGII (Input from the caregiver/adult is permitted.)


(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.)

(Note: Perform the Severity Ratings of OCD symptoms 
[Questions 1 through 10] only. Checklist assessments do not need to be 
performed. 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.)

inquire about adverse events

review concomitant medications
3.13.4.2.
Week 14
For patients not rolling over into open-label safety extension study, following 
procedures/assessments will be performed via telephone contact at week 14:

inquire about adverse events

review concomitant medications
3.13.5.
Unscheduled Visits
An unscheduled telephone contact may be performed at the discretion of the investigator.
An in-clinic unscheduled visit should be performed if a patient requires a dose adjustment for 
adverse events reported during a telephone contact. An unscheduled visit may be performed at 
any time during the study as deemed necessary by the investigator or at the request of the patient 
or caregiver/adult. The date and reason for the unscheduled visit will be recorded on the CRF as 
well as any other data obtained (eg, adverse events, concomitant medications and treatments, and 
results from procedures or tests).
The following procedures/assessments will be performed at in-clinic unscheduled visits:

conduct clinic visit

evaluate and/or adjust IMP dose (see Section 5.1)

measure vital signs (pulse, BP, body temperature, and respiratory rate)


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
measure weight (Note: Weight must be measured with shoes and outerwear off) 

inquire about adverse events

review concomitant medications
The following procedures/assessments may be performed at unscheduled visits per the 
investigator’s discretion:

measure height

perform physical examination 

perform neurological examination 

perform 12-lead ECG (Note: ECG will be performed after at least 5 minutes rest in a 
supine or semi-supine position.)

perform clinical laboratory tests, including chemical, hematological, and urine 
analyses 

perform a urine/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 (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.)

dispense additional IMP and patient diary, if applicable

collect used and unused IMP blister packs

assess drug accountability/compliance/supply 
Other procedures may also be performed at the discretion of the investigator.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by sponsor or Syneos Health (see Section 11.1.2).
4.1.
Patient Inclusion Criteria
Patients may be enrolled 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 provide 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 β-HCG test at baseline or are sterile. Definitions of sterile are given 
in Appendix L.
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 L.
4.2.
Patient Exclusion Criteria
Patients will not be 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.


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b. The patient’s predominant movement disorder is stereotypy (coordinated movements 
that repeat continually and identically) associated with autism spectrum disorder. 
c.
Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another 
psychotic disorder.
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 screening.
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 clinically significant OCD at baseline that, in the opinion of the 
investigator, is the primary cause of impairment.
i.
Patient has received CBIT for TS or CBT for OCD within 4 weeks of screening.
j.
Patient has received any of the following concomitant medications for tics within the 
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 A), metoclopramide, levodopa, and dopamine agonists 
Note: Use of stimulant medications, including amphetamine, methylphenidate, 
and lisdexamfetamine, is allowed if primary use is for the treatment of ADHD and 
dosing has been stable for at least 2 weeks before screening 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 and 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 Tourette syndrome) if the dosing has been stable for at least 


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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. 
k. Patient has received treatment with deep brain stimulation, transmagnetic stimulation, 
or transcranial direct current stimulation for reduction of tics within 4 weeks of the 
screening visit. 
l.
Patient has an unstable or serious medical illness at screening or baseline
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 >480msec (with right 
bundle branch block) on 12-lead ECG at screening, OR requires treatment with drugs 
known to prolong the QT interval (see Appendix A, Table 6 for a complete list of 
prohibited QT-prolonging drugs).
n. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart failure.
o. Patient has evidence of hepatic impairment, as indicated by:

aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × 
the upper limit of the normal range (ULN) at screening

alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
Note: Patients with Gilbert’s Syndrome are eligible to participate, if approved by 
the medical monitor. 
Note: Patients with abnormalities in 2 or more of the following clinical laboratory 
parameters must be approved for enrollment by the medical monitor: AST, ALT, 
ALP, and Tbil. 
p. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5 × ULN at screening. 
q. Patient has received a MAOI within 14 days of the baseline visit.
r.
Patient has a known allergy to any of the components of the IMP.
s.
Patient has participated in an investigational drug or device study and received 
IMP/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
t.
The patient is a pregnant or lactating female, or plans to become pregnant during the 
study.
u. Patient has a history of or acknowledges alcohol-related disorder in the previous 
12 months, as defined in the DSM-V™.
v. Patient has a positive UDS test result, or is unable to refrain from substance abuse 
throughout the study.


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w. Patient has a DSM diagnosis based on the MINI Kid modules performed at screening 
that, in the opinion of the investigator, makes the patient unsuitable for the study.
4.3.
Justification for Key Inclusion and Exclusion Criteria
Inclusion and exclusion criteria have been designed to minimize the risk to patients while 
maintaining a consistent level of TS symptoms to allow detection and analysis of a drug effect. 
Exclusion criteria were designed to exclude patients with concomitant conditions that may 
increase their risk to drug treatment.
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (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 Sections 4.3 and 7.1.7). The investigator should repeat the ECG assessment twice 
and compare the average of the 2 pre-treatment QTcF values (baseline and screening) 
to the average of the 3 post-baseline QTcF values. The IMP must be stopped for any 
confirmed post-baseline QTcF value >500 msec or increase from baseline >60 msec.
g. when a blind is broken due to safety concerns (see Section 3.7.2). If a patient is 
unblinded by mistake, the investigator should discuss with the medical monitor 
whether or not the patient should be withdrawn.
h. if the investigator or the sponsor determines that the patient is not in compliance with 
the study protocol, the investigator and the sponsor should determine whether the 
patient should be withdrawn from the study (Section 5.4).
In addition, a patient may be withdrawn from the study as described in Sections 3.7, 3.11, 3.13.4, 
5.4, and 7.1.7. 
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 given as to why the 
patient is withdrawing or being withdrawn from the study. Assessments to be conducted at the 
early termination visit are described in Section 3.13.3.2.2.


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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 (Section 3.13.4). 
A patient who is enrolled but does not complete the treatment period will not be replaced.


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5.
TREATMENT OF PATIENTS
5.1.
Drugs Administered During the Study 
IMP (see Section 3.8) will be administered as oral tablets at a starting dose of 6 mg. Titration 
schemes based on body weight at baseline are shown in Table 2. The maximum daily dose is 
determined by body weight and CYP2D6 impairment status at baseline. Although dose 
adjustments can be made up to and including the week 7 telephone call, if a stable dose is 
reached before then, the patient should continue taking that dose for the remainder of the titration 
period and throughout maintenance dosing. If a patient experiences a “clinically significant” 
adverse event that is attributed to the IMP, the investigator will determine if a dose reduction or 
suspension is necessary. At the end of the titration period, the patient’s dose will be established 
for the maintenance period. If a patient experiences an adverse event during the maintenance 
period and the investigator believes a dose reduction is warranted, the dose may be reduced.
IMP will be dispensed in the clinic. Patients will receive doses for 2 weeks at baseline, week 2, 
and week 4 visits (current dose level and next dose level) to cover the telephone contacts. At 
week 6 and week 9 visits, patients will receive doses for 3 weeks. 
IMP will be administered as follows:

IMP should be swallowed whole and taken with food. Tablets should be taken with 
food (eg, a snack) and should not be taken on an empty stomach.

Dosing will be based on body weight and CYP2D6 impairment status at the baseline 
visit, as shown in Table 2.

The starting dose is 6 mg in all patients. Daily doses will be administered twice daily, 
approximately 8 to 10 hours apart during the day. A minimum of 6 hours should 
elapse between doses. If a patient misses a dose and it is within 6 hours of their next 
dose, the missed dose should be skipped. 

After week 1, dose increases may not occur more frequently than every 5 days.

Dose reductions, if required, should be in increments of 6 mg. If more than 1 dose 
reduction is required for an adverse event, the medical monitor must be notified.

During the titration period, the dose of the IMP will be adjusted weekly according to 
Table 2 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.
IMP will be packaged in blister packs and provided for patients to take at home (see Section 3.8). 


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Table 2:
Maximum Daily Dose of IMP by Study Day and Weight Category at Baseline
Weight category
Study daya
20 to <30 kg
30 to <40 kg
≥40 kg
CYP 
impairment 
status
Not 
impaired
Impaired
Not 
impaired
Impaired
Not 
impaired
Impaired
Day 1-7
6 mg 
6 mg 
6 mg
6 mg
6 mg (Days 
1 and 2)
12 mgb
6 mg (Days 
1 and 2)
12 mgb
Day 8-14
12 mg
12 mg
12 mg
12 mg
18 mg
18 mg
Day 15-21
18 mg
18 mg
18 mg
18 mg
24 mg
24 mg
Day 22-28
18 mg
18 mg
24 mg
24 mg
30 mg
30 mg
Day 29-35
24 mg
18 mg
30 mg
24 mg
36 mg
36 mg
Day 36-42
24 mg
18 mg
36 mg
24 mg
42 mg
36 mg
Day 43-49
30 mg
18 mg
42 mg
24 mg
48 mg
36 mg
a Administration of a given dose will take place throughout the days indicated. The new dose starts the morning 
after the telephone contact or the morning after the clinic visit (ie, Days 8, 15, 22, 29, 36, and 43), as applicable.
b Patients will receive 6 mg on days 1 and 2, and 12 mg starting on day 3.
bid=twice a day; CYP=cytochrome P450; IMP=investigational medicinal product.
Note: CYP impaired patients are those patients who are receiving a strong CYP2D6 inhibitor or who are a CYP2D6 
poor metabolizer. The investigator, in consultation with the patient and caregiver/adult, will determine if a dose 
increase is warranted to achieve optimal tic reduction.
5.2.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.3. 
While patients receiving strong CYP2D6 inhibitors such as 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 use of quinidine and terbinafine are prohibited (see Appendix A, Table 8). 
Restrictions in regard to sexual activity and required laboratory values are provided in the 
inclusion and exclusion criteria. 
As with other VMAT2 inhibitors (tetrabenazine, reserpine), patients should be advised that the 
concomitant use of alcohol or other sedating drugs with TEV-50717 may have additive effects 
and cause or worsen somnolence. Given the age of the study population, the use of alcohol 
during this study is prohibited. 
Patients should be advised not to drive a car or operate dangerous machinery until they 
understand how TEV-50717 affects them.


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Use of illicit drugs is prohibited from the time of signing of the informed consent/assent form 
and throughout study participation.
Patients may not donate blood from the time of informed consent/assent, while taking the IMP, 
and for 14 days after the last dose.
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or procedure a patient has had within 3 months 
before IMP administration and up to the end of the study period, including follow-up, will be 
recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
sponsor will encode all therapy and medication according to the World Health Organization drug 
dictionary.
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. 
Medications that are allowed, provided that conditions outlined in the table are met, are shown in 
Appendix A, Table 5.
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving 
during the study) a medication that is associated with QTc prolongation or that is a known strong 
CYP inhibitor. Addition of a strong CYP inhibitor is prohibited.
Prohibited medications that are associated with QTc prolongation are listed in Appendix A, 
Table 6, while prohibited antipsychotic drugs are listed in Appendix A, Table 7.
5.4.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. A check of IMP 
compliance will be performed during each visit after the initial dispensation of IMP, and IMP 
accountability records will be completed. If the investigator or the sponsor determines that the 
patient is not in compliance with the study protocol, the investigator and the sponsor should 
determine whether the patient should be withdrawn. The IEC/IRB should be notified as required 
by national and local regulations.


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5.5.
Dose Reduction and Temporary IMP Discontinuation
Dose Reduction
If a patient experiences a “clinically significant” adverse event that is attributed to IMP, the 
investigator will determine if a dose reduction or suspension is necessary. Dose adjustments 
should be made based on all available information, including the patient and caregiver/adult 
reports of adverse events and tic reduction, the clinical assessment of safety and efficacy by the 
investigator, and information from rating scales. If more than 1 dose reduction is required for 
an adverse event, the medical monitor must be notified.
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 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. The Medical Monitor must be contacted to determine the appropriate investigation 
and treatment. TEV-50717 may only be restarted once serum potassium or magnesium have
normalized. 
The reason for a dose reduction or suspension must be clearly documented.
If a dose reduction or suspension occurs before a scheduled clinic visit, the clinic visit will 
be postponed so that efficacy evaluations can be performed at least 5 days after the change. 
The patients who restart IMP treatment will follow the visit schedule as outlined in Table 1. 
Patients who withdraw from the study will proceed as described in Section 4.4.
5.6.
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 3.


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Table 3:
Blood Volumes
Type of samples
Volume per sample
Total number of samples
Total volume
Clinical laboratory 
(chemistry/hematology)
10 mL
2
20 mL
Pharmacokinetic 
5 mL
1 time point (week 12) × 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 the YGTSS and the 
, and self-administered 
efficacy scales include the TS-PGII, 
 and C&A-GTS-QOL.
6.1.
Primary Efficacy Measure and Justification
The primary efficacy measure is the TTS of the YGTSS. 
The YGTSS is administered at screening; baseline; and weeks 2, 4, 6, 9, 12, and 13:

Complete assessment (Checklist and Severity Ratings) at screening, baseline, and 
weeks 4 and 12

Severity Ratings assessment only at weeks 2, 6, 9, and 13

Input from caregiver/adult is required for all patients 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 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 
 can then be determined by combining the patient’s severity rating with the TTS.
A reference sample is provided in Appendix G.
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, 6, 9, 12, and 13. The TS-CGI scale is 
a 7-point Likert scale that allows the clinician to use all available information to assess the 
impact of tics on the patient’s quality of life. The TS-CGI is rated as follows: 1 (normal), 
2 (borderline), 3 (mild), 4 (moderate), 5 (marked), 6 (severe), and 7 (extreme). 
A reference sample is provided in Appendix H.
6.2.2.
Tourette Syndrome-Patient Global Impression of Impact
The TS-PGII is administered at baseline and weeks 2, 4, 6, 9, 12, and 13. 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 


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change have face validity and have been shown to correlate with disability for a number of 
chronic conditions.
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 6, and week 12. 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 K.
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 the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, 
physical examination findings (including body weight and height measurements), use of 
concomitant medication, neurological examination, C-SSRS, and CDI-2.
7.1.
Adverse Events 
7.1.1.
Definition of an Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the IMP (TEV-50717). A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during this study will not be considered adverse 
events. 
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions (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 the washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant (Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.) 


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7.1.2.
Recording and Reporting Adverse Events
For recording of adverse events, the study period is defined for each patient as that time period 
from signature of the informed consent/assent form to the end of the follow-up period. 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.
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the Serious Adverse Event Form must be completed, and 
the serious adverse event must be reported immediately (see Section 7.1.5.3.1). The investigator 
does not need to actively monitor patients for adverse events after the defined period. Serious 
adverse events occurring to a patient after the treatment of that patient has ended should be 
reported to the sponsor if the investigator becomes aware of them, following the procedures 
described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
Serious Adverse Event Form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; until the patient is referred for continued care to a health care 
professional; or until a determination of a cause unrelated to the IMP or study procedure is made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF.
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
Further details are given in the safety monitoring plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the following:
Mild: 
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe: 
Inability to carry out usual activities


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


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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 a 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 signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
preexisting condition during the patient’s participation in this study.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3 × the upper limit of normal (ULN)

total bilirubin increase of >2 × ULN

absence of initial findings of cholestasis (ie, no substantial increase of 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.
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.


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A serious adverse event that is not included in the listing of adverse reactions in the RSI by its 
specificity, severity, outcome, or frequency is considered an unexpected adverse event.
The sponsor’s GPSP 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.
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 local safety officer (LSO) or designee (a 
contract research organization in a country without a sponsor LSO) (contact information is in the 
Clinical Study Personnel Contact Information section); the LSO will forward the report to the 
sponsor’s 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

severity

explanation of assessment of relatedness


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
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/Syneos Health for submission to the competent authorities, IEC/IRBs, and investigators, 
according to regulations. The investigator must ensure that the IEC/IRB is also informed of the 
event, in accordance with national and local regulations.
Blinding will be maintained for all study personnel. Therefore, in case of a SUSAR, only the 
LSO/Syneos Health 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 7.3). 
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of TEV-50717 and the appropriate competent authorities (and IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and regulatory 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

modifying the existing consent form and informing current study participants of new 
findings


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
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 or sponsor. 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 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 C.
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. The C-SSRS children’s 
SLV scale is administered at baseline and at weeks 2, 4, 6, 9, 12, and 13. 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 the medical 


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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 E.
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, 6, 9, 12, and 13. 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 D.
7.3.
Pregnancy
Any female patient becoming pregnant during the study will discontinue IMP.
All pregnancies of female patients participating in the study that occur during the study, or 
within 14 days after the end of the study, are to be reported immediately to the individual 
identified in the Clinical Study Personnel Contact Information section of this protocol, and the 
investigator must provide the sponsor (LSO/Syneos Health) with the completed pregnancy form. 


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The process for reporting a pregnancy is the same as that for reporting a serious adverse event
but using the pregnancy form (see Section 7.1.5.3). 
The investigator is not required to report patients who are found to be pregnant between 
screening and 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 patients participating in the study does not continue to term, 1 of 
the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event. 

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.4.
Medication Error and Special Situations Related to the 
Investigational Medicinal Product
Any administration of IMP that is not in accordance with the study protocol should be reported 
on the CRF either as a violation, if it meets the violation criteria specified in the protocol 
(Section 11.1.2), or as a deviation, in the patients source documents, regardless of whether or not 
an adverse event occurs as a result. All instances of incorrect medication administration should 
be categorized on the CRF as “Non-Compliance with IMP”.
The following are types of medication errors and special situations:
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 the dose 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.


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5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
7. Breastfeeding: Suspected adverse reactions that occur in infants following exposure to a 
medicinal product from breast milk.
7.5.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 

abnormal and not clinically significant

abnormal and clinically significant
The clinical significance of the laboratory values will be evaluated by the criteria described in 
the 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 
cessation of IMP or medical treatment, or further diagnostic work-up. Abnormal laboratory tests 
can be repeated without approval from the medical monitor. (Note: Abnormal laboratory or 
diagnostic test results at the screening visit that preclude a patient from entering the study or 
receiving IMP are not considered adverse events.)
7.5.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (eg, serum chemistry, hematology, urinalysis) will be performed at the 
time points detailed in Table 1. Clinical laboratory tests will be performed using the central 
laboratory. Specific laboratory tests to be performed are provided in Table 4.


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Table 4:
Clinical Laboratory Tests
Serum Chemistry
Hematology
Urinalysis
calcium
phosphate
sodium
potassium
chloride
creatinine
glucose
magnesium
blood urea nitrogen (BUN)
total cholesterol 
uric acid
alanine aminotransferase (ALT)
aspartate aminotransferase (AST)
lactate dehydrogenase (LDH)
alkaline phosphatase (ALP)
bicarbonate or carbon dioxide
total protein
albumin
total bilirubin
direct bilirubin
hemoglobin
hematocrit
red blood cell (RBC) count
mean cell volume
platelet count
white blood cell (WBC) count, and 
differential count 

absolute neutrophil 
count (ANC)
polymorphonuclear leukocytes 
(neutrophils)

lymphocytes

eosinophils

monocytes

basophils
protein
glucose
ketones
blood (hemoglobin)
pH
specific gravity
microscopic

bacteria

RBCs

WBCs

casts

crystals
7.5.2.
Other Clinical Laboratory Tests
7.5.2.1.
Human Chorionic Gonadotrophin Test
Human chorionic gonadotrophin tests in urine or serum will be performed for all females who 
are postmenarchal or ≥12 years of age as detailed in Table 1, and if clinically indicated. Any 
female patient who becomes pregnant during the study will be withdrawn. Procedures for 
reporting the pregnancy are provided in Section 7.3.
7.5.2.2.
Urine Drug Screen 
A UDS will be performed at time points specified in Table 1. The UDS detects the presence of 
drugs prohibited according to the laboratory manual. If a given parameter cannot be tested using 
urine, an alternative matrix (eg, serum) may be considered acceptable. The sponsor’s medical 
expert must be made aware in advance of, and provide approval for, drug screen parameters to 
which this will apply.
A positive result for any of the specified drugs or their metabolites, without medical explanation, 
will preclude the patient from enrollment or continued participation in the study. 


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7.5.3.
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, pharmacokinetics, tolerability, and 
safety features or disease susceptibility and severity features). See Section 8.3.1 for further 
details.
7.6.
Vital Signs
Vital signs (pulse, BP, body temperature, and respiratory rate) will be measured at the time 
points detailed in Table 1. All vital signs results outside of the reference ranges will be judged by 
the investigator as belonging to one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Before pulse and BP 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). At baseline, week 4, and week 12, orthostatic BP and pulse will be 
measured after the patient is in a standing position for at least 3 minutes.
For any abnormal vital sign finding, the measurement should be repeated as soon as possible. 
Any vital sign value that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event, and monitored as described 
in Section 7.1.2. 
7.7.
Electrocardiography
A 12-lead ECG will be conducted at the time points detailed in Table 1. All ECGs will be 
performed after at least 5 minutes rest in a supine or semi-supine position. A qualified physician 
at a central diagnostic center will be interpreting the ECG.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event, recorded on the source documentation and 
in the CRF, and monitored as described in Section 7.1.2.
If a post-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.


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7.8.
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 1.
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. 
7.9.
Assessment of Suicidality
TEV-50717 is considered to be CNS-active. In addition, there have been some reports of suicidal 
ideation or behavior as reported in the product label when it has been given to some patients with 
certain conditions. The sponsor considers it important to monitor for such events before and 
during this clinical study.
Some CNS-active IMPs may be associated with an increased risk of suicidal ideation or behavior 
when given to some patients with certain conditions. Although this IMP or other similar 
medicinal products in this class have not been shown to be associated with an increased risk of 
suicidal thinking or behavior when given to this study population, the sponsor considers it 
important to monitor for such events before or during this clinical study.
The study population being administered TEV-50717 should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing TEV-50717 in participants who experience signs 
of suicidal ideation or behavior and detailed recommendations are provided in Section 7.2.2.
Baseline assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation 
and behavior will be assessed during the study using the C-SSRS described in Section 7.2.2. 
Depression and Suicidality as an Adverse Event
Families and caregivers of subjects in Study 30046 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 


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with a pediatric psychiatrist or licensed child and adolescent mental health clinician will be 
arranged.
In cases where it is determined that IMP did not contribute to the adverse event of depression or 
suicidality, the investigator will consult with the medical monitor and/or sponsor to determine 
whether the patient should continue in the study.
A reference sample is provided in Appendix E.
7.10.
Neurological Examinations
Neurological examination, including mental status, cranial nerves, motor system (strength, tone, 
and posture), coordination, gait and balance, tendon reflexes, and sensation, will be performed at 
the time points detailed in Table 1. Any neurological examination finding that is judged by the 
investigator as a potentially clinically significant change (worsening) compared with the 
screening value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2. 
7.11.
Concomitant Therapy or Medication
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 A, Table 5. The tables of 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. Prohibited medications that are associated with QTc prolongation are listed in 
Appendix A, Table 6, while prohibited antipsychotic drugs are listed in Appendix A, Table 7.
7.12.
Methods and Timing 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 timing of assessing safety data are discussed in Section 3.13. Procedures for 
recording safety data are discussed in Section 13.1, and methods of analyses are discussed in 
Section 9.7.2. 
Information about the IDMC used for this study is provided in Section 3.7.3.


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8.
ASSESSMENT OF PHARMACOKINETICS AND SCREENING 
ASSESSMENTS
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 needed. 
Blood sampling for pharmacokinetic analysis will be performed at the week 12 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 before the 
week 12 visit. The date and time of the last dose of study medication before the week 12 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 12, 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 metabolites will be pooled with previous data 
and incorporated into a population pharmacokinetic analysis. The population pharmacokinetic 
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. 
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 PGx evaluation on the optional informed consent/assent, a pharmacogenetic 
(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 
related to pharmacokinetics, safety features, drug mechanism of action, Tourette syndrome, or 


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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 clinical study report.
9.1.
Sample Size and Power Considerations
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 12 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. 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.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of IMP. In this 
population, treatment will be assigned based upon the treatment patients actually receive, 
regardless of the treatment to which they were randomized. 
9.2.3.
Modified Intent-to-Treat Analysis Set
The Modified Intent-to-Treat (mITT) analysis set will include all patients in the ITT population 
who receive at least 1 dose of IMP and have both a baseline and at least 1 post-baseline YGTSS 
assessment. In this population, 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.
9.2.4.
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 week 9 or week 12, who have not 
taken prohibited concomitant medications as indicated in exclusion criterion, and who have no 


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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. All exclusions from the per-
protocol analysis set will be reviewed in the blinded data review meeting before database lock.
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the primary and 
secondary statistical analyses.
9.4.
Study Population
The mITT analysis set (see Section 9.2) 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 for this study is the change in the TTS (of the YGTSS) from 
baseline to week 12. 
9.5.2.
Key Secondary Endpoints
Key secondary endpoints for this study are as follows: 
1.
Change in the TS-CGI score from baseline to week 12
2.
Change in the TS-PGII score from baseline to week 12
3.
Change in the C&A-GTS-QOL ADL subscale score from baseline to week 12


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9.5.3.
Exploratory Endpoints
Exploratory endpoints for this study are as follows: 
 
 
 
 
9.5.4.
Planned Method of Analysis
The mITT analysis set (see Section 9.2) will be used for all efficacy analyses. Summaries will be 
presented by treatment group. 
9.5.4.1.
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 (5 levels: 
weeks 2, 4, 6, 9, and 12), 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. 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 least squares means of the change in TTS from baseline at 
week 12 will be compared (the active 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.


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9.5.4.2.
Sensitivity Analysis
Sensitivity analyses for missing data, the statistical model, and the increase in sample size will be 
provided in the statistical analysis plan.
9.5.4.3.
Key Secondary Efficacy Analyses
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. The change in the TS-CGI (1) and C&A-GTS-QOL ADL subscale (3) scores from 
baseline to week 12 will be summarized and analyzed in the same fashion as the primary 
analysis, with the exception that the baseline value of the given endpoint will be included as the 
covariate. TS-PGII (2) will be analyzed using a Cochran-Mantel-Haenszel row mean score test 
with a modified ridit scoring that controls for age group.
9.5.4.4.
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 secondary endpoints (Section 9.5.2) until 
either an analysis produces a p-value >0.05 or all analyses result in a p-value ≤0.05.
9.7.
Safety Endpoints and Analysis
Safety analyses will be performed on the safety analysis set.
9.7.1.
Safety Endpoints
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 CDI-2 (Parent and Self-report 
versions)

observed values in the C-SSRS

observed values in 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)
9.7.2.
Safety Analysis
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events, 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.


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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 versions) will be presented by treatment group for all patients.
9.8.
Pharmacokinetic Analysis
The pharmacokinetic endpoint is listed in Section 2.3.5. Samples collected for pharmacokinetic 
analysis will be quantified for α-HTBZ and β-HTBZ of TEV-50717, and other metabolites (as 
needed), will be analyzed using population pharmacokinetic techniques. Analysis methods will 
be detailed in a separate population pharmacokinetic analysis plan. Exploratory 
pharmacokinetic/PD analysis may be performed on PD/safety endpoints.
9.9.
Planned Interim Analysis
No interim analysis is planned for this study.
9.10.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable national, local, and 
regional requirements and regulations.


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


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


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


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


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


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12.
ETHICS
Details of compliance with regulatory requirements and applicable laws are provided in 
Section 1.6.
12.1.
Informed Consent/Assent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and parent/legally acceptable representative of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB. All written and oral information 
about the study will be provided in a language as nontechnical as practical to be understood by 
the parent/legally acceptable representative and the patient. The patient and parent/legally 
acceptable representative should be given ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study. The above should be detailed in 
the source documents.
A personally signed and dated informed consent form will be obtained from parent/legally 
acceptable representative, and a signed and dated assent, depending on the child’s age, as 
appropriate, will be obtained from each patient (if the patient is able) before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained; according to national and local IEC/IRB requirements. The 
forms will be signed and dated also by the person who conducted the informed consent 
discussion. The investigator will keep the original informed consent/assent forms, depending on 
the child’s age, as appropriate, and copies will be given to the patients. It will also be explained 
to the patients (and parent/legally acceptable representative) that they are free to refuse 
participation in the study and free to withdraw from the study at any time without prejudice to 
future treatment.
12.2.
Competent Authorities and Independent Ethics 
Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national and local competent 
authority and to each IEC/IRB for review. As required, the study will not start at a given 
investigational center before the IEC/IRB and competent authority (where applicable) for the 
investigational center give written approval or a favorable opinion.
12.3.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number.
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and transcribed to the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, Global Quality Assurance, or 
competent authorities. Personal medical information will always be treated as confidential.


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12.4.
Declaration of the End of Clinical Study
The end of study is defined as the date of the week 14 visit of the last participant.
For investigational centers located in the European Union, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/EC, Article 10(c); 
for other countries, national and local regulations will be followed.
12.5.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study may be registered on clinical studies registry websites.


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


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


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records to the sponsor. The investigator shall notify the sponsor of any accidental loss or 
destruction of study records. 


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


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


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16.
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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.
Rubin DB. Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & Sons. 
1987.
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.
Schenker N and Taylor JMG. Partially Parametric Techniques for Multiple Imputation. 
Computational Statistics and Data Analysis 1996;22:425-446.
Scherman D, Gasnier B, Jaudon P, Henry JP. Hydrophobicity of the tetrabenazine-binding site of 
the chromaffin granule monoamine transporter. Mol Pharmacol 1988;33(1):72-7.
Shaw Z, Coffey B. Tics and Tourette syndrome. Psychiatr Clin North Am 2014 Sep;37(3):269-
86.
Su M, McFarlane F, Cavanna A, et al. The English Version of the Gilles de la Tourette 
Syndrome–Quality of Life Scale for Children and Adolescents (C&A-GTS-QOL). J Child 
Neurol 2017;32(1):76-83. 
Sun S, Wang S. The Children’s Depression Inventory in worldwide child development research: 
a reliability generalization study. J Child Fam Stud 2015;24(8):2352-63.
Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor 
and other hyperkinetic movements. Tremor Other Hyperkinet Mov 2013;3.
Wijemanne S, Wu LJ, Jankovic J. Long-term efficacy and safety of fluphenazine in patients with 
Tourette syndrome. Mov Disord 2014 Jan;29(1):126-30.
Xenazine: Highlights of Prescribing Information. 2015. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021894s010lbl.pdf. Accessed 27 
Oct 2015.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 01 Dated 22 June 2017
The primary reason for this amendment is to change aspects of the conduct, concomitant 
mediations, titration instructions, sample size, acceptable contraceptive methods, analysis of the 
data, and clinical study personnel.
This amendment is considered to be substantial (ie, requires approval by CA, IEC, and/or IRB) 
by the sponsor’s Authorized Representative. Other nonsubstantial changes have been made to the 
protocol (and protocol synopsis, as appropriate). These changes are unlikely to affect the safety 
or rights (physical or mental integrity) of the patients in this clinical study or the scientific value 
of the clinical study.
Original text with changes shown
New wording
Reason/Justifi
cation for 
change
CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed 
below: 
For medical issues, contact the 
physician listed below: 
This change 
was made to 
update the 
medical issue 
contact 
physician.
For operational issues, contact the operational 
lead listed below: 
 
For operational issues, contact the 
operational lead listed below: 
 
 
 
This change 
was made to 
update the 
protocol 
contact 
physicians.


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change
For protocol issues, contact the study leader 
listed below:
 
 
 
1.4. Known and Potential Risks and Benefits to Human Patients (Other sections affected by this 
change: 1.4.1.1., 1.4.1.2., 1.4.2.)
Additional information regarding benefits and 
risks to patients may be found in the current IB 
and in the United States prescribing information 
for AUSTEDO™(deutetrabenazine).
1.4.1.1.Benefits of TEV50717
Although the efficacy of TEV 50717 in patients 
with TS has not yet been definitively 
established, preliminary efficacy data from 
Study SD 809 C 17 indicates a clinically 
meaningful reduction in motor and phonic tics 
observed by patients, parents, and treating 
clinicians. Furthermore, TEV 50717 has the 
same mechanism of action and indistinguishable 
pharmacology as tetrabenazine, an agent that is 
generally accepted among movement disorder 
experts to provide clinical benefit in this patient 
population (Jankovic and Kurlan 2011). Based 
on the nonclinical data discussed above and 
similar efficacy observed for tetrabenazine and 
TEV 50717 in studies of other indications (see 
Additional information regarding 
benefits and risks to patients may be 
found in the current IB and in the 
United States prescribing 
information for AUSTEDO™
(deutetrabenazine).
The section 
was modified 
to reflect 
accurate 
information 
regarding 
known and 
potential 
benefits and 
risks to 
patients.


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


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3.1.2 Screening Period (Other sections affected by this change: Sections 3.13, 3.13.1., 4.1, 12.1.)
After informed consent (and written assent 
and/or co-consent for patients 14 years of age 
and older, as appropriate) is obtained, patients 
who are stable from a medical and psychiatric 
standpoint will undergo a screening evaluation, 
including medical history, physical and 
neurological examination, laboratory testing, 
and 12-lead ECG, along with rating scales to 
assess severity, frequency, and impairment of 
tics and comorbid TS symptoms and behavioral 
status. 
After informed consent (and written 
assent and/or co-consent for patients 
14 years of age and older, as 
appropriate) is obtained, patients 
who are stable from a medical and 
psychiatric standpoint will undergo 
a screening evaluation, including 
medical history, physical and 
neurological examination, 
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.
An option was 
added for co-
consent for 
patients 
14 years of age 
and older.
3.1.3 Titration Period (Other sections affected by this change: Section 5.1)
Patients who remain eligible for participation in 
the study will be randomized at the baseline 
visit (day 1), and that evening (ie, after the 
study visit) will receive 6 mg of blinded IMP 
with food. Tablets should be taken with food 
(eg, a snack) and should not be taken on an 
empty stomach.
Patients who remain eligible for 
participation in the study will be 
randomized at the baseline visit 
(day 1), and that evening (ie, after 
the study visit) will receive 6 mg of 
blinded IMP with food. Tablets 
should be taken with food (eg, a 
snack) and should not be taken on 
an empty stomach.
A statement 
was added to 
further clarify 
that the IMP 
should be taken 
with a snack 
and not on an 
empty stomach.
3.1.3 Titration Period
The dose of the study drug IMP should be 
increased on a weekly basis until one of the 
following criteria is met:

The investigator determines there has been 
a clinically meaningful reduction in tics, as 
indicated by a sustained reduction in the 
TS-CGI

there is optimal reduction of tics, as 
determined by the investigator, in 
consultation with the patient and 
caregiver/adult
The dose of the IMP should be 
increased on a weekly basis until 
one of the following criteria is met:
The investigator determines there 
has been a clinically meaningful 
reduction in tics, as indicated by 
a sustained reduction in the TS-
CGI
The titration 
instructions 
were modified 
to provide more 
objective 
guidance to 
investigators, 
who are now 
directed to 
increase the 
dose until there 
is a sustained 
reduction in the 
TS-CGI.


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3.1.5. Washout Period and Follow-up
Patients who complete the study may be eligible 
to begin participation in an open-label safety 
extension study of TEV-50717 at that 
time(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 (Study TV50717-CNS-30047) 
may begin/resume tic therapy medication after 
the first week of the washout period.
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).
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 (Study 
TV50717-CNS-30047) may 
begin/resume tic therapy medication 
after the first week of the washout 
period.
The study 
number of the 
extension study 
was added, the 
washout period 
was clarified, 
and 
concomitant 
medications 
allowed during 
the washout 
period were 
clarified.
3.6 Randomization and Blinding
In addition, the sponsor’s clinical personnel and 
all vendors (with exception of the Interactive 
Response Technology [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 
In addition, the sponsor’s clinical 
personnel and all vendors (with 
exception of the Interactive 
Response Technology [IRT] vendor 
and the bioanalytical sample 
analysis vendor) involved in the 
study will be blinded to the IMP 
Statement was 
added about 
blinding until 
completion of 
the safety 
extension study 
TEV-50717-


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Original text with changes shown
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Reason/Justifi
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change
of this study, the study site may remain blinded 
to patient treatment assignments until 
completion of the safety extension study 
TV50717-CNS-30047.
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.
CNS-30047.
3.8.1 IMP (Other sections affected by this change: Section 1.2)
The IMP is a matrix formulation and is 
designed as a gastro-erosional tablet to be 
administered with food and should not be taken 
on an empty stomach. The IMP is coated with a 
white polymer coating to aid in swallowing. 
TEV-50717 tablets have been manufactured 
according to current Good Manufacturing 
Practice regulations. TEV-50717 tablets are 
available in the following strengths: 6, 9, 12, 15, 
and 18 mg, all of which are identical in size, 
shape, and color (white). IMP will be supplied 
in 20-count tablets per dose strength per bottle. 
The placebo tablets and packaging will match 
those for TEV-50717. Each bottle (20-count 
tablets per dose strength per bottle) will contain 
a sufficient supply of drug until the next 
specified visit/telephone contact, plus overage 
to account for potential delays in study visits.
The IMP is a matrix formulation and 
is designed as a gastro-erosional 
tablet to be administered with food 
and should not be taken on an empty 
stomach. The IMP is coated with a 
white polymer coating to aid in 
swallowing. TEV-50717 tablets 
have been manufactured according 
to current Good Manufacturing 
Practice regulations. TEV-50717 
tablets are available in the following 
strengths: 6, 9, 12, 15, and 18 mg, 
all of which are identical in size, 
shape, and color (white). IMP will 
be supplied in 20-count tablets per 
dose strength per bottle. The 
placebo tablets and packaging will 
match those for TEV-50717. Each 
bottle (20-count tablets per dose 
strength per bottle) will contain a 
sufficient supply of drug until the 
next specified visit/telephone 
contact, plus overage to account for 
potential delays in study visits.
Additional 
details were 
added to the 
description of 
IMP.
3.13. Study Procedures
Study procedures and assessments with their 
timinge points are summarized presented in
Table 1. During a visit, study procedures and 
assessments should be performed in the order 
specified in the study manual.
Study procedures and assessments 
with their time points are presented 
in Table 1. During a visit, study 
procedures and assessments should 
be performed in the order specified 
in the study manual.
The section 
was modified 
to provide 
guidance that 
the order of 
procedures will 
be determined 
in a study 
manual. 


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3.13. Study Procedures (Other sections affected by this change: Sections 5.3, 7.10)
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. 
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. 
This additional 
instruction will 
allow the 
investigator to 
monitor new 
concomitant 
medications, 
thus enhancing 
patient safety.
3.13.1. Procedures for Screening and Enrollment
After informed consent is obtained, patients 
who are screened will be assigned an 8 digit 
permanent identification number such that all 
patients from each investigational center are 
given consecutive identification numbers in 
successive order of inclusion. The first 2 digits 
of the screening number will be the number 
assigned to the country where the 
investigational center is located, the next 
3 digits will be the designated investigator 
center number, and the last 3 digits will be 
assigned at the investigator center (eg, if the 
number assigned to the country is 01, the 
third patient screened at center 5 would be 
given the number of 01005003).
This paragraph 
was deleted to 
remove the 
detailed 
specificity for 
patient ID 
assignment.
3.13.1. Procedures for Screening and Enrollment
administer the following questionnaires 
(Note: For MINI Kid and C-SSRS, children 
13 years of age and under must be 
interviewed in conjunction with the 
caregiver/adult. For children over 13 years of 
age, caregiver/adult involvement is strongly 
encouraged. Questions should be directed to 
the child, but the caregiver/adult should be 
encouraged to add relevant information. The 
administer the following 
questionnaires (Note: For MINI 
Kid and C-SSRS, children 13 
years of age and under must be 
interviewed in conjunction with 
the caregiver/adult. For children 
over 13 years of age, 
caregiver/adult involvement is 
strongly encouraged. Questions 
Specific 
instruction was 
provided for 
the YGTSS 
assessment to 
be performed 
before any 
blood draws or 
ECG.


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change
YGTSS questionnaire should be performed 
before any blood draws or ECG 
assessments.):
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.):
3.13.1.1. YGTSS Rater Certification
3.13.1.1. YGTSS Rater Certification
All investigators and subinvestigators who will 
be administering the YGTSS from screening 
through the end of study visit must undergo and 
pass a Rater Certification Program which will
be provided separately from this protocol. Every 
effort must be made to ensure that the same 
certified rater administers the YGTSS to a 
specific patient at all visits, especially at the 
baseline and week 12/early termination visits. 
However, if due to unforeseen circumstances 
the same rater is absolutely unavailable to 
complete a visit rating, the YGTSS can be 
administered only by another certified 
individual from that study site.
3.13.1.1. YGTSS Rater Certification
All investigators and 
subinvestigators who will be 
administering the YGTSS from 
screening through the end of study 
visit must undergo and pass a Rater 
Certification Program which will be 
provided separately from this 
protocol. Every effort must be made 
to ensure that the same certified 
rater administers the YGTSS to a 
specific patient at all visits, 
especially at the baseline and week 
12/early termination visits. 
However, if due to unforeseen 
circumstances the same rater is 
absolutely unavailable to complete a 
visit rating, the YGTSS can be 
administered only by another 
certified individual from that study 
site.
This section 
was added for 
instruction 
related to 
protocol 
specific 
YGTSS rater 
certification.
3.13.2. Procedures before IMP Treatment (Baseline/Day 1) (Other sections affected by this change: 
3.13.3.1.2., 3.13.3.2.1., 3.13.3.2.2., 3.13.4.1.)
administer the following questionnaires 
(Note: For C-SSRS, 
 
, and GTS-QOL, children 13 years 
of age and under must be interviewed in 
conjunction with the caregiver/adult. For 
children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. 
Questions should be directed to the child, but 
the caregiver/adult should be encouraged to 
add relevant information. The YGTSS, TS-
CGI, and 
 questionnaires should be 
performed before any blood draws or ECG 
administer the following 
questionnaires (Note: For C-
SSRS, 
 
and GTS-QOL, 
children 13 years of age and 
under must be interviewed in 
conjunction with the 
caregiver/adult. For children over 
13 years of age, caregiver/adult 
involvement is strongly 
encouraged. Questions should be 
directed to the child, but the 
Specific 
instruction was 
provided for 
the YGTSS, 
TS-CGI, and 
 
assessments to 
be performed 
before any 
blood draws or 
ECG.


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Study TV50717-CNS-30046
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Original text with changes shown
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assessments.):
caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS, TS-
CGI, and 
 questionnaires 
should be performed before any 
blood draws or ECG 
assessments.):
4.1 Patient Inclusion Criteria
j.
Females may be included only if they have 
a negative β-HCG test at baseline or are sterile. 
Definitions of sterile given in Appendix L.
k.
Females of childbearing potential whose 
male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth 
control methods for the duration of the study 
(ie, starting at screening) and for 30 days or 5 
half-lives, whichever is longer after last dose of 
IMP. Further details are included in Appendix 
L.
j.
Females may be included only if 
they have a negative β-HCG test at 
baseline or are sterile. Definitions of 
sterile given in Appendix L.
k.
Females of childbearing 
potential whose male partners are 
potentially fertile (ie, no vasectomy) 
must use highly effective birth 
control methods for the duration of 
the study (ie, starting at screening) 
and for 30 days or 5 half-lives, 
whichever is longer after last dose 
of IMP. Further details are included 
in Appendix L.
Additional 
inclusion 
criteria for 
females were 
added to 
include β-HCG 
test and the 
requirement to 
use highly 
effective birth 
control 
methods.
4.2 Patient Exclusion Criteria
m. Patient has a QT interval corrected for heart 
rate using Frederica’s formula (QTcF) interval 
value >4450 msec (males) or >460 msec 
(females) or >480 msec (with right bundle 
branch block) on 12-lead ECG at screening. 
n.
Patients with a history of torsade de pointes, 
congenital long QT syndrome, 
bradyarrhythmias, or uncompensated heart 
failure.
m. Patient has a QT interval 
corrected for heart rate using 
Frederica’s formula (QTcF) interval 
value >450 msec (males) or >460 
msec (females) or >480msec (with 
right bundle branch block) on 12-
lead ECG at screening. 
n.
Patients with a history of 
torsade de pointes, congenital long 
QT syndrome, bradyarrhythmias, or 
uncompensated heart failure.
The exclusion 
criteria were 
modified to 
define criteria 
for QTc.
4.2 Patient Exclusion Criteria
s.t. The pPatient is a pregnant or lactating 
female, breastfeeding or plans to become 
pregnant during the study.
t.
The patient is a pregnant or 
lactating female, or plans to become 
pregnant during the study.
Wording of 
patient 
exclusion 
criteria 
regarding 
pregnancy or 
lactation was 


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changed.
4.4 Withdrawal Criteria and Procedures (Other sections affected by this change: 7.1.7; Section 7.5)
In accordance with the Declaration of Helsinki 
(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 in the event of intercurrent illness, 
adverse events, pregnancy (see Section 7.3), or 
other reasons concerning the health or 
well-being of the patient, or in the event of lack 
of cooperation. If a post-baseline QTcF value 
>500 msec or change from baseline >60 msec is 
found, the investigator should repeat the ECG 
assessment twice and compare the average of 
the 2 pre-treatment QTcF values (baseline and 
screening) to the average of the 3 post-baseline 
QTcF values. The IMP must be stopped for any 
confirmed post-baseline QTcF value >500 msec 
or increase from baseline >60 msec.
In accordance with the Declaration 
of Helsinki (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 in 
the event of intercurrent illness, 
adverse events, pregnancy (see 
Section 7.3), or other reasons 
concerning the health or well-being 
of the patient, or in the event of lack 
of cooperation. If a post-baseline 
QTcF value >500 msec or change 
from baseline >60 msec is found, 
the investigator should repeat the 
ECG assessment twice and compare 
the average of the 2 pre-treatment 
QTcF values (baseline and 
screening) to the average of the 3 
post-baseline QTcF values. The IMP 
must be stopped for any confirmed 
post-baseline QTcF value >500 
msec or increase from baseline >60 
msec.
Text to identify 
QTc changes 
that will require 
IMP 
suspension was 
added.
5.1. Drugs Administered During the Study
Weight category Daily dose 
(mg) at the start of visit/week
Study 
weeka
20 to <30 
kg
(44 to 
<66 lbs)
30 to 
<40 kg
66 to 
<88 lbs)
≥40 kg
(≥88 lbs)
Week 1 
Baseline
6 mg
6 mg
6 mg 
(Days 1 
and 2)
12 mgb
Week 2 1
12 mg
12 mg
18 mg
Week 3 2
18 mg
18 mg
24 mg
Week 43
18 mgc
24 mgc
30 mg
Daily dose (mg) at 
the start of 
visit/week
Stud
y 
week
a
20 to 
<30
kg
(44 to 
<66
lbs)
30 to 
<40 
kg
(66 
to 
<88 l
bs)
≥40 
kg
(≥88
lbs)
The table was 
updated with 
weight details 
and 
clarifications 
regarding how 
study weeks are 
defined with 
the occurring at 
the beginning 
of the week.


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Week 54
24 mgc 
30 mgc
36 mgc
Week 6 5
24 mgc
36 mgc
42 mgc
Week 7 6
30 mgc
42 mgc
48 mgc
Basel
ine
6 mg
6 mg
6 mg 
(Days 
1 and 
2)
12 
mgb
Wee
k 1 
12 
mg
12 
mg
18 
mg
Wee
k 2 
18 
mg
18 
mg
24 
mg
Wee
k 3 
18 
mgc
24 
mgc
30 
mg
Wee
k 4
24 
mgc
30 
mgc
36 
mgc
Wee
k 5 
24 
mgc
36 
mgc
42 
mgc
Wee
k 6 
30 
mgc
42 
mgc
48 
mgc
7.5. Clinical Laboratory Tests
The clinical significance of the lab values will 
be evaluated by the criteria described in the 
study lab manual and by the judgment of the 
investigator.
The clinical significance of the lab 
values will be evaluated by the 
criteria described in the study lab 
manual and by the judgment of the 
investigator.
This sentence 
included to 
provide further 
guidance 
regarding 
clinical 
significance of 
laboratory 
values and 
investigator 
judgement. 
7.7. Electrocardiography
A 12-lead ECG will be conducted at the time 
points detailed in Table 1. All ECGs will be 
performed after at least 5 minutes rest in a 
supine or semi-supine position. A qualified 
physician at a central diagnostic center will be 
interpreting the ECG.
All ECG results outside of the reference ranges 
will be judged by the investigator as belonging 
to one of the following categories:
A 12-lead ECG will be conducted at 
the time points detailed in Table 1. 
All ECGs will be performed after at 
least 5 minutes rest in a supine or 
semi-supine position. A qualified 
physician at a central diagnostic 
center will be interpreting the ECG.
All ECG results outside of the 
reference ranges will be judged by 
Twelve-lead 
ECG 
interpretation 
details were 
updated.


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
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.The 12 lead 
ECGs will be interpreted by a cardiologist at a 
central diagnostic center. Heart rate and ECG 
intervals (PR, QRS, QT, and QTcF) and clinical 
interpretation will be assessed by the central 
cardiologist, recorded, and monitored as 
described in Section 7.1.2.
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
8.1. Pharmacokinetic Assessment 
Plasma samples for both α-HTBZ and β-HTBZ 
metabolites will be pooled with previous data 
and incorporated into a population 
pharmacokinetic analysis. The population 
pharmacokinetic 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.
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. 
Plasma samples for both α-HTBZ 
and β-HTBZ metabolites will be 
pooled with previous data and 
incorporated into a population 
pharmacokinetic analysis. The 
population pharmacokinetic 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.
Samples for 
pharmacokinetic 
assessment were 
updated.
9.1 Sample Size and Power Considerations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5.4.2 Sensitivity Analysis

The primary analysis at week 12 will be 
repeated on a complete data set using 
multiple imputation methodology for 
imputing missing data using an MNAR 
missing data assumption to investigate 
when statistical significance disappears.

Using the same repeated measures model as 
described for the primary analysis, the 
groups will be compared at each of weeks 
2, 4, 6, and 9.

An analysis of covariance (ANCOVA) 
model will be fit using the change from 
baseline to week 12 as the dependent 
variable, treatment group, and the baseline 
value as a covariate. For patients with 
missing data at week 12, the least favorable 
change from baseline to week 12 observed 
in either treatment group will be used as the 
dependent variable.

An ANCOVA model, as described above, 
will be fit. For patients with missing data at 
week 12, the last available change from 
baseline for the patients will be used as the 
dependent variable. 

The primary analysis at week 12 
will be repeated on a complete 
data set using multiple 
imputation methodology for 
imputing missing data using an 
MNAR missing data assumption 
to investigate when statistical 
significance disappears.
Sensitivity 
analyses were 
simplified and 
made 
consistent with 
Study 
TV50717-
CNS-30060.
9.5.4.3. Key Secondary Efficacy Analyses
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, 
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 
The purpose of 
the hierarchical 
analysis was 
added.


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and remaining hypotheses will be considered 
exploratory rather than confirmatory. The 
change in the TS-CGI (1), 
(2), and 
GTS-QOL physical/ADL subscale (3) scores 
from baseline to week 12 will be summarized 
and analyzed in the same fashion as the primary 
analysis, with the exception that the baseline 
value of the given endpoint will be included as 
the covariate. 
testing will not be carried out on the 
remaining hypotheses, and 
remaining hypotheses will be 
considered exploratory rather than 
confirmatory. The change in the 
TS-CGI (1), 
2), and GTS-
QOL physical/ADL subscale (3) 
scores from baseline to week 12 will 
be summarized and analyzed in the 
same fashion as the primary 
analysis, with the exception that the 
baseline value of the given endpoint 
will be included as the covariate.
APPENDIX A ALLOWED AND DISALLOWED MEDICATIONS
Prohibited QTc Prolonging Drugs
Generic
Class/clinical use
Note
Azithromyc
in
Antibiotic/bacterial 
infection
Chloroquin
e / 
Mefloquine
Anti malarial/malaria 
infection
Clarithromy
cina
Antibiotic/bacterial 
infection
Domperido
ne
Anti nausea/nausea
Not 
availa
ble in 
USA
Droperidol
Sedative; anti
nausea/anesthesia 
adjunct, nausea
Erythromyc
ina
Antibiotic; 
gastrointestinal (GI) 
stimulant; GI motility
Moxifloxac
in
Antibiotic/bacterial 
infection
Sevoflurane Anesthetic, 
general/anesthesia
Probucol
Antilipemic/hypercholest
erolemia
Not 
availa
ble in 
Not applicable
The restriction 
on the use of 
concomitant 
medications 
that are 
commonly used 
within the 
pediatric 
population and 
that prolong the 
QT interval 
(eg, antibiotics) 
was removed. 
Antipsychotic 
medications 
remain 
prohibited 
owing to their 
ability to 
confound the 
efficacy and 
safety of TEV-
50717. These 
changes were 
made based on 
the 
cardiodynamic 
data from the 
thorough QT 
study, the PK-
PD modeling of 
maximal steady 


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change
USA
Sparfloxaci
n
Antibiotic/bacterial 
infection
Not 
availa
ble in 
USA
a Systemic use only. Topical use is allowed.
USA=United States of America.
exposure in 
studies with 
HD and TD, 
and with 
observed data 
from the TD 
program in 
which QT 
prolonging
drugs were 
safely 
administered in 
conjunction 
with TEV-
50717.
APPENDIX I TOURETTE SYNDROME-PATIENT GLOBAL IMPRESSION OF SEVERITY
Not applicable
Pictorial added
A pictorial of 
the recently 
tested PGIS 
questions 
designed for 
pediatric 
patients was 
inserted.
APPENDIX L BIRTH CONTROL METHODS AND PREGNANCY TESTING
Not applicable
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, 
Acceptable 
contraceptive 
methods for 
females have 
been altered to 
include 
abstinence in 
the definition 
of highly 
effective birth 
control.


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change
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
Description of different birth control 
methods
Highly effective birth control 
methods:
Highly effective birth control 
methods that can achieve a failure 
rate of less than 1% per year when 
used consistently and correctly are 
considered. Such methods include:
•
Combined estrogen and 
progestogen hormonal contraception 
(oral, intravaginal, transdermal) 
associated with inhibition of 
ovulation; these should be initiated 
at least 7 days (for IMPs without 
suspected 
teratogenicity/genotoxicity) and 1 
month (for IMPs potentially 
teratogenic/genotoxic) before the 
first dose of IMP.
•
Progestogen-only hormonal 
contraception (oral, injectable, 
implantable) associated with 
inhibition of ovulation; these should 
be initiated at least 7 days (for IMPs 


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change
without suspected 
teratogenicity/genotoxicity) and 1 
month (for IMPs potentially 
teratogenic/genotoxic) before the 
first dose of IMP.
•
Intrauterine device and 
intrauterine hormone-releasing 
system need to be in place at least 2 
months before screening.
•
Bilateral tubal occlusion
•
Vasectomized partner provided 
he is the sole sexual partner and has 
received medical assessment of the 
surgical process.
•
Sexual abstinence is only
considered a highly effective 
method if defined as refraining from 
heterosexual intercourse in the 
defined period. The reliability of 
sexual abstinence needs to be 
evaluated in relation to the duration 
of the clinical study and the 
preferred and usual lifestyle of the 
patient.
•
Periodic abstinence (eg, 
calendar, ovulation, symptothermal, 
post-ovulation methods), declaration 
of abstinence for the duration of a 
study, and withdrawal are not
acceptable methods of contraception 
(according to the Medicines and 
Healthcare Products Regulatory 
Agency).
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 


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Reason/Justifi
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change
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.
Vasectomy:
Use of contraceptive methods 
applies also to vasectomized men, 
because of the risk associated with 
transfer of a drug via seminal fluid.
Contraception for female partners of 
male study participants:
Female partners (who are not 
pregnant) of male study participants 
must use contraception for non-
pregnant WOCBP until the end of 
relevant systemic exposure in case 
of IMPs with genotoxicity or IMPs 
with no genotoxicity but 
demonstrated or suspected human 
teratogenicity/fetotoxicity.
Pregnancy tests in females of 
childbearing potential:
1. Conduct monthly pregnancy 
testing from first dose of IMP 
until last dose of IMP and 
additional 30 days in case the 
IMP does not have a marketing 
authorization and has suspected 


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


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New wording
Reason/Justifi
cation for 
change
study participants:
Male study participants must use 
condoms during intercourse if their 
female partners are pregnant.


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17.2.
Amendment 02 Dated 03 October 2017
The primary reason for this amendment is to incorporate CYP2D6 genotyping results into the 
IRT in order to allow for a dose cap to be applied in a blinded manner, update drug packaging to 
ensure blinding of CYP2D6 impairment status, reorder the statistical testing methodology (ie, the 
inclusion of TS-PGII assessment after TS-CGI and before the C&A-GTS-QOL ADL subscale), 
clarify the study day window for each visit or call, and include prohibited medications that are 
associated with QTc prolongation.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, 
IEC, and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial changes 
have been made to the protocol (and protocol synopsis, as appropriate). These changes are 
unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical 
study or the scientific value of the clinical study.
Protocol Amendment 01 text with 
changes shown
New wording
Reason/Justification 
for change
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Central Institutional Review Board
Quorum Review IRB
1501 Fourth Avenue, Suite 800
Seattle, WA 98101
USA 
Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Copernicus Group IRB
1 Triangle Drive
Durham, NC 27709
USA
Change to central 
IRB
CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For operational issues, contact the 
operational lead listed below: 
 
 
For protocol issues, contact the study 
For operational issues, contact the 
operational lead listed below:
 
For protocol issues, contact the study 
leader listed below:
 
Change in 
Nuvelution study 
personnel


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 01 text with 
changes shown
New wording
Reason/Justification 
for change
leader listed below:
 
 
 
1.2 Name and Description of IMP (Other sections affected by this change: 3.8.1, 3.13 [Table 1, 
footnote “y”], 3.13.2, 3.13.3.1.1, 3.13.3.1.2, 3.13.3.2.1, 3.13.3.2.2, 3.13.5, 5.1, 11.4.1)
The IMP will be supplied in 
2040-count tablets per dose strength 
per bottleblister packs
The IMP will be supplied in 40-count 
blister packs
Blister pack IMP 
replacing bottled 
IMP for blinding 
maintenance 
purposes
1.5.1 Justification for Dosage of Active Drug (Other section affected by this change: 3.1.3 and 5.1)
The dose ranges to be evaluated in this 
study, based on body weight and the 
use of strong CYP2D6 inhibitors 
impairment status at baseline, were 
selected on the basis of the safety, 
preliminary efficacy, and population 
pharmacokinetic data generated from 
Study SD-809-C-17 (Table 2 and Table 
3).
The dose ranges to be evaluated in this 
study, based on body weight and 
CYP2D6 impairment status at baseline, 
were selected on the basis of the safety, 
preliminary efficacy, and population 
pharmacokinetic data generated from 
Study SD-809-C-17 (Table 2).
CYP2D6 genotyping 
adjusted to be 
incorporated at 
screening and by 
CYP Impairment 
status
1.8 Location and Study Duration
This study is planned to be conducted 
in the North America, Russia, and 
Europe, at approximately 50 centers. It 
is expected to start in October 2017 
January 2018 and have a duration of 
approximately 15 months.
This study is planned to be conducted 
in North America, Russia, and Europe, 
at approximately 50 centers. It is 
expected to start in January 2018 and 
have a duration of approximately 
15 months.
Study start date 
pushed out to 
January 2018, and 
Russia was specified 
as a location to be 
included for this 
study’s conduct.


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Protocol Amendment 01 text with 
changes shown
New wording
Reason/Justification 
for change
2.3.2 Key Secondary Efficacy Endpoint (Other sections affected by this change: 3.13 [Table 1]), 
9.5.2, 3.3.2
The key secondary efficacy endpoints 
are as follows:
1.
Change in the TS-CGI score from 
baseline to week 12
2.
Change in the
 score from baseline to week 
12 Change in the Tourette Syndrome-
Patient Global Impression of Impact 
(TS-PGII) score from baseline to 
week 12
3.
Change in the Child and 
Adolescent Gilles de la Tourette 
Syndrome - Quality of Life (C&A-
GTS-QOL) physical/activities of daily 
living (ADL) subscale score from 
baseline to week 12
The key secondary efficacy endpoints 
are as follows:
1.
Change in the TS-CGI score from 
baseline to week 12
2.
Change in the Tourette Syndrome-
Patient Global Impression of Impact 
(TS-PGII) score from baseline to 
week 12
3.
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 12
Adjusting of the Key 
secondary efficacy 
endpoint hierarchy. 
was 
removed, and placed 
as an exploratory 
endpoint. TS-PGII 
was inserted as the 
new (2) Secondary 
efficacy endpoint. 
The child and 
adolescent version of 
the GTS-QOL scale 
is now being used to 
assess the (3) 
secondary efficacy 
endpoint.
2.3.3 Exploratory Endpoints (Other sections affected by this change: 3.3.3 and 9.5.3)
Exploratory endpoints are as follows:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory endpoints are as follows:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
was moved 
(removed as a 
secondary efficacy 
endpoint) and is now 
included as an 
exploratory endpoint.


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Protocol Amendment 01 text with 
changes shown
New wording
Reason/Justification 
for change
 
 
 
 
 
 
 
 
 
 
 
 
3.1.1 Overall Design and Screening Period (Other section affected by this change: 5.1)
Throughout the study, patients will 
interact regularly with investigative site 
personnel, in clinic and by telephone, 
for the evaluation of safety, tic severity, 
and behavioral status (in clinic only). 
Based on this information, theThe 
target dose for each patient receiving 
TEV-50717 will be based on body 
weight and 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 dose of IMP for 
each patient will be titrated to an 
optimal level followed by maintenance 
therapy at that dose. Investigators will 
be blinded to CYP status, with a dose 
cap for poor metabolizers prespecified 
by the IRT (Table 2). The overall 
treatment period will be 12 weeks in 
duration, including a titration period of 
7 weeks, a maintenance period of 5 
weeks, followed by a washout period of 
1 week. Site- administered scales 
include the YGTSS, 
Mini 
International Neuropsychiatric 
Interview For Children and 
Adolescents (MINI Kid), and the 
C-SSRS; and self-administered scales 
Throughout the study, patients will 
interact regularly with investigative site 
personnel, in clinic and by telephone, 
for the evaluation of safety, tic 
severity, and behavioral status (in 
clinic only). The target dose for each 
patient receiving TEV-50717 will be 
based on body weight and 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 dose of IMP for each patient will 
be titrated to an optimal level followed 
by maintenance therapy at that dose. 
Investigators will be blinded to CYP 
status, with a dose cap for poor 
metabolizers prespecified by the IRT 
(Table 2). The overall treatment period 
will be 12 weeks in duration, including 
a titration period of 7 weeks, a 
maintenance period of 5 weeks, 
followed by a washout period of 1 
week. Site- administered scales include 
the YGTSS, 
, Mini 
International Neuropsychiatric 
Interview For Children and 
Adolescents (MINI Kid), and the 
C-SSRS; and self-administered scales 
CYP2D6 genotyping 
adjusted to be 
incorporated at 
screening and by 
CYP Impairment 
status. Text has also 
been updated to 
indicate that 
investigators will be 
blinded to CYP 
impairment status 
and how that will be 
addressed throughout 
the study. 
Clarification on the 
involvement of the 
adult/caregiver was 
provided for the 
scales to be used.


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Protocol Amendment 01 text with 
changes shown
New wording
Reason/Justification 
for change
include the TS-PGII, TS PGIS, 
 
 CDI-2, and C&A-GTS QOL. 
For the YGTSS, input from the 
caregiver/adult is required. For both the 
TS-PGII and TS PGIS, input from the 
caregiver/adult is required permitted. 
For all other scales, for children 13 
years of age and under must, interviews
may be interviewed in conjunction
performed separately or jointly with the 
caregiver/adult as appropriate or 
defined by the scale; for children over 
13 years of age, caregiver/adult 
involvement is strongly encouraged.
include the TS-PGII, TS PGIS, 
 
 CDI-2, and C&A-GTS QOL. 
For the YGTSS, input from the 
caregiver/adult is required. For both the 
TS-PGII and TS PGIS, input from the 
caregiver/adult is permitted. For all 
other scales, 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.
3.1.2 Screening Period (Other sections affected by this change: 3.10, 3.13 [Table 1], 3.13.1, 3.13.2)
The screening period in this study is up 
to 4 weeks 31 days (and a minimum of 
3 days).
Patients may be rescreened 1 time if 
there is a change in the patient’s 
medical background, a modification of 
study entry criteria, or other relevant 
change. (Note: Details of rescreening 
must be approved by the study 
monitor.)
The screening period in this study is up 
to 31 days.
Patients may be rescreened 1 time if 
there is a change in the patient’s 
medical background, a modification of 
study entry criteria, or other relevant 
change. (Note: Details of rescreening 
must be approved.)
The screening period 
was updated to more 
clearly indicate a 
maximum of 
31 days, and a 
minimum of 3 days. 
Specific details on 
who must approve of 
rescreening were 
removed.
3.1.4 Maintenance Period (Other section affected by this change: 6)
At week 12, patients will undergo a 
complete evaluation, including physical 
and neurological examination, safety 
laboratory testing, 12-lead ECG, CDI-
2, and C SSRS assessments, as well as 
the YGTSS, TS-CGI, TS-PGII, TS 
PGIS, 
 and 
C&A-GTS-QOL.
At week 12, patients will undergo a 
complete evaluation, including 
physical and neurological examination, 
safety laboratory testing, 12-lead ECG, 
CDI-2, and C SSRS assessments, as 
well as the YGTSS, TS-CGI, TS-PGII, 
TS PGIS, 
 
and C&A-GTS-QOL.
An adjustment was 
made to the scales 
used due to the 
addition of the 
TS-PGII assessment 
and child and 
adolescent version of 
the GTS-QOL.
3.9.2 Drug Accountability
A record of IMP accountability (ie, 
IMP and other materials received, used, 
retained, returned, or destroyed) must 
be prepared and signed by the principal 
investigator or designee, with an 
account given for any discrepancies. 
Empty, partially used, and unused IMP 
will be disposed of per site policy, or
returned to the sponsor or its designee, 
as agreed with the sponsor.
A record of IMP accountability (ie, 
IMP and other materials received, used, 
retained, returned, or destroyed) must 
be prepared and signed by the principal 
investigator or designee, with an 
account given for any discrepancies. 
Empty, partially used, and unused IMP 
will be returned to the sponsor or its 
designee, as agreed with the sponsor.
This update was 
made to clarify that 
unused IMP should
be returned to the 
sponsor or its 
designee.


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3.12 Source Data Recorded on the Case Report Form (Other sections affected by this change: 13.1 
and 13.3.2)
If patient data are processed from other 
vendors (eg, clinical laboratory, central 
ECG, electronic diary data), the results will 
be sent to the investigational center, where 
they will be retained but not entered into 
the CRF.
If patient data are processed from other 
vendors (eg, clinical laboratory, central 
ECG, diary data), the results will be 
sent to the investigational center, where 
they will be retained but not entered 
into the CRF.
A paper diary will be 
used. The indication 
of an “electronic” 
diary was removed.
3.13 Study Procedures
Table 1 was updated
Screening was updated to 31 days
Study days were added in addition to 
the study weeks for clarification of 
study procedure timing.
The visit window was increased 
throughout titration from ±1 day to 
±3 days
A 12-lead ECG assessment was added 
as a baseline assessment
The TS-PGII assessment was added to 
the table, because it was added as a key 
secondary efficacy endpoint
The table of 
procedures was 
updated to provide 
greater clarity of 
study procedure 
timing, to include 
additional/clarified 
assessments, and to 
provide overall 
consistency to all 
changes made during 
this amendment.
3.13.1 Procedures for Screening and Enrollment (Other sections affected by this change: 3.1.1, 
3.13.2, 3.13.3.1.2, 3.13.3.2.1, 3.13.3.2.2, 3.13.4.1, 3.13.5, 6.2.4, 6.2.6, 6.2.7, 7.2.1, 7.2.2) 
The screening visit will take place not 
more than 4 weeks 31 days and no less 
than 3 days before the baseline visit. 
The screening visit may be conducted 
over 2 separate visits at the discretion 
of the investigator. The following 
procedures will be performed at 
screening:
•
obtain written informed 
consent/assent and/or co-consent for 
patients 14 years of age and older 
before any other study related 
procedures are performed
•
review eligibility (inclusion and 
exclusion) criteria
•
inform patients of study restrictions 
and compliance requirements
•
review medical and psychiatric 
history
The screening visit will take place not 
more than 31 days and no less than 
3 days before the baseline visit. The 
screening visit may be conducted over 
2 separate visits at the discretion of the 
investigator. The following procedures 
will be performed at screening:
•
obtain written informed 
consent/assent and/or co-consent for 
patients 14 years of age and older 
before any other study related 
procedures are performed
•
review eligibility (inclusion and 
exclusion) criteria
•
inform patients of study restrictions 
and compliance requirements
•
review medical and psychiatric 
history
•
review demographics information
The procedures to be 
followed (ie, the 
involvement of the 
adult/caregiver) for 
various scales used 
to assess results of 
patients in this study 
have been further 
clarified for children 
under the age of 13.


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•
review demographics information
•
measure vital signs (pulse, BP, 
body temperature, and respiratory rate) 
•
perform full physical and 
neurological examinations (including 
height and weight. Note: Weight must 
be measured with shoes and outerwear 
off)
•
perform 12-lead ECG (Note: ECG 
will be performed after at least 5 
minutes rest in a supine or semi-supine 
position)
•
perform clinical laboratory tests, 
including chemical, hematological, and 
urine analyses
•
obtain a blood sample (5 mL) for 
analysis of CYP2D6 genotype
•
perform urine drug screen (UDS)
•
perform a serum pregnancy (beta 
human chorionic gonadotropin [β-
HCG]) test (only in females of 
childbearing potential)
•
administer the following 
questionnaires (Note: For MINI Kid 
and C-SSRS, children 13 years of age 
and under must may be interviewed in 
conjunction separately or jointly with 
the caregiver/adult as appropriate or 
defined by the scale. For children over 
13 years of age, caregiver/adult 
involvement is strongly encouraged. 
Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS 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], 
OCD [Module J], Alcohol 
Dependence/Abuse [Module L], 
Substance Dependence/Abuse [Non-
alcohol; Module M], Attention Deficit 
Hyperactivity Disorder [ADHD; 
•
measure vital signs (pulse, BP, 
body temperature, and respiratory rate) 
•
perform full physical and 
neurological examinations (including 
height and weight. Note: Weight must 
be measured with shoes and outerwear 
off)
•
perform 12-lead ECG (Note: ECG 
will be performed after at least 5 
minutes rest in a supine or semi-supine 
position)
•
perform clinical laboratory tests, 
including chemical, hematological, and 
urine analyses
•
obtain a blood sample (5 mL) for 
analysis of CYP2D6 genotype
•
perform urine drug screen (UDS)
•
perform a serum pregnancy (beta 
human chorionic gonadotropin [β-
HCG]) test (only in females of 
childbearing potential)
•
administer the following 
questionnaires (Note: For MINI Kid 
and C-SSRS, children 13 years of age 
and under may be interviewed 
separately or jointly with the 
caregiver/adult as appropriate or 
defined by the scale. For children over 
13 years of age, caregiver/adult
involvement is strongly encouraged. 
Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS questionnaire 
should be performed before any blood 
draws or ECG assessments.):
-
MINI Kid (Note: The following 
modules will be used: 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], Attention Deficit 
Hyperactivity Disorder [ADHD; 
Module O], Conduct Disorder [Module 


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Module O], Conduct Disorder [Module 
P], and Psychotic Disorders and Mood 
Disorders with Psychotic Features 
[Module R])
-
CDI-2, Parent and Self-report 
(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 (Note: Input from the 
caregiver/adult is required.)
•
review medication history and 
concomitant medications
•
inquire about adverse events
P], and Psychotic Disorders and Mood 
Disorders with Psychotic Features 
[Module R])
-
CDI-2, Parent and Self-report 
(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 (Note: Input from the 
caregiver/adult is required.)
•
review medication history and 
concomitant medications
•
inquire about adverse events
3.13.2 Procedures Before IMP Treatment (Baseline/Day 1) (Other sections affected by this change: 
3.13.3.1.2, 3.13.3.2.1, 3.13.3.2.2, 3.13.4.1
Patients who meet the 
inclusion/exclusion criteria at screening 
will continue to the baseline visit, when 
baseline evaluations will be conducted.
The following procedures will be 
performed at baseline:
•
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) 
•
measure 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 urine pregnancy (β-HCG) 
test (only in females of childbearing 
potential)
•
randomization with stratification 
by age at baseline (6 to 11 years, 12 to 
16 years) 
•
administer the following 
Patients who meet the 
inclusion/exclusion criteria at screening 
will continue to the baseline visit, when 
baseline evaluations will be conducted.
The following procedures will be 
performed at baseline:
•
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) 
•
measure 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 urine pregnancy (β-HCG) 
test (only in females of childbearing 
potential)
•
randomization with stratification 
by age at baseline (6 to 11 years, 12 to 
16 years) 
•
administer the following 
The procedures to be 
followed at certain 
time points/days and 
the involvement of 
the adult/caregiver 
for various scales 
used to assess results 
of patients in this 
study have been 
further 
clarified/updated. 
The process of IMP 
randomization has 
also been clarified.


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questionnaires (Note: For C-SSRS, Tic-
free Interval, CY BOCS, and C&A-
GTS-QOL, children 13 years of age 
and under must may be interviewed in 
conjunction separately or jointly with 
the caregiver/adult. as appropriate or 
defined by the scale. For children over 
13 years of age, caregiver/adult 
involvement is strongly encouraged. 
Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS, TS-CGI, 
TS-PGII, and
 questionnaires 
should be performed before any blood 
draws or ECG assessments.):
-
CDI-2, Parent and Self-report 
(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 (Input from the 
caregiver/adult is permitted.)
-
 (Note: Input from the 
caregiver/adult is required permitted.)
-
-
CY BOCS
-
C&A-GTS QOL
•
dispense 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 meal times and critical 
information on dosing 
•
review concomitant medications
•
inquire about adverse events
A patient who is not enrolled in the 
study on the basis of results of baseline 
assessments (eg, because inclusion and 
exclusion criteria were not met or 
questionnaires (Note: For C-SSRS, 
 CY BOCS, and 
C&A-GTS-QOL, children 13 years of 
age and under may be interviewed 
separately or jointly with the 
caregiver/adult as appropriate or 
defined by the scale. For children over 
13 years of age, caregiver/adult 
involvement is strongly encouraged. 
Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant 
information. The YGTSS, TS-CGI, 
TS-PGII, and 
 questionnaires 
should be performed before any blood 
draws or ECG assessments.):
-
CDI-2, Parent and Self-report 
(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.)
-
 (Input from the 
caregiver/adult is permitted.)
-
-
CY BOCS
-
C&A-GTS QOL
•
dispense 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 meal times and critical 
information on dosing 
•
review concomitant medications
•
inquire about adverse events
A patient who is not enrolled in the 
study on the basis of results of baseline 
assessments (eg, because inclusion and 
exclusion criteria were not met or 


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enrollment did not occur within the 
specified time) may be screened again 
1 more time if there is a change in the 
patient’s medical background, a 
modification of study entry criteria, or 
other relevant change. (Note: Details of 
rescreening must be approved.)
Patients will be assigned a permanent 
unique number at screening (see 
Section 3.13.1). Patients who continue 
to meet the inclusion/exclusion criteria 
at baseline will be assigned randomized 
to a treatment (active or placebo)
number (kit, bottle) using an IRT, and 
the appropriate IMP will be dispensed.
enrollment did not occur within the 
specified time) may be screened again 
1 more time if there is a change in the 
patient’s medical background, a 
modification of study entry criteria, or 
other relevant change. (Note: Details of 
rescreening must be approved.)
Patients will be assigned a permanent 
unique number at screening (see 
Section 3.13.1). Patients who continue 
to meet the inclusion/exclusion criteria 
at baseline will be randomized to a 
treatment (active or placebo) using an 
IRT, and the appropriate IMP will be 
dispensed.
4.1 Inclusion Criteria
j.
Females of childbearing potential
may be included only if they have a 
negative β- HCG test at baseline or are 
sterile. Definitions of sterile is given in 
Appendix L.
k.
Females of childbearing potential 
whose male partners are potentially 
fertile (ie, no vasectomy) or female 
partners of male participants must use 
highly effective birth control methods 
for the duration of the study (ie, 
starting at screening) and for 30 days or 
5 half-lives, whichever is longer after 
last dose of IMP. Further details are 
included in Appendix L.
j.
Females of childbearing potential 
may be included only if they have a 
negative β- HCG test at baseline or are 
sterile. Definitions of sterile is given in 
Appendix L.
k.
Females of childbearing potential 
whose male partners are potentially 
fertile (ie, no vasectomy) or female 
partners of male participants must use 
highly effective birth control methods 
for the duration of the study (ie, 
starting at screening) and for 30 days or 
5 half-lives, whichever is longer after 
last dose of IMP. Further details are 
included in Appendix L.
Pregnancy language 
was updated to more 
clearly specify that 
only women of 
childbearing 
potential would 
undergo β-HCG test 
at baseline. Female 
partners of male 
participants were 
also included in the 
inclusion criteria to 
use effective means 
of birth control.
4.2 Exclusion Criteria
m. Patient has a QT interval corrected 
for heart rate using Frederica’s formula 
(QTcF) interval value >450 msec (males) 
or >460 msec (females) or >480 msec 
(with right bundle branch block) on 12-
lead ECG at screening, OR requires 
treatment with drugs known to prolong 
the QT interval (see Appendix A for a 
complete list of prohibited QT-prolonging 
drugs).
u.
Patient has a history of or 
acknowledges alcohol or substance abuse
related disorder in the previous 
m. Patient has a QT interval 
corrected for heart rate using 
Frederica’s formula (QTcF) interval 
value >450 msec (males) or >460 
msec (females) or >480 msec (with 
right bundle branch block) on 12-
lead ECG at screening, OR requires 
treatment with drugs known to 
prolong the QT interval (see 
Appendix A for a complete list of 
prohibited QT-prolonging drugs).
u.
Patient has a history of or 
acknowledges alcohol related 
Exclusion criteria 
“m” was updated to 
account for the 
exclusion of patients 
who require 
treatment with drugs 
known to prolong the 
QT interval. 
Exclusion criteria 
“u” was updated to 
be more consistent 
with the current 
language in the fifth 
edition of the DSM. 


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12 months, as defined in the DSM-V.
w. Patient has a DSM V diagnosis based 
on the MINI Kid modules performed at 
screening that, in the opinion of the 
investigator, makes the patient unsuitable 
for the study.
disorder in the previous 12 months, 
as defined in the DSM-V.
w. Patient has a DSM diagnosis 
based on the MINI Kid modules 
performed at screening that, in the 
opinion of the investigator, makes 
the patient unsuitable for the study.
Exclusion criteria 
“x” was updated to 
remove fifth edition 
from the DSM 
diagnosis criteria.
5.1 Drugs Administered During the Study
IMP (see Section 3.8) will be 
administered as oral tablets at a starting 
dose of 6 mg once daily. Titration 
schemes based on body weight at 
baseline are shown in Table 2. The 
maximum daily dose is determined by 
body weight and CYP2D6 impairment 
status at baseline and any use of strong 
CYP2D6 inhibitors (see Table 3). 
Although dose adjustments can be 
made up to and including the week 7 
telephone call, if a stable dose is 
reached before then, the patient should 
continue taking that dose for the 
remainder of the titration period and 
throughout maintenance dosing. If a 
patient experiences a “clinically 
significant” adverse event that is 
attributed to the IMP, the investigator 
will determine if a dose reduction or 
suspension is necessary. At the end of 
the titration period, the patient’s dose 
will be established for the maintenance 
period. If a patient experiences an 
adverse event during the maintenance 
period and the investigator believes a 
dose reduction is warranted, the dose 
may be reduced.
IMP will be dispensed in the clinic. 
Patients will receive doses for 2 weeks 
at baseline, week 2, and week 4 visits 
(current dose level and next dose level) 
to cover the telephone contacts. At 
week 6 and week 9 visits, patients will 
receive doses for 3 weeks. 
IMP will be administered as follows:
•
IMP should be swallowed whole 
and taken with food. Tablets should be 
IMP (see Section 3.8) will be 
administered as oral tablets at a starting 
dose of 6 mg. Titration schemes based 
on body weight at baseline are shown 
in Table 2. The maximum daily dose is 
determined by body weight and 
CYP2D6 impairment status at baseline. 
Although dose adjustments can be 
made up to and including the week 7 
telephone call, if a stable dose is 
reached before then, the patient should 
continue taking that dose for the 
remainder of the titration period and 
throughout maintenance dosing. If a 
patient experiences a “clinically 
significant” adverse event that is 
attributed to the IMP, the investigator 
will determine if a dose reduction or 
suspension is necessary. At the end of 
the titration period, the patient’s dose 
will be established for the maintenance 
period. If a patient experiences an 
adverse event during the maintenance 
period and the investigator believes a 
dose reduction is warranted, the dose 
may be reduced.
IMP will be dispensed in the clinic. 
Patients will receive doses for 2 weeks 
at baseline, week 2, and week 4 visits 
(current dose level and next dose level) 
to cover the telephone contacts. At 
week 6 and week 9 visits, patients will 
receive doses for 3 weeks. 
IMP will be administered as follows:
•
IMP should be swallowed whole 
and taken with food. Tablets should be 
taken with food (eg, a snack) and 
should not be taken on an empty 
Updated to clarify 
dosing instructions 
and the timing of 
dosing for patients. 
Text has also been 
updated to indicate 
that investigators will 
be blinded to CYP 
impairment status. 


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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 and strong 
CYP2D6 inhibitor use, as shown in 
Table 2 and Table 3.
•
The starting dose is 6 mg in all 
patients. This dose will be administered 
in the evening on days 1 and 2, 
followed by AM administration for the 
remainder of week 1 (if body weight is 
<40 kg). Subsequent Daily doses of 
12 mg and higher will be administered 
twice daily in 2 divided doses, 
approximately 8 to 10 hours apart 
during the day. A minimum of 6 hours 
should elapse between doses. If a 
patient misses a dose and it is within 
6 hours of their next dose, the missed 
dose should be skipped. If patients 
experience insomnia while taking the 
initial 6 mg dose in the evening, they 
may switch to taking it as a morning 
dose on day 2.
•
After week 1, dose increases may 
not occur more frequently than every 
5 days.
•
Dose reductions, if required, should 
be in increments of 6 mg. If more than 
1 dose reduction is required for an 
adverse event, the medical monitor 
should be notified.
•
During the titration period, the dose 
of the IMP should will be adjusted 
weekly according to Table 2 to identify 
a dose level that optimally reduces tics 
(as determined by the investigator, in 
consultation with the patient and 
caregiver/adult) and is well tolerated. 
Investigators will be blinded to CYP 
status, with a dose cap for poor 
metabolizers prespecified by the IRT.
IMP will be packaged in bottles blister 
packs and provided for patients to take 
stomach.
•
Dosing will be based on body 
weight and CYP2D6 impairment status 
at the baseline visit, as shown in Table 
2.
•
The starting dose is 6 mg in all 
patients. Daily doses will be 
administered twice daily, 
approximately 8 to 10 hours apart 
during the day. A minimum of 6 hours 
should elapse between doses. If a 
patient misses a dose and it is within 
6 hours of their next dose, the missed 
dose should be skipped.
•
After week 1, dose increases may 
not occur more frequently than every 
5 days.
•
Dose reductions, if required, 
should be in increments of 6 mg. If 
more than 1 dose reduction is required 
for an adverse event, the medical 
monitor should be notified.
•
During the titration period, the 
dose of the IMP will be adjusted 
weekly according to Table 2 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.
IMP will be packaged in blister packs 
and provided for patients to take at 
home (see Section 3.8).


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at home (see Section 3.8).
Table 2 was updated
Table 3 from version 01 was removed.
Table 2 was updated to include CYP 
Impairment status. Column headers 
remained divided by weight, but also to 
include “not impaired” versus 
“impaired” daily doses by weight 
categories. Additional editorial changes 
were made to the table and table 
footnotes to more clearly specify daily 
dosing expectations by weight category 
and by CYP impairment status, and to 
enhance study visit clarity.
Table 3 from the previous version 
protocol amendment 01 was removed, 
as Table 2 was updated to include the 
additional information provided by this 
table.
Updates wer made to 
account for CYP2D6 
genotyping status 
determined at 
baseline, and to 
specify daily dosing 
from baseline 
through week 6 
based on both weight 
category and CYP 
impairment.
Table 3 was removed 
to remove duplicate 
protocol detail.
5.3 Prior and Concomitant Medications
Medications that are allowed, provided 
that conditions outlined in the table are 
met, are shown in Appendix A, Table 6 
Table 5. 
The medical monitor must be contacted 
if a patient is receiving (or has to begin 
or stop receiving during the study) a 
medication that is associated with QTc 
prolongation or that is a known strong 
CYP inhibitor. 
Addition of a strong CYP inhibitor is 
prohibited.
Prohibited medications that are 
associated with QTc prolongation are 
listed in Appendix A, Table 6, while
prohibited antipsychotic drugs are 
listed in Appendix A, Table 7.
Medications that are allowed, provided 
that conditions outlined in the table are 
met, are shown in Appendix A, 
Table 5. 
The medical monitor must be contacted 
if a patient is receiving (or has to begin 
or stop receiving during the study) a 
medication that is associated with QTc 
prolongation or that is a known strong 
CYP inhibitor. 
Addition of a strong CYP inhibitor is 
prohibited.
Prohibited medications that are 
associated with QTc prolongation are 
listed in Appendix A, Table 6, while 
prohibited antipsychotic drugs are 
listed in Appendix A, Table 7.
Updates were made 
to clarify that the 
addition of strong 
CYP inhibitors are 
prohibited once a 
patient is enrolled. In 
addition, prohibited 
medications 
associated with QTc 
prolongation have 
been inserted into the 
protocol appendices 
and are referenced 
here.
6.2.2 Tourette Syndrome-Patient Global Impression of Impact
The TS-PGII is administered at 
baseline and weeks 2, 4, 6, 9, 12, and 
13. Input from the caregiver/adult is 
permitted.
The TS-PGII is administered at 
baseline and weeks 2, 4, 6, 9, 12, and 
13. Input from the caregiver/adult is 
permitted.
The TS-PGII was 
included as a key 
secondary efficacy 
endpoint, so a brief 


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The TS-PGII is a single-item 
questionnaire that asks the patient to 
assess the degree of impact due to 
current tics. The TS-PGII uses a 5 point 
scale, ranging from not at all (1) to very 
much (5), to assess overall response to 
therapy. In general, patient rated global 
measures of change have face validity 
and have been shown to correlate with 
disability for a number of chronic 
conditions.
The TS-PGII is a single-item 
questionnaire that asks the patient to 
assess the degree of impact due to 
current tics. The TS-PGII uses a 5 
point scale, ranging from not at all (1) 
to very much (5), to assess overall 
response to therapy. In general, patient 
rated global measures of change have 
face validity and have been shown to 
correlate with disability for a number 
of chronic conditions.
description of the 
scale has been 
included.
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 6, and week 12. 
Children 13 years of age and under 
must may be interviewed in 
conjunction separately or jointly with 
the caregiver/adult. as appropriate or 
defined by the scale. For children over 
13 years of age, caregiver/adult 
involvement is strongly encouraged. 
Questions should be directed to the 
child, but the caregiver/adult should be 
encouraged to add relevant 
information. 
The 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 
The C&A-GTS-QOL is administered at 
baseline, week 6, and week 12. 
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 
The child and 
adolescent version of 
the GTS-QOL is now 
to be used in this 
study. 
Adult/caregiver 
involvement has 
been clarified, and 
the scale now 
contains 6 subscales.
The reference for this 
version of the scale 
(“C&A” version) 
replaced the prior 
reference.


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C&A-GTS-QOL contains 46 subscales 
(cognitive, coprophenomena, 
psychological, physical, obsessional
obsessive-compulsive, and cognitive 
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 
(Cavanna et al 2008).Su et al 2017).
(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).
6.2.5 Yale Global Tic Severity Scale
 
 
 
are 
exploratory measures. YGTSS and its 
components are described in Section 
6.1. Input from the caregiver/adult is 
required.
 
 
are 
exploratory measures. YGTSS and its 
components are described in Section 
6.1. Input from the caregiver/adult is 
required.
This was updated to 
specify that input 
from the 
caregiver/adult is 
required when 
performing the 
YGTSS.
7.1.1 Definition of an Adverse Event
An adverse event is anyAny untoward 
medical occurrence in a patient or 
clinical investigation subject
administered a pharmaceutical product, 
regardless of whether it has and which 
does not necessarily have to have a 
causal relationship with this treatment. 
In this study, any adverse event 
occurring after the clinical study patient 
has signed the informed consent form 
should be recorded and reported as an 
adverse event. 
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 
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.
This was updated to 
include the most 
recent definition of 
an adverse event per 
Teva template text.


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present before study entry and do not 
worsen during this study will not be 
considered adverse events.
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 or an adverse event 
leading to discontinuation of IMP at 
any time during the study. If study 
center personnel are unable to obtain a 
blood sample in a timely fashion, this 
should be discussed with the medical 
monitor to determine whether the 
sample still needs to be obtained.
For recording of serious adverse 
events, the study period is defined for 
each patient as the time period from 
signature of the informed consent form 
to the end of the follow up period, as 
defined in Section 7.1.2. If the 
investigator becomes aware of serious 
adverse events occurring in a patient 
after the end of the follow up period, 
the serious adverse events should be 
reported to the sponsor following the 
procedures described in Section 
7.1.5.3.1.
An additional blood sample for the 
measurement of IMP concentration 
should be collected, if possible, from 
each patient experiencing a serious 
adverse event or an adverse event 
leading to discontinuation of IMP at 
any time during the study. If study 
center personnel are unable to obtain a 
blood sample in a timely fashion, this 
should be discussed with the medical 
monitor to determine whether the 
sample still needs to be obtained.
For recording of serious adverse 
events, the study period is defined for 
each patient as the time period from 
signature of the informed consent form 
to the end of the follow up period, as 
defined in Section 7.1.2. If the 
investigator becomes aware of serious 
adverse events occurring in a patient 
after the end of the follow up period, 
the serious adverse events should be 
reported to the sponsor following the 
procedures described in Section 
7.1.5.3.1.
Additional text was 
included to define 
the period for 
recording serious 
adverse events 
occurring in patients, 
and to specify the 
actions to be taken 
by the investigator 
should they become 
aware of a serious 
adverse event after 
the end of the follow-
up period.
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 a life threatening adverse event 
(ie, the patient was at immediate risk of 
death from at the time of the event as);
it occurred); does not include refer to
an event that, had it occurred in a more 
severe form, which hypothetically
might have caused death if it were 
more severe.
•
requires inpatient hospitalization or 
prolongation of existing 
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 a 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 
This was updated to 
include the most 
recent definition of a 
serious adverse event 
per Teva template 
text.


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hospitalization, which means that 
hospital inpatient admission and/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 prior to 
study entry before the patient signed 
the informed consent form will not be 
considered serious adverse events, 
unless there was worsening of the 
preexisting condition during the 
patient’s participation in this study. 
•
results in persistent or significant 
disability or /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.
prolongation of hospital stay were 
required for treatment of an adverse 
event, or that they occurred as a 
consequence of the event. 
Hospitalizations scheduled before the 
patient signed the informed consent 
form will not be considered serious 
adverse events, unless there was 
worsening of the preexisting condition 
during the patient’s participation in this 
study. 
•
results in persistent or significant 
disability or /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.
7.1.5.3.1 Investigator Responsibility
The investigator must ensure that the 
IEC/IRB is also informed of the event, 
in accordance with national and local 
regulations.
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 
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 
Updates were made 
to more clearly 
indicate investigator 
responsibilities and 
expectations.


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disease. 
Additional information (follow up) 
about any serious adverse event 
unavailable at the initial reporting 
should be forwarded by the 
investigational center 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/INC Research for submission to 
the competent authorities, IEC/IRBs, 
and investigators, according to 
regulations. The investigator is 
responsible for ensuring must ensure
that the IEC/IRB is also informed of 
the event, in accordance with national 
and local regulations.
Blinding will be maintained for the 
people who are involved directly in the 
all study personnel. Therefore, in case 
of a SUSAR, only the LSO/INC 
Research will receive the unblinded 
report for regulatory submission; the 
others will receive a blinded report.
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/INC Research 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/INC Research 
will receive the unblinded report for 
regulatory submission; the others will 
receive a blinded report.
7.1.6. Protocol-Defined Adverse Events for Expedited Reportingof Special Interest
No protocol defined adverse events for 
expedited reportingof special interest
were identified for this study.
No protocol defined adverse events of 
special interest were identified for this 
study.
This was updated to 
more specifically 
state adverse events 
of special interest 
7.1.8 Overdose of IMP
Any dose of IMP (whether the IMP 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 3.7.
Not applicable
Section 7.1.8 of the 
previous version has 
been deleted.


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7.3 Pregnancy
Any female patient becoming pregnant 
during the study will discontinue IMP.
All pregnancies of females female 
patients participating in the study and 
female partners of male 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/INC Research) with the 
completed pregnancy form. The 
process for reporting a pregnancy is the 
same as that for reporting a serious 
adverse event but using the pregnancy 
form (see Section 7.1.5.3). 
Any female patient becoming The 
investigator is not required to report 
patients who are found to be pregnant
during between screening and baseline, 
provided no IMP was given. All female 
patients or female partners of male 
patients participating in the study will 
discontinue treatment. All patients who 
become pregnant will be monitored for 
the outcome of the pregnancy 
(including spontaneous, elective, or 
voluntary termination abortion). If the 
pregnancy continues to term, the 
outcome (health of the infant up to 168 
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.
Since this IMP has suspected human 
Any female patient becoming pregnant 
during the study will discontinue IMP.
All pregnancies of female patients 
participating in the study and female 
partners of male 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/INC Research) with the 
completed pregnancy form. The 
process for reporting a pregnancy is the 
same as that for reporting a serious 
adverse event but using the pregnancy 
form (see Section 7.1.5.3). 
The investigator is not required to 
report patients who are found to be 
pregnant between screening and 
baseline, provided no IMP was given. 
All female patients or female partners 
of male patients participating in the 
study who become pregnant will be 
monitored for the outcome of the 
pregnancy (including spontaneous, 
elective, or voluntary abortion). If the 
pregnancy continues to term, the 
outcome (health of the infant up to 8 
weeks of age), including details of birth 
and presence or absence of any birth 
defect, congenital abnormalities, or 
maternal and newborn complications, 
will be reported to the sponsor. Any 
complication of pregnancy during the 
study and any complication of 
pregnancy that the investigator 
becomes aware of after withdrawal 
from the study will be reported as an 
adverse event or serious adverse event, 
as appropriate.
Since this IMP has suspected human 
teratogenicity, genotoxicity, 
fetotoxicity, or spermatoxicity, female 
partners of male patients participating 
This was updated to 
include additional 
pregnancy details 
and guidance for the 
patients and study 
personnel (ie, when 
reporting of events is 
expected, where the 
information must be 
provided, how the 
pregnancy should be 
reported, and the 
investigators 
responsibilities). 


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teratogenicity, genotoxicity, 
fetotoxicity, or spermatoxicity, female 
partners of male patients participating 
in the study who become pregnant will 
be asked to sign an informed consent 
form and 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 
termination withdrawal from the study 
will be reported as an adverse event or 
serious adverse event, as appropriate.
If the pregnancy in the female patients 
participating in the study and/or the 
female partners of male patients 
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.
in the study who become pregnant will 
be asked to sign an informed consent 
form and 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 
termination withdrawal from the study 
will be reported as an adverse event or 
serious adverse event, as appropriate.
If the pregnancy in the female patients 
participating in the study and/or the 
female partners of male patients 
participating in the study does not 
continue to term, 1 of the following 
actions will be taken:
•
For a spontaneous abortion, report 
as a serious adverse event. 
•
For an elective abortion due to 
developmental anomalies, report as a 
serious adverse event.
•
For an elective abortion not due to 
developmental anomalies, report on the 
pregnancy form; do not report as an 
adverse event.
7.4 Medication Error and Special Situations Related to the Investigational Medicinal Product
Any administration of medication IMP
that is not in accordance with the study 
protocol should be reported on the CRF 
either as a violation, if it meets the 
violation criteria specified in the 
protocol (Section 11.1.2), or as a 
deviation, in the patients source 
documents, regardless of whether or 
Any administration of IMP that is not 
in accordance with the study protocol 
should be reported on the CRF either as 
a violation, if it meets the violation 
criteria specified in the protocol 
(Section 11.1.2), or as a deviation, in 
the patients source documents, 
regardless of whether or not an adverse 
Updates were made 
to clarify medication 
error could be with 
both the test product 
and IMP. 
Breastfeeding was 
added as an 
additional special 


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not an adverse event occurs as a result. 
All instances of incorrect medication 
administration should be categorized 
on the CRF as “Non-Compliance with 
IMP”.
Types 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 IMP), whether 
taken intentionally or unintentionally in 
excess of the dose prescribed, must be 
immediately reported to the sponsor.
3.
Misuse: Situations where the 
medicinal product IMP is intentionally 
and inappropriately used not in 
accordance with the authorized product 
information.
4.
Abuse: Persistent or sporadic, 
intentional excessive use of medicinal 
products IMP, which is accompanied 
by harmful physical or psychological 
effects.
5.
Off-label use: Situations where 
medicinal product an IMP is 
intentionally used for a medical 
purpose not in accordance with the 
authorized product information.
6.
Occupational exposure: Exposure 
to a medicinal product an IMP, as a 
result of one’s professional or non-
professional occupation.
7.
Breastfeeding: Suspected adverse 
event occurs as a result. All instances 
of incorrect medication administration 
should be categorized on the CRF as 
“Non-Compliance with IMP”.
The following are types of medication 
errors and special situations:
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 IMP), whether 
taken intentionally or unintentionally in 
excess of the dose prescribed, must be 
immediately reported to the sponsor.
3.
Misuse: Situations where the IMP 
is intentionally and inappropriately 
used not in accordance with the 
authorized product information.
4.
Abuse: Persistent or sporadic, 
intentional excessive use of IMP, 
which is accompanied by harmful 
physical or psychological effects.
5.
Off-label use: Situations where an 
IMP is intentionally used for a medical 
purpose not in accordance with the 
authorized product information.
6.
Occupational exposure: Exposure 
to an IMP, as a result of one’s 
professional or non-professional 
occupation.
7.
Breastfeeding: Suspected adverse 
reactions that occur in infants 
following exposure to a medicinal 
product from breast milk.
situation.


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reactions that occur in infants following 
exposure to a medicinal product from 
breast milk.
7.5 Clinical Laboratory Tests
All clinical laboratory test results 
outside of the reference range will be 
interpreted judged by the investigator 
as belonging to one of the following 
categories: 
•
abnormal and not clinically 
significant
•
abnormal and clinically significant
The clinical significance of the 
laboratory values will be evaluated by 
the criteria described in the 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, 
transcribed to and the CRF as an 
adverse event, and monitored as 
described in Section 7.1.2. An event 
may include a laboratory or diagnostic 
test abnormality (once confirmed by 
repeated testing) that results in the 
withdrawal of the patient from the 
study, the temporary or permanent 
cessation of treatment with IMP or 
medical treatment, or further diagnostic 
work up. Abnormal laboratory tests can 
be repeated without approval from the 
medical monitor. (Note: Abnormal 
laboratory or diagnostic test results at 
the screening visit that preclude a 
patient from entering the study or 
receiving IMP are not considered 
adverse events.)
All clinical laboratory test results 
outside of the reference range will be 
judged by the investigator as belonging 
to one of the following categories: 
•
abnormal and not clinically 
significant
•
abnormal and clinically significant
The clinical significance of the 
laboratory values will be evaluated by 
the criteria described in the 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 
cessation of IMP or medical treatment, 
or further diagnostic work up. 
Abnormal laboratory tests can be 
repeated without approval from the 
medical monitor. (Note: Abnormal 
laboratory or diagnostic test results at 
the screening visit that preclude a 
patient from entering the study or 
receiving IMP are not considered 
adverse events.)
A note was added to 
clarify that abnormal 
test results at 
screening that 
preclude a patient 
from entering the 
study are not 
considered adverse 
events.
7.6 Vital Signs
Vital signs (pulse, BP, body 
temperature, and respiratory rate) will 
be measured at the time points detailed 
in Table 1. All vital signs results 
outside of the reference ranges will be 
judged by the investigator as belonging 
Vital signs (pulse, BP, body 
temperature, and respiratory rate) will 
be measured at the time points detailed 
in Table 1. All vital signs results 
outside of the reference ranges will be 
judged by the investigator as belonging 
This was updated to 
specify that patients 
must rest in a supine 
or semi-erect 
position for 
5 minutes before 


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to one of the following categories:
•
abnormal and not clinically 
significant 
•
abnormal and clinically significant
Before pulse and BP are measured, the 
patient must be rest in a supine or semi 
erect/seated position and resting for at 
least 35 minutes. (The same position 
and arm should be used each time vital 
signs are measured for a given patient). 
At baseline, week 4, and week 12, 
orthostatic BP and pulse will be 
measured after the patient is in a 
standing position for at least 3 minutes.
For any abnormal vital sign finding, the 
measurement should be repeated as 
soon as possible. Any vital sign value 
that is judged by the investigator as a 
clinically significant will be recorded 
both on the source documentation, 
transcribed onto and the CRF as an 
adverse event, and monitored as 
described in Section 7.1.2. 
At baseline, week 4, and week 12, 
orthostatic BP and pulse will be 
measured after the patient is in a 
standing position for at least 3 minutes.
to one of the following categories:
•
abnormal and not clinically 
significant 
•
abnormal and clinically significant
Before pulse and BP are measured, the 
patient must be 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). At 
baseline, week 4, and week 12, 
orthostatic BP and pulse will be 
measured after the patient is in a 
standing position for at least 3 minutes.
For any abnormal vital sign finding, the 
measurement should be repeated as 
soon as possible. Any vital sign value 
that is judged by the investigator as a 
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. 
pulse and BP are 
measured.
7.8 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 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.
This minor 
clarification was 
made.
7.9.Assessment of Suicidality
TEV-50717 is considered to be 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.
TEV-50717 is considered to be 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.
This was updated to 
include a section on 
the assessment of 
suicidality.


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Some CNS-active IMPs may be 
associated with an increased risk of 
suicidal ideation or behavior when 
given to some patients with certain 
conditions. Although this IMP or other 
similar medicinal products in this class 
have not been shown to be associated 
with an increased risk of suicidal 
thinking or behavior when given to this 
study population, the sponsor considers 
it important to monitor for such events 
before or during this clinical study.
The study population being 
administered TEV-50717 should be 
monitored appropriately and observed 
closely for suicidal ideation and 
behavior or any other unusual changes 
in behavior. Consideration should be 
given to discontinuing TEV-50717 in 
participants who experience signs of 
suicidal ideation or behavior.
Families and caregivers of participants 
being treated with TEV-50717 should 
be instructed to monitor participants for 
the emergence of unusual changes in 
behavior, as well as the emergence of 
suicidal ideation and behavior, and to 
report such symptoms immediately to 
the study investigator.
Baseline assessment of suicidal 
ideation and behavior and treatment-
emergent suicidal ideation and 
behavior will be assessed during the 
study using the C-SSRS described in 
Section 7.2.2. 
A reference sample is provided in 
Appendix E.
Some CNS-active IMPs may be 
associated with an increased risk of 
suicidal ideation or behavior when 
given to some patients with certain 
conditions. Although this IMP or other 
similar medicinal products in this class 
have not been shown to be associated 
with an increased risk of suicidal 
thinking or behavior when given to this 
study population, the sponsor considers 
it important to monitor for such events 
before or during this clinical study.
The study population being 
administered TEV-50717 should be 
monitored appropriately and observed 
closely for suicidal ideation and 
behavior or any other unusual changes 
in behavior. Consideration should be 
given to discontinuing TEV-50717 in 
participants who experience signs of 
suicidal ideation or behavior.
Families and caregivers of participants 
being treated with TEV-50717 should 
be instructed to monitor participants for 
the emergence of unusual changes in 
behavior, as well as the emergence of 
suicidal ideation and behavior, and to 
report such symptoms immediately to 
the study investigator.
Baseline assessment of suicidal 
ideation and behavior and treatment-
emergent suicidal ideation and 
behavior will be assessed during the 
study using the C-SSRS described in 
Section 7.2.2. 
A reference sample is provided in 
Appendix E.
7.11 Concomitant Therapy or Medication
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 
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 
This was updated to 
include a cross 
reference and 
statement that 
medications 
associated with QTc 
prolongation have 
been inserted into the 


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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 A, Table 
5. 
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. Table 6.
Prohibited medications that are 
associated with QTc prolongation are 
listed in Appendix A, Table 6, while 
prohibited antipsychotic drugs are 
listed in Appendix A, Table 7.
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 A, Table 
5. 
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 A, Table 6, while 
prohibited antipsychotic drugs are 
listed in Appendix A, Table 7.
protocol into 
Appendix A.
7.12 Methods and Timing 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. Safety 
data will additionally be evaluated 
periodically and ad hoc (if necessary) 
in the Product Safety Group.
Methods and timing of assessing safety 
data are discussed in Section 3.13. 
Procedures for recording safety data are 
discussed in Section 13.1, and methods 
of analyses are discussed in Section 
9.7.2. 
Information about the IDMC used for 
this study is provided in Section 3.7.3.
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 timing of assessing safety 
data are discussed in Section 3.13. 
Procedures for recording safety data 
are discussed in Section 13.1, and 
methods of analyses are discussed in 
Section 9.7.2. 
Information about the IDMC used for 
this study is provided in Section 3.7.3.
This was updated to 
remove the ad hoc 
evaluation of safety 
data by the Product 
Safety Group.
8.2 Pharmacodynamics Assessment
Exposure-response (eg, 
pharmacodynamic [PD] and/or safety 
endpoints) may be assessed if the 
appropriate data are available.
Exposure-response (eg, 
pharmacodynamic [PD] and/or safety 
endpoints) may be assessed if the 
appropriate data are available.
This section was 
added to account for 
possible 
pharmacodynamics 
assessment of data.


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8.3 Pharmacogenetics
Not applicable
Level 2 heading added to the protocol
This level 2 heading 
was added to 
streamline the 
genotyping portion 
of the protocol
8.3.1 CYP2D6 Genotype 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.
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. 
This section was 
updated to include 
greater clarity on the 
process of CYP2D6 
genotyping and the 
genetic samples that 
may be obtained 
from patients.
9.5.4.3 Key Secondary Efficacy Analyses
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. The change in the 
TS CGI (1), 
 (2), and C&A-
GTS-QOL physical/ADL subscale (3) 
scores from baseline to week 12 will be 
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. The change in the 
TS CGI (1) and C&A-GTS-QOL ADL 
subscale (3) scores from baseline to 
week 12 will be summarized and 
This section was 
updated to present 
the changes in the 
key secondary 
efficacy endpoints 
and analyses (ie, the 
addition of TS-PGII, 
the removal of TS-
PGIS, and the use of 
the child and 
adolescent version of 
the GTS-QOL scale.)


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summarized and analyzed in the same 
fashion as the primary analysis, with 
the exception that the baseline value of 
the given endpoint will be included as 
the covariate. TS PGII (2) will be 
analyzed using a Cochran-Mantel-
Haenszel row mean score test with a 
modified ridit scoring that controls for 
age group.
analyzed in the same fashion as the 
primary analysis, with the exception 
that the baseline value of the given 
endpoint will be included as the 
covariate. TS PGII (2) will be analyzed 
using a Cochran-Mantel-Haenszel row 
mean score test with a modified ridit
scoring that controls for age group.
9.5.4.4 Exploratory Analyses
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This section was 
updated to present 
the changes in the 
exploratory 
endpoints and 
analyses 
 
 
 
 


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APPENDIX A. ALLOWED AND DISALLOWED MEDICATIONS
The medical monitor must be contacted 
if a patient is receiving (or has to begin 
or stop receiving during the study) a 
medication that is associated with QTc 
prolongation or that is a known strong 
cytochrome P450 inhibitor. 
Prohibited medications that are
associated with QTc prolongation are 
listed in Table 6, while prohibited 
antipsychotic drugs are listed in 
Table 7.
“Table 6: Prohibited QTc Prolonging 
Drugs” was added to the protocol
The medical monitor must be contacted 
if a patient is receiving (or has to begin 
or stop receiving during the study) a 
medication that is associated with QTc 
prolongation or that is a known strong 
cytochrome P450 inhibitor. 
Prohibited medications that are 
associated with QTc prolongation are 
listed in Table 6, while prohibited 
antipsychotic drugs are listed in 
Table 7.
“Table 6: Prohibited QTc Prolonging 
Drugs” was added to the protocol
Table 6: Prohibited 
QTc Prolonging 
Drugs” was added to 
the protocol to 
include additional 
safety precautions 
and exclusion 
criteria.
APPENDIX I. TOURETTE SYNDROME-PATIENT GLOBAL IMPRESSION OF IMPACT AND
SEVERITY
Appendix I was updated to include 
only PGIS and PGII assessments from 
the latest RTI report. Assessments of 
change and the parent/guardian items 
were removed.
Appendix I was updated to include 
only PGIS and PGII assessments from 
the latest RTI report. 
Appendix I was 
updated to include 
only PGIS and PGII 
assessments from the 
latest RTI report. 
Assessments of 
change and the 
parent/guardian 
items were removed.
APPENDIX K.CHILD AND ADOLESCENT GILLES DE LA TOURETTE SYNDROME –
QUALITY OF LIFE SCALE FOR PATIENTS AGED 13 TO 18 YEARS (C&A-GTS-QOL 13-18)
The existing GTS-QOL scale was 
replaced by the Children and 
Adolescent version of the scale for 
patients aged 6 to 12 (C&A-GTS-QOL 
6-12) and aged 13 to 18 (C&A-GTS-
QOL 13-18)
The Children and Adolescent version 
of the scale for patients aged 6 to 12 
(C&A-GTS-QOL 6-12) and aged 13 to 
18 (C&A-GTS-QOL 13-18) replaced 
the existing GTS-QOL scale.
The existing GTS-
QOL scale was 
replaced by the 
Children and 
Adolescent version 
of the scale for 
patients aged 6 to 12 
(C&A-GTS-QOL 
6-12) and aged 13 to 
18 (C&A-GTS-QOL 
13-18), in alignment 
with the adjustments 
made to the 
secondary and 
exploratory 
endpoints.


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17.3.
Amendment 03 Dated 06 November 2017
The primary reason for this amendment is to update dosing instructions/timing, further specify 
timing of enrollment into the open-label extension study TV50717-CNS-30047, update 
pregnancy language, and update the timing/frequency of a few assessments.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, 
IEC, and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial changes 
have been made to the protocol (and protocol synopsis, as appropriate). These changes are 
unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical 
study or the scientific value of the clinical study.
Protocol Amendment 02 text with 
changes shown
New wording
Reason/Justification for 
change
Section 3.1.1 Overall Design and Screening Period (Other section affected by this change: 3.1.5
Washout Period and Follow-up)
Patients who complete the study may 
be eligible to begin participation in an 
open-label safety extension study 
TV50717-CNS-30047 after the end of 
the washout period. At the week 13 
visit, patients may choose to enter 
study TV50717-CNS-30047 (on that 
day), or they will have an additional 
week to make a decision and return for 
day 1. Patients not participating in 
Study TV50717-CNS-30047 will have 
a follow-up telephone contact to 
evaluate safety 1 week after the end of 
the washout period (2 weeks after their 
last dose of IMP).
Patients who complete the study 
may be eligible to begin 
participation in an open-label 
safety extension study TV50717-
CNS-30047 after the end of the 
washout period. At the week 13 
visit, patients may choose to enter 
study TV50717-CNS-30047 (on 
that day), or they will have an 
additional week to make a 
decision and return for day 1. 
Patients not participating in Study 
TV50717-CNS-30047 will have a 
follow-up telephone contact to 
evaluate safety 1 week after the 
end of the washout period (2 
weeks after their last dose of 
IMP).
Updated to clarify the 
timing of 
participation/enrollment 
into open-label study 
TV50717-CNS-30047
Section 3.1.5 Washout Period and Follow up (Figure 1)
Not applicable
[Minor updates were made to 
Figure 1. An updated Figure 1 
was inserted.]
Minor updates were made 
to Figure 1 to enhance the 
clarity of the study design 
and anticipated enrollment 
numbers
Section 3.4 Safety Measures and Time Points
•
12-lead ECG: Screening; baseline;
and weeks 4, 6, and 12
•
Pregnancy testing: Screening, 
baseline, and weekweeks 4 and 12
•
12-lead ECG: Screening; 
baseline; and weeks 4, 6, and 12
•
Pregnancy testing: Screening, 
baseline, and weeks 4 and 12
Updated to include specific 
assessments at additional 
time points


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change
Section 3.13 Study Procedures (Table 1)
Not applicable
[Minor updates were included in 
Table 1. Assessments were 
added/removed, and footnotes 
were edited/adjusted. Updates 
were made in alignment with 
assessments added/removed 
within the protocol. Visit 
windows were also adjusted]
Updates were made to the 
table and table footnotes in 
alignment with 
assessments 
added/removed within the 
protocol, in order to 
enhance protocol clarity
Section 3.13.1 Procedures for Screening and Enrollment (Other sections affected by this change: 
3.13.2 and 3.13.3.2.2)
The screening visit will take place not 
more than 31 days and no less than 3 
days before the baseline visit. The 
screening visit may be conducted over 
2 separate visits at the discretion of the 
investigator. The following procedures 
will be performed at screening:
•
perform a serum pregnancy (beta 
human chorionic gonadotropin [β-
HCG]) test (only in females of 
childbearing potentialwho are 
postmenarchal or ≥12 years of age)
The screening visit will take 
place not more than 31 days 
before the baseline visit. The 
screening visit may be conducted 
over 2 separate visits at the 
discretion of the investigator. The 
following procedures will be 
performed at screening:
•
perform a serum pregnancy 
(beta human chorionic 
gonadotropin [β-HCG]) test (only 
in females who are 
postmenarchal or ≥12 years of 
age)
Screening visit updated to 
be “up to 31 days” before 
the baseline visit, in 
alignment with the table of 
assessments
Updated the definition of 
females of childbearing 
potential throughout the 
protocol 
Section 3.13.3.1.2 Clinic Visits (Weeks 2, 4, and 6)
Not applicable
•
perform urine pregnancy (β-
HCG) test at week 4 (only in 
females who are postmenarchal 
or ≥12 years of age) 
Updated to add the 
assessment of a urine 
pregnancy test at week 4, 
per updates made to Table 
1
Section 3.13.5 Unscheduled Visits
•
perform a urine/serum pregnancy 
(β-HCG) test (only in females who are 
postmenarchal or ≥12 years of age)
•
perform a urine/serum 
pregnancy (β-HCG) test (only in 
females who are postmenarchal 
or ≥12 years of age)
Updated to include that the 
urine pregnancy test should 
only occur in “females who 
are postmenarchal or ≥12 
years of age”
Section 4.1.Patient Inclusion Criteria
j.
Females of childbearing 
potentialwho are postmenarchal or ≥12 
years of age may be included only if 
they have a negative β HCG test at 
baseline or are sterile. Definitions of 
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. Definitions 
Updated the inclusion 
criteria to more specifically 
define females of 
childbearing potential and 
to adjust some of the text 


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change
sterile is given in Appendix L
.
k.
Females who are postmenarchal or 
≥12 years of age childbearing potential
whose male partners are potentially 
fertile (ie, no vasectomy) or female 
partners of male participants must use 
highly effective birth control methods 
for the duration of the study (ie, 
starting at screening) and for 30 days or 
5 half-lives, whichever is longer after 
last dose of IMP. Further details are 
included in Appendix L
.
of sterile is given in Appendix L.
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 L
.
regarding birth-control 
methods
Section 5.1. Drugs Administered During the Study
•
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 shouldmust be notified.
Table 2 was updated
•
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.
[Table 2 was updated to remove 
specification of dosing “week.” 
The timing of dosing and dosing 
instructions are indicated by 
study day.]
[Footnote “a” was also updated to 
correct the start time of a 
patient’s new dose.]
Updated to include more 
clear direction and 
instruction on the timing of 
IMP dosing during the 
study
Section 5.5 Dose Reduction and Temporary IMP Discontinuation
Dose Reduction
If more than 1 dose reduction is 
required for an adverse event, the 
medical monitor shouldmust be 
notified.
Dose Suspension
The patients who restart IMP treatment 
will follow the visit schedule as 
outlined in the protocol.Table 1.
Dose Reduction
If more than 1 dose reduction is 
required for an adverse event, the 
medical monitor must be notified.
Dose Suspension
The patients who restart IMP 
treatment will follow the visit 
schedule as outlined in Table 1.
Updated to more clearly 
guide study personnel on 
the expectations following 
dose reductions or 
suspensions
Section 7.3.Pregnancy
All pregnancies of female patients 
participating in the study and female 
partners of male patients participating 
All pregnancies of female 
patients participating in the study 
that occur during the study, or 
Updated pregnancy 
language.


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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/INC Research) with the 
completed pregnancy form. The 
process for reporting a pregnancy is the 
same as that for reporting a serious 
adverse event but using the pregnancy 
form (see Section 
7.1.5.3
 .(
The investigator is not required to 
report patients who are found to be 
pregnant between screening and 
baseline, provided no IMP was given. 
All female patients or female partners 
of male patients participating in the 
study who become pregnant will be 
monitored for the outcome of the 
pregnancy (including spontaneous, 
elective, or voluntary abortion). If the 
pregnancy continues to term, the 
outcome (health of the infant up to 8 
weeks of age), including details of birth 
and presence or absence of any birth 
defect, congenital abnormalities, or 
maternal and newborn complications, 
will be reported to the sponsor. Any 
complication of pregnancy during the 
study and any complication of 
pregnancy that the investigator 
becomes aware of after withdrawal 
from the study will be reported as an 
adverse event or serious adverse event, 
as appropriate.
Since this IMP has suspected human 
teratogenicity, genotoxicity, 
fetotoxicity, or spermatoxicity, female 
partners of male patients participating 
in the study who become pregnant will 
be asked to sign an informed consent 
form and 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 
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/INC Research) 
with the completed pregnancy 
form. The process for reporting a 
pregnancy is the same as that for 
reporting a serious adverse event 
but using the pregnancy form 
(see Section 
7.1.5.3
 .(
The investigator is not required to 
report patients who are found to 
be pregnant between screening 
and 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 
patients participating in the study 
does not continue to term, 1 of 
the following actions will be 
taken:


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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 patients 
participating in the study and/or the 
female partners of male patients 
participating in the study does not 
continue to term, 1 of the following 
actions will be taken:
Section 7.5.2.1. Human Chorionic Gonadotrophin Test
Human chorionic gonadotrophin tests 
in urine or serum will be performed for 
all females of childbearing 
potentialwho are postmenarchal or ≥12 
years of age as detailed in Table 1, and 
if clinically indicated.
Human chorionic gonadotrophin 
tests in urine or serum will be 
performed for all females who 
are postmenarchal or ≥12 years 
of age as detailed in Table 1, and 
if clinically indicated.
Updated to more 
specifically define females 
of childbearing potential
APPENDIX L. FEMALES OF CHILDBEARING POTENTIAL AND BIRTH CONTROL 
METHODS AND PREGNANCY TESTING
Contraception recommendations and 
pregnancy testing should encompass all 
IMPs as well as non investigational 
medicinal products, eg, background 
therapy, and the measures to be
followed should be based on the 
medicinal product with highest risk.
Assessment of likelihood of possible 
interaction between IMP or 
concomitant medications and hormonal 
contraception should be conducted. 
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 
Females of childbearing 
potential are defined as:
•
not surgically (documented 
hysterectomy, bilateral 
oophorectomy, or bilateral 
salpingectomy) or congenitally 
sterile
•
postmenarchal or ≥12 years 
of age
Recommendations for 
application of birth control 
methods:
•
IMP (TEV-50717) with 
possible human 
teratogenicity/fetotoxicity
-
Highly effective method 
of contraception
Updated pregnancy 
expectations/language/risks 
to be consistent with 
changes made to the 
protocol


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Reason/Justification for 
change
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 postmenopausalpostmenarchal 
or ≥12 years of age
Description of 
differentRecommendations for 
application of birth control methods:
•
IMP (TEV-50717) with possible 
human teratogenicity/fetotoxicity
-
Highly effective method of 
contraception
-
Contraception during treatment 
and until the end of relevant 
systemic exposure
-
Additional pregnancy testing to 
be considered; as a minimum, at 
the end of relevant systemic 
exposure
-
In each case of delayed 
menstrual period (over 1 month 
between menstruations), 
confirmation of absence of 
pregnancy is strongly 
recommended. This 
recommendation also applies to 
women of childbearing potential 
with infrequent or irregular 
menstrual cycles.
Highly effective birth control 
methods:
Highly effective birth control methods 
that can achieve a failure rate of less 
than 1% per year when used 
-
Contraception during 
treatment and until the end of 
relevant systemic exposure
-
Additional pregnancy 
testing to be considered; as a 
minimum, at the end of 
relevant systemic exposure
-
In each case of delayed 
menstrual period (over 1 
month between 
menstruations), confirmation 
of absence of pregnancy is 
strongly recommended. This
recommendation also applies 
to women of childbearing 
potential with infrequent or 
irregular menstrual cycles.
Highly effective birth control 
methods:
Highly effective birth control 
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 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 


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Reason/Justification for 
change
consistently and correctly are 
considered. Such methods include:
•
Combined estrogen and 
progestogen hormonal contraception 
(oral, intravaginal, transdermal) 
associated with inhibition of ovulation; 
these should be initiated at least 7 days 
(for IMPs without suspected
teratogenicity/genotoxicity) and 1 
month (for IMPs potentially 
teratogenic/genotoxic) before the first 
dose of IMP.
•
Progestogen-only hormonal 
contraception (oral, injectable, 
implantable) associated with inhibition 
of ovulation; these should be initiated 
at least 7 days (for IMPs without 
suspected teratogenicity/genotoxicity) 
and 1 month (for IMPs potentially 
teratogenic/genotoxic) before the first 
dose of IMP.
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.
method (LAM) are not acceptable 
methods of contraception. Female 
condom and male condom should 
not be used together.
Pregnancy tests in females of 
childbearing potential:
1.
Consider additional 
pregnancy testing, but at least at 
the end of relevant systemic 
exposure.


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Reason/Justification for 
change
Male contraception:
Male patients must always use a 
condom, except in cases of no 
genotoxicity; or no demonstrated or 
suspected human 
teratogenicity/fetotoxicity.
Vasectomy:
Use of contraceptive methods applies 
also to vasectomized men, because of 
the risk associated with transfer of a 
drug via seminal fluid.
Contraception for female partners of 
male study participants:
Female partners (who are not pregnant) 
of male study participants must use 
contraception for non pregnant 
WOCBP until the end of relevant 
systemic exposure in case of IMPs with 
genotoxicity or IMPs with no 
genotoxicity but demonstrated or 
suspected human 
teratogenicity/fetotoxicity.
Pregnancy tests in females of 
childbearing potential:
1.
Conduct monthly pregnancy 
testing from first dose of IMP until last 
dose of IMP and additional 30 days in 
case the IMP does not have a 
marketing authorization and has 
suspected human 
teratogenicity/genotoxicity/fetotoxicity. 
Conduct monthly pregnancy testing 
and in case the IMP has a marketing 
authorization, if the IMP has a 
demonstrated or suspected human 
teratogenicity/genotoxicity/fetotoxicity 
according to Risk Safety Information. 
Shorter testing intervals are to be 
considered depending on drug dosing 
schedule.
2.
Consider additional pregnancy 
testing, but at least at the end of 
relevant systemic exposure., in case of 
possible human 
teratogenicity/fetotoxicity. This refers 
to IMPs, for which human data on 


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Reason/Justification for 
change
pregnancies is limited or not available, 
there is no suspicion of human 
teratogenicity based on class effects or 
genotoxic potential, and nonclinical 
reproductive toxicity studies of 
relevance for early human pregnancy 
show positive findings that do not 
generate a strong suspicion of human 
teratogenicity/ fetotoxicity.
3.
For IMPs with unlikely risk of 
human teratogenicity/fetotoxicity, 
additional pregnancy testing is 
generally not necessary. This refers to 
IMPs for which assessment of the 
completed necessary nonclinical 
studies does not indicate teratogenicity/ 
fetotoxicity in early pregnancy and 
human data are not available or do not 
contradict these findings or there is 
already sufficient evidence for lack of 
risk based on human data.
Pregnant female partners of male 
study participants:
Male study participants must use 
condoms during intercourse if their 
female partners are pregnant.


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17.4.
Amendment 04 Dated 13 September 2018
The primary reason for this amendment is to 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 and security; update/clarify patient inclusion criteria, exclusion criteria, and withdrawal 
criteria; provide updates on allowed and prohibited medications; include additional guidance for 
evaluation and handling of suicidal ideation, suicidal behavior, and depression; and to streamline 
birth control methods language for females of childbearing potential.
This amendment is considered to be substantial (ie, requires approval by Competent Authority, 
IEC, and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial changes 
have been made to the protocol (and protocol synopsis, as appropriate). These changes are 
unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical 
study or the scientific value of the clinical study.
Protocol Amendment 03 text with 
changes shown
New wording
Reason/Jus
tification 
for change
LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Central Clinical Laboratory
Q2 Solutions (Quest) LLC1201 S. 
Collegeville Road 
Collegeville, PA 19426
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Central Clinical Laboratory
Q2 Solutions (Quest) LLC
27027 Tourney Road, Suite 2E
Valencia, CA 91355
USA
Administrat
ive change.
Contract Research Organization; Safety 
and Efficacy Data Analysis
INC Research, LLC, a Syneos health group 
company (“Syneos Health”)
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604-1547
USA
Contract Research Organization; Safety 
and Efficacy Data Analysis
INC Research, LLC, a Syneos health group 
company (“Syneos Health”)
3201 Beechleaf Court
Suite 600
Raleigh, NC 27604-1547
USA
Administrat
ive change.
Central Electrocardiogram Evaluation
Biomedical Systems
77 Progress Parkway
St. Louis, MO 63043 ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Integrated Response Technology
Central Electrocardiogram Evaluation
ERT
1818 Market Street 10th Floor
Philadelphia, PA 19103
USA
Integrated Response Technology
Endpoint
55 Francisco Street, Suite 200
Change in 
central ECT 
and IRT 
vendors.


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Reason/Jus
tification 
for change
Bracket Global, LLC
575 East Swedesford Road Endpoint
55 Francisco Street, Suite 200
Wayne, PA 19087 San Francisco, CA 
94133
USA
ePRO, eCOA, and Scales Training 
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA
Bioanalytical Pharmacokinetics 
Evaluation Data Analysis
Information will be included in the Trial 
Master File.
San Francisco, CA 94133
USA
ePRO, eCOA, and Scales Training 
Bracket Global, LLC
575 East Swedesford Road, Suite 200
Wayne, PA 19087 
USA
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
Sponsor’s Authorized Representative:
 
 
For medical issues, contact the physician 
listed below: 
For operational issues, contact the 
operational lead listed below: 
Sponsor’s Authorized Representative:
 
 
For medical issues, contact the physician 
listed below: 
 
 
Update to 
the 
Sponsor’s 
authorized 
representati
ve. In 
addition, 
medical 
director/me
dical 
monitor 
contacts 
outside of 
North 
America 
have been 
included. 
Administrat
ive changes 
carried out 
for clarity.


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Protocol Amendment 03 text with 
changes shown
New wording
Reason/Jus
tification 
for change
 
 
 
 
 
 
 
 
 
 
 
For protocol issues, contact the study 
leaders listed below:
 
 


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Reason/Jus
tification 
for change
For protocol issues, contact the study 
leaderleaders listed below:
 
 
 
 
 
 
 
 
For operational issues, contact the 
operational lead listed below: 
 
 
CLINICAL STUDY PROTOCOL SYNOPSIS
Type of the Study Phase of Clinical 
Development: Efficacy and Safety (Phase 
2/3)
Type of the Study: Efficacy and Safety
(Phase 2/3)
Template 
update.
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 3.1.2 
Screening Period, 3.4 Safety Measures and Time Points, 3.13.1 Procedures for Screening and 
Enrollment, 4.1 Patient Inclusion Criteria, 5.2 Restrictions, 7.1.2 Recording and Reporting Adverse 
Events, 7.1.5 Serious Adverse Events, 11.3 Study Monitoring, 12.1 Informed Consent/Assent, 13.1 
Data Collection, 13.3.2 Investigator Responsibilities)
After informed consent (and written /assent
and/or co consent for patients 14 years of, 
depending on the child’s age and older, as 
appropriate), is obtained
After informed consent/assent, depending 
on the child’s age, as appropriate, is 
obtained 
Provisions
on informed 
consent/ass
ent have 
been more 
clearly 
provided
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 3.1.2 
Screening Period)


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At the discretion of the investigator, the 
screening visit may be divided into 2 visits 
if the visit length is felt to be too 
burdensome for the patient. If the screening 
visit is divided into 2 visits, the blood 
sample should be obtained during the first 
of the 2 visits.
At the discretion of the investigator, the 
screening visit may be divided into 2 visits 
if the visit length is felt to be too 
burdensome for the patient. If the screening 
visit is divided into 2 visits, the blood 
sample should be obtained during the first 
of the 2 visits.
Guidance 
provided on 
the timing 
of obtaining 
blood 
samples in 
situations 
where the 
screening 
visit is 
divided into 
2 visits.
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 3.1.2 
Screening Period, 3.13.1 Procedures for Screening and Enrollment)
(Note: Details of rescreening must be 
approved.) and documented by the medical 
monitor and/or Clinical Surveillance and 
Training (CST) team.
(Note: Details of rescreening must be 
approved and documented by the medical 
monitor and/or Clinical Surveillance and 
Training [CST] team.)
Further 
elaborated 
on the 
documentat
ion process 
for 
rescreening 
of patients.
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 3.13.1 
Procedures for Screening and Enrollment, 4.1 Patient Inclusion Criteria, 12.1 Informed 
Consent/Assent)
Patient and caregiver/adult (may also 
include an adult other than a parent or legal 
representative). 
Patient and caregiver/adult (may also 
include an adult other than a parent or legal 
representative).
Provisions 
on informed 
consent/ass
ent have 
been more 
clearly 
provided. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 4.2 Patient 
Exclusion Criteria)
Patient has received any of the following 
concomitant medications for tics within the 
specified exclusionary washout windows of 
screening first dose:
Withinwithin 3 months: depot neuroleptics, 
botulinum toxin, or tetrabenazine
Withinwithin 4 weeks: cannabidiol oil and 
Valbenazine
within 21 days: reserpine 
Patient has received any of the following 
concomitant medications for tics within the 
specified exclusionary washout windows of 
first dose:
within 3 months: depot neuroleptics, 
botulinum toxin, or tetrabenazine
within 4 weeks: cannabidiol oil and 
valbenazine
within 21 days: reserpine 
Further 
guidance 
provided on 
prohibited
and allowed 
medication. 


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Withinwithin 14 days: neuroleptics (oral), 
typical and atypical antipsychotics (see 
Appendix A), metoclopramide, levodopa, 
and dopamine agonists 
Note: Use of stimulant medications, 
including amphetamine, methylphenidate, 
and lisdexamfetamine, is allowed if primary 
use is for the treatment of ADHD, dosing 
has been stable for at least 2 weeks before 
screening, 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 ifregardless of indication (ie, if 
prescribed for tics or Tourette syndrome) if 
the dosing has been stable for at least 4 
weeks before screening and no changes to 
dose or frequency are anticipated during the 
course of the study. 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.
within 14 days: neuroleptics (oral), typical 
and atypical antipsychotics (see 
Appendix A), metoclopramide, levodopa, 
and dopamine agonists 
Note: Use of stimulant medications, 
including amphetamine, methylphenidate, 
and lisdexamfetamine, is allowed if primary 
use is for the treatment of ADHD, dosing 
has been stable for at least 2 weeks before 
screening, 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 Tourette syndrome) if 
the dosing has been stable for at least 4 
weeks before screening and no changes to 
dose or frequency are anticipated during the 
course of the study. 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.
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 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 option for PGx evaluation on the 
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 
PGx evaluation on the optional informed 
Clarificatio
n on PGx 
sampling 
and details. 


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optional informed consent/assent, a 
pharmacogenetic (PGx) the remaining
sample (2 mL) will be obtained and stored 
for exploratory pharmacogenetics PGx 
evaluation. 
consent/assent, a pharmacogenetic (PGx) 
sample (2 mL) will be obtained and stored 
for exploratory PGx evaluation. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by this change: 9.5.4.1 
Primary Efficacy Analysis)
The baseline TTS, region, and age group at 
baseline will be included as covariates.
The baseline TTS, region, and age group at 
baseline will be included as covariates.
Addition of 
region to 
covariate 
list. 
Section 1.1 Introduction 
To address the limitations of commercial 
tetrabenazine, (Xenazine®), Auspex, a 
wholly owned subsidiary of Teva 
Pharmaceutical Products R&D, Inc, has 
developed a deuterated form of 
tetrabenazinedeutetrabenazine (referred to 
as TEV-50717 or, previously SD-809) that 
is eliminated more slowly than 
tetrabenazine.
TEV-50717 was granted breakthrough 
status for treatment of TD by the Food and 
Drug Administration (FDA) based on the 
results of Study SD-809-C-18, and NDA 
209885 was granted priority review status. 
TEV-50717 was approved for the treatment 
of chorea associated with HD on 
03 April 2017. and for the treatment of 
chorea associated with TD on 
30 August 2017.
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.
TEV-50717 was granted breakthrough 
status for treatment of TD by the Food and 
Drug Administration (FDA) based on the 
results of Study SD-809-C-18, and NDA 
209885 was granted priority review status. 
TEV-50717 was approved for the treatment 
of chorea associated with HD on 
03 April 2017 and for the treatment of 
chorea associated with TD on
30 August 2017.
Alignment 
of drug 
naming and 
drug 
approval 
status. 
Section 1.3.1.3 Toxicology
Not applicable
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 two factors. First, the effects 
of TEV-50717 on behavior and weight gain 
recovered with cessation of test article 
Nonclinical 
background 
information 
addition. 


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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 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).
Section 1.3.2 Clinical Studies
The clinical development plan for TEV 
50717 to date includes:
•
6 completed Phase 1 studies in healthy 
adult subjects
•
1 completed Phase 3 pivotal study for 
the treatment of chorea associated with HD
•
1 ongoing 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 ongoing Phase 3 long-term safety 
study in patients with TD
•
1 completed Phase 1b study in patients 
with TS
Further details may be found in the IB.
The clinical development plan for TEV 
50717 to date includes:
•
6 completed Phase 1 studies in healthy 
adult subjects
•
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 ongoing Phase 3 long-term safety 
study in patients with TD
•
1 completed Phase 1b study in patients 
with TS
Further details may be found in the IB.
Update to 
current 
clinical 
study status 
within the 
clinical 
developmen
t plan for 
TEV-
50717.
Figure 1: Overall Study Schema
a Maximum total daily dose for patients ≥40 
kg is 48 mg/day (24 mg bid), 30 to <40 kg 
is 42 mg/day (21 mg bid), and 20 to <30 kg 
is 30 mg/day (15 mg bid). For those taking 
strong CYP inhibitors such as 
paroxetine/fluoxetine/bupropionFor those 
considered CYP2D6 impaired , maximum 
daily dose for patients ≥40 kg is 36 mg/day, 
30 to <40 kg is 24 mg/day, and 20 to <30 kg 
is 18 mg/day (Table 2).
a Maximum total daily dose for patients ≥40 
kg is 48 mg/day (24 mg bid), 30 to <40 kg 
is 42 mg/day (21 mg bid), and 20 to <30 kg 
is 30 mg/day (15 mg bid). For those 
considered CYP2D6 impaired , maximum 
daily dose for patients ≥40 kg is 36 mg/day, 
30 to <40 kg is 24 mg/day, and 20 to <30 kg 
is 18 mg/day (Table 2).
Clarity for 
CYP2D6 
impaired. 
Section 3.9.1 Drug Storage and Security 


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The IMP (TEV-50717 and placebo) must 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 
toand 30°C (59°F to 86°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 placebo) must 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 
30°C (59°F to 86°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.
Drug 
storage and 
security 
specificatio
n. 
Section 3.9.2 Drug Accountability 
Empty, partially used, and unused IMP will 
be returned to the sponsor or its 
designeedisposed of, as agreed with the 
sponsor/development partner.
Empty, partially used, and unused IMP will 
be disposed of, as agreed with the 
sponsor/development partner.
Drug 
disposal 
details. 
Table 1: Study Procedures and Assessments 
Informed consent/assent and/or co consent 
for patients 14 years of age and older
Informed consent/assent 
Provisions 
on informed 
consent/ass
ent have 
been more 
clearly 
provided
Not applicable 
w
Contact IRT and dispense IMP and 
patient diary. 
Addition of 
footnote to 
study 
procedures 
for 
specificatio
n. 
Table 1: Study Procedures and Assessments, footnote c (Other sections affected by this change: 
3.13.2 Procedures Before IMP Treatment [Baseline/Day 1]) 
Patients will be provided with a diary to 
record meal times and critical information 
on dosing.
Patients will be provided with a diary to 
record critical information on dosing.
Clarificatio
n of diary 
entries. 
Section 3.13.1 Procedures for Screening and Enrollment

obtain a blood sample (53 mL) for 
analysis of CYP2D6 genotype

obtain a blood sample (3 mL) for 
analysis of CYP2D6 genotype
Blood 
sample 
quantity 
specificatio
n. 


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Section 3.13.2 Procedures Before IMP Treatment (Baseline/Day 1) (Other sections affected by this 
change: 3.13.3.1.2 Clinic Visits [Weeks 2, 4, and 6] and 3.13.3.2.1 Week 9)

dispense IMP (…) and patient diary

dispense IMP (…) and patient diary
Clarificatio
n that 
patient 
diaries 
should also 
be 
dispensed at 
these 
visits/weeks
.
Section 4.4 Withdrawal Criteria and Procedures
The investigator also has the right to 
withdraw a patient from the study inif any 
of the event of following events occur:
a.
intercurrent illness, 
b.
adverse events, (any patient 
who experiences an adverse 
event may be withdrawn from 
the study or from study 
treatment at any time at the 
discretion of the investigator as 
indicated in Section 7.1.7)
c.
pregnancy (see Section 7.3), or 
)
d.
other reasons concerning the 
health or well-being of the 
patient, or in the event of 
e.
lack of cooperation. If a 
f.
post-baseline QTcF value >500 
msec or change from baseline 
>60 msec is found, the(as 
described in Sections 4.3 and
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 
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 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 
Sections 4.3 and 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.
Withdrawal 
criteria 
elaboration. 


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from baseline >60 msec.
g.
when a blind is broken due to 
safety concerns (see 
Section 3.7.2). If a patient is 
unblinded by mistake, they 
should not be withdrawn.
h.
if the investigator or the 
sponsor determines that the 
patient is not in compliance 
with the study protocol, the 
investigator and the sponsor 
should determine whether the 
patient should be withdrawn 
from the study (Section 5.4).
g.
when a blind is broken due to 
safety concerns (see 
Section 3.7.2). If a patient is 
unblinded by mistake, they 
should not be withdrawn.
h.
if the investigator or the 
sponsor determines that the 
patient is not in compliance 
with the study protocol, the 
investigator and the sponsor 
should determine whether the 
patient should be withdrawn 
from the study (Section 5.4).
Section 5.2 Restrictions 
While patients receiving strong CYP2D6 
inhibitors (such as 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 use of quinidine and 
terbinafine are prohibited (see Appendix A, 
Table 8). 
While patients receiving strong CYP2D6 
inhibitors such as 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 use of quinidine and 
terbinafine are prohibited (see Appendix A, 
Table 8). 
Clarificatio
n on the use 
of quinidine 
and 
terbinafine 
as 
prohibited.
Section 5.5 Dose Reduction and Temporary IMP Discontinuation 
Suspension of study medication for up to 1
one 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 fallswere tested 
and found to be below the lower limit of 
normal, IMP must be suspended. The 
Medical Monitor must be contacted to 
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, 
IMP must be suspended. The medical 
monitor must be contacted to determine the 
Blood 
sampling 
quantity 
specificatio
n. 


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determine the appropriate investigation and 
treatment. SD 809TEV-50717 may only be 
restarted once serum potassium or 
magnesium have normalized. 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.
appropriate investigation and treatment. 
TEV-50717 may only be restarted once 
serum potassium or magnesium have 
normalized. 
Table 3: Blood Volumes
Type of samples
Volu
me 
per 
sampl
e
Total 
numbe
r of 
sample
s
Total 
volu
me
Clinical 
laboratory 
(chemistry/hemato
logy)
10 
mL
2
20 
mL
Pharmacokinetic 
5 mL
1 time 
point 
(week 
12) × 
2 samp
les
10 
mL
CYP2D6 
genotyping
53
mL
1
53
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.
Type of samples
Volu
me 
per 
samp
le
Total 
numbe
r of 
sample
s
Total 
volu
me
Clinical laboratory 
(ch mistry/hemat
ology)
10 
mL
2
20 
mL
Pharmacokinetic 
5 mL
1 time 
point 
(week 
12) × 
samp
les
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.
Blood 
sampling 
quantity 
specificatio
n. 
Section 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 satisfy regulatory requirements, all 
serious adverse events that occur during the 
study, regardless of judged relationship to 
administration of the IMP, must be reported 
Clarificatio
n on the 
expectation 
of reporting 


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to the sponsor 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.
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.
serious 
adverse 
events.
Section 7.2.2 Columbia-Suicide Severity Rating Scale
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 1) endorse or 2) 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 
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 1) endorse or 2) 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 
Suicide and 
depression 
details 
required by 
authorities. 


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investigator will consult with the 
medical monitor, the consulting 
psychiatrist, and/or sponsor to 
determine whether the patient 
should continue in the study.
Suicidal behavior

Actual attempt: 
If patients report any suicidal behavior that 
is an actual attempt as assessed in the C-
SSRS, they will be evaluated immediately 
by the study investigator, referred for 
psychiatric evaluation, and terminated from 
the study.

Interrupted attempt, aborted 
attempt, or Preparatory Acts or 
Behavior: 
If patients report any suicidal behavior that 
is interrupted, aborted, or preparatory as 
assessed in the C-SSRS, they will be 
evaluated immediately by the study 
investigator and referred for psychiatric 
evaluation. In cases where it is determined 
in the psychiatric evaluation that IMP did 
not contribute to changes in suicidal 
behavior, the investigator will consult with 
the medical monitor, the consulting 
psychiatrist, and/or sponsor to determine 
whether the patient should continue in the 
study.
investigator will consult with the 
medical monitor, the consulting 
psychiatrist, and/or sponsor to 
determine whether the patient 
should continue in the study.
Suicidal behavior

Actual attempt: 
If patients report any suicidal behavior that 
is an actual attempt as assessed in the C-
SSRS, they will be evaluated immediately 
by the study investigator, referred for 
psychiatric evaluation, and terminated from 
the study.

Interrupted attempt, aborted 
attempt, or Preparatory Acts or 
Behavior: 
If patients report any suicidal behavior that 
is interrupted, aborted, or preparatory as 
assessed in the C-SSRS, they will be 
evaluated immediately by the study 
investigator and referred for psychiatric 
evaluation. In cases where it is determined 
in the psychiatric evaluation that IMP did 
not contribute to changes in suicidal 
behavior, the investigator will consult with 
the medical monitor, the consulting 
psychiatrist, and/or sponsor to determine 
whether the patient should continue in the 
study.
Section 7.5.3 Cytochrome P450 2D6 Genotyping 
One 53-mL sample for CYP2D6 genotyping 
will be collected from all patients in the 
study at screening.
One 3-mL sample for CYP2D6 genotyping 
will be collected from all patients in the 
study at screening.
Blood 
sampling 
quantity 
specificatio
n. 
Section 7.9 Assessment of Suicidality 
Consideration should be given to 
discontinuing TEV-50717 in participants 
who experience signs of suicidal ideation or 
behavior and detailed recommendations are 
provided in Section 7.2.2.
Families and caregivers of participants 
being treated with TEV 50717 should be 
instructed to monitor participants for the 
Consideration should be given to 
discontinuing TEV-50717 in participants 
who experience signs of suicidal ideation or 
behavior and detailed recommendations are 
provided in Section 7.2.2.
Baseline assessment of suicidal ideation and 
behavior and treatment-emergent suicidal 
ideation and behavior will be assessed 
Suicide and 
depression 
details 
required by 
authorities.


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emergence of unusual changes in behavior, 
as well as the emergence of suicidal 
ideation and behavior, and to report such 
symptoms immediately to the study 
investigator.Baseline assessment of suicidal 
ideation and behavior and treatment-
emergent suicidal ideation and behavior will 
be assessed during the study using the 
Children’s C-SSRS described in 
Section 7.2.2.
Depression and Suicidality as an Adverse 
Event 
Families and caregivers of subjects in Study 
30046 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.
during the study using the Children’s C-
SSRS described in Section 7.2.2.
Depression and Suicidality as an Adverse 
Event 
Families and caregivers of subjects in Study 
30046 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.


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In cases where it is determined that IMP did 
not contribute to the adverse event of 
depression or suicidality, the investigator 
will consult with the medical monitor 
and/or sponsor to determine whether the 
patient should continue in the study.
Section 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 option for PGx evaluation on the 
optional informed consent/assent, the 
remaining a pharmacogenetic (PGx) sample 
(2 mL) will be obtained and stored for 
exploratory pharmacogenetics (PGx) 
evaluationPGx.
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 
PGx evaluation on the optional informed 
consent/assent, a pharmacogenetic (PGx) 
sample (2 mL) will be obtained and stored 
for exploratory PGx.
Clarificatio
n on PGx 
sampling 
and details.
Section 9.2.1 Intent-to-Treat Analysis Set
Not applicable 
Enrolled subjects who are not randomized 
will be summarized separately as “Not 
randomized,” and randomized subjects will 
be analyzed based on their randomized 
treatment.
ITT 
analysis 
population 
specificatio
n. 
Section 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 week 9 or 
week 12, 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. All exclusions 
from the per-protocol analysis set will be 
reviewed in the blinded data review meeting 
before database lock.
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 week 9 or 
week 12, 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. All exclusions 
from the per-protocol analysis set will be 
reviewed in the blinded data review meeting 
before database lock.
Protocol 
deviation 
elaboration. 
Section 9.5.4.1 Primary Efficacy Analysis 


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The baseline TTS, region, and age group at 
baseline (2 levels: 6 to 11 years, 12 to 16 
years) will be included as a 
covariatecovariates.
The baseline TTS, region, and age group at 
baseline (2 levels: 6 to 11 years, 12 to 16 
years) will be included as covariates.
Addition of 
region to 
covariate 
list. 
Section 9.5.4.2 Sensitivity Analysis
To assess the robustness of the primary 
efficacy analysis, the following 
additionalSensitivity 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 12 will be 
repeated on a complete data set using 
multiple imputation methodology for 
imputing missing data using an MNAR 
missing data assumption to investigate 
when and the statistical significance 
disappears.
Data will be imputed for patients missing 
data at week 12 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 12 
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 12 
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 
bemodel are provided in the statistical 
Sensitivity analyses for missing data and the 
statistical model are provided in the 
statistical analysis plan.
Alignment 
of 
sensitivity 
analysis 
text with 
SAP. 


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analysis plan.
Section 14 FINANCING AND INSURANCE
A separate clinical study agreement, 
including a study budget, will be signed 
between each principal investigator and the 
sponsor (or INC Research) before the IMP 
is delivered.
A separate clinical study agreement, 
including a study budget, will be signed 
between each principal investigator and 
INC Research before the IMP is delivered.
Administrat
ive change. 
APPENDIX A. ALLOWED AND DISALLOWED MEDICATIONS
Medications that are allowed, provided that 
conditions outlined in the table are met, are 
shown in Table 9. Tables for allowed and 
prohibited medications are not exhaustive 
and may not include all possible 
concomitant medications. 
The medical monitor must be contacted if a 
patient is receiving (or has to begin or stop 
receiving during the study) a medication 
that is associated with QTc prolongation or 
that is a known strong 
cytochrome P450 inhibitor, or if there are 
any questions regarding any medication not 
listed in the tables below.
Table 5:
Allowed Medications
Generic/Drug 
class
Condition
Stable medications allowed according to 
inclusion/exclusions criteria
Hormonal 
birth control
Must be receiving stable 
treatment (including dose) 
for at least 3 months before 
screening.
Antidepressan
ts
Must be receiving stable 
treatment (including dose) 
for at least 6 weeks before 
screening.
Benzodiazepin
es
Primary use must not be 
for tics; dosing must have 
been stable QT for at least 
4 weeks before screening.
Note: PRN (as needed) 
Medications that are allowed, provided that 
conditions outlined in the table are met, are 
shown in Table 9. Tables for allowed and 
prohibited medications are not exhaustive 
and may not include all possible 
concomitant medications. 
The medical monitor must be contacted if a 
patient is receiving (or has to begin or stop 
receiving during the study) a medication 
that is associated with QTc prolongation or 
that is a known strong 
cytochrome P450 inhibitor, or if there are 
any questions regarding any medication not 
listed in the tables below.
Table 5:
Allowed Medications
Generic/Drug 
class
Condition
Stable medications allowed according to 
inclusion/exclusions criteria
Hormonal 
birth control
Must be receiving stable 
treatment (including dose) 
for at least 3 months before 
screening.
Antidepressan
ts
Must be receiving stable 
treatment (including dose) 
for at least 6 weeks before 
screening.
Benzodiazepin
es
Primary use must not be 
for tics; dosing must have 
been stable QT for at least 
4 weeks before screening.
Note: PRN (as needed) 
To update 
the list of 
prohibited 
drugs, and 
to clarify 
prior and 
concomitan
t use of 
guanfacine, 
clonidine, 
stimulants, 
and SNRIs.


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use is prohibited.
Topiramate 
(up to 
200 mg/day)
Must be receiving stable 
treatment (including dose) 
for at least 4 weeks before 
screening.
Guanfacine
Allowed, regardless of 
indication (ie, if prescribed 
for tics or Tourette 
syndrome). Must be 
receiving stable treatment 
(including dose) for at 
least 4 weeks before 
screening and no changes 
to dose or frequency are 
anticipated during the 
course of the study. 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
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.
use is prohibited.
Topiramate 
(up to 
200 mg/day)
Must be receiving stable 
treatment (including dose) 
for at least 4 weeks before 
screening.
Guanfacine
Allowed, regardless of 
indication (ie, if prescribed 
for tics or Tourette 
syndrome). Must be 
receiving stable treatment 
(including dose) for at 
least 4 weeks before 
screening and no changes 
to dose or frequency are 
anticipated during the 
course of the study. 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
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.


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Protocol Amendment 03 text with 
changes shown
New wording
Reason/Jus
tification 
for change
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
Includes atomoxetine. 
Primary use is for the 
treatment of ADHD; 
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 
preapproval from medical monitor
Albuterol, 
levalbuterol
Asthma
Guaifenesin
Cold symptoms
Antihistamine
s
Allergies
Melatonin
Insomnia
Allowed strong CYP inhibitorsa
Bupropion
Antidepressant 
(aminoketone)
Fluoxetine
Antidepressant (selective 
serotonin reuptake 
inhibitor)
Paroxetine
Antidepressant (selective 
serotonin reuptake 
inhibitor)
a
The use of these medications will affect 
the maximum daily dose of IMP, as shown 
in Table 2. ADHD=Attention-
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
Includes atomoxetine. 
Primary use is for the 
treatment of ADHD; 
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 
preapproval from medical monitor
Albuterol, 
levalbuterol
Asthma
Guaifenesin
Cold symptoms
Antihistamine
s
Allergies
Melatonin
Insomnia
Allowed strong CYP inhibitorsa
Bupropion
Antidepressant 
(aminoketone)
Fluoxetine
Antidepressant (selective 
serotonin reuptake 
inhibitor)
Paroxetine
Antidepressant (selective 
serotonin reuptake 
inhibitor)
a
The use of these medications will affect 
the maximum daily dose of IMP, as shown 
in Table 2. ADHD=Attention-


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Protocol Amendment 03 text with 
changes shown
New wording
Reason/Jus
tification 
for change
deficit/hyperactivity disorder; 
CYP=cytochrome P450; 
IMP=investigational medicinal product; 
SNRIs=serotonin-norepinephrine reuptake 
inhibitor Note: No dosing changes can be 
made during the study.
Table 6:
Prohibited Antipsychotic Drugs
Typical/first generation 
antipsychotics
Atypical/seco
nd generation 
antipsychotic
s
Chlorpromazine
Aripiprazole 
Haloperidol
Asenapine 
maleate 
Loxapine
Clozapine 
Molindone
Iloperidone 
Perphenazine
Lurasidone 
Pimozide 
Olanzapine 
Prochlorperazine 
Olanzapine/flu
oxetine 
Thioridazine
Paliperidone 
Thiothixene
Quetiapine 
Trifluoperazine
Risperidone 
Promethazine-containing 
compounds
Ziprasidone 
Fluphenazine
Tiapride
Note: This table does not apply in the 
second week of washout for patients not 
rolling over to the open-label extension 
study (Study TV50717-CNS-30047). 
Table 8:
Other Prohibited Drugs
Generic
Class/clinical 
use
Note
Cannabidio
l oil
Cannabis
Also 
includes 
other forms 
deficit/hyperactivity disorder; 
CYP=cytochrome P450; 
IMP=investigational medicinal product; 
SNRIs=serotonin-norepinephrine reuptake 
inhibitor Note: No dosing changes can be 
made during the study.
Table 6:
Prohibited Antipsychotic Drugs
Typical/first generation 
antipsychotics
Atypical/seco
nd generation 
antipsychotic
s
Chlorpromazine
Aripiprazole 
Haloperidol
Asenapine 
maleate 
Loxapine
Clozapine 
Molindone
Iloperidone 
Perphenazine
Lurasidone 
Pimozide 
Olanzapine 
Prochlorperazine 
Olanzapine/flu
oxetine 
Thioridazine
Paliperidone 
Thiothixene
Quetiapine 
Trifluoperazine
Risperidone 
Promethazine-containing 
compounds
Ziprasidone 
Fluphenazine
Tiapride
Note: This table does not apply in the 
second week of washout for patients not 
rolling over to the open-label extension 
study (Study TV50717-CNS-30047). 
Table 8:
Other Prohibited Drugs
Generic
Class/clinical 
use
Note
Cannabidio
l oil
Cannabis
Also 
includes 
other forms 


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Protocol Amendment 03 text with 
changes shown
New wording
Reason/Jus
tification 
for change
of 
cannabinoid
s 
Valbenazin
e
Vesicular 
monoamine 
transporter 2 
inhibitor
Ingrezza 
off-label
Quinidine
Class I 
antiarrhythmic 
agent
Strong 
CYP2D6 
inhibitor
Terbinafine Antifungal 
medication
Weak 
CYP2D6 
inhibitor
of 
cannabinoid
s 
Valbenazin
e
Vesicular 
monoamine 
transporter 2 
inhibitor
Ingrezza 
off-label
Quinidine
Class I 
antiarrhythmic 
agent
Strong
CYP2D6 
inhibitor
Terbinafine Antifungal 
medication
Weak 
CYP2D6 
inhibitor


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17.5.
Amendment 05 Dated 25 March 2019
The primary reason for this amendment is to update the anticipated patient enrollment numbers 
and related statistical considerations, update requirements on drug storage and security, to 
update/clarify patient inclusion criteria and withdrawal criteria, to update administrative details 
with regards to clinical study personnel contact information and vendor selection, and to provide 
additional guidance on dose suspension.
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.


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
Global
INC ResearchSyneos Health
Syneos Health
Administrative update to account 
for vendor name change
Title Page
601 Gateway Boulevard
Suite 1270
South San Francisco, California 94080 
101 Main Street, 12th Floor
Cambridge, Massachusetts 02142
101 Main Street, 12th Floor
Cambridge, Massachusetts 02142
Address update
This clinical study will be conducted in accordance 
with current Good Clinical Practice (GCP) as directed 
by the provisions of the International 
ConferenceCouncil 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 
regulationslegislation; 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/or its affiliates and 
Nuvelution TS Pharma, INC.
© 20172019 Teva Branded Pharmaceutical Products 
R&D, Inc. and Nuvelution TS Pharma, INC. All rights 
reserved.
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/or its affiliates and 
Nuvelution TS Pharma, INC.
© 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
LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Contract Research Organization; Safety and 
Efficacy Data Analysis
INC Research, LLC, a Syneos health group company 
(Syneos Health, LLC)
3201 Beechleaf Court
Contract Research Organization; Safety and 
Efficacy Data Analysis
Syneos Health, LLC
1030 Sync Street
Morrisville, NC 27560
Administrative change


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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
Suite 600
Raleigh, NC 27604 1547
1030 Sync Street
Morrisville, NC 27560
USA
USA
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
Legal Representative of the Sponsor in the EU
Syneos Health Netherlands B.V.
For medical issues, contact the physician listed 
below: 
 
For protocol issues, contact the study leaders 
listed below:
Legal Representative of the Sponsor in the EU
Syneos Health Netherlands B.V.
For medical issues, contact the physician listed 
below:
 
For protocol issues, contact the study leaders 
listed below:
Update to the sponsor’s legal
representative in the EU. 
Additional administrative changes 
have been carried out.


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
 
For operational issues, contact the Head of 
Operationsoperational lead listed below: 
 
For operational issues, contact the Head of 
Operations listed below: 
Section 1.3.2 Clinical Studies (other section affected: Section 1.3.2.1 Clinical Pharmacology Studies)
The clinical development plan for TEV-50717 to date 
includes:

67 completed Phase 1 studies in healthy adult 
subjects

2 ongoing Phase 1 studies in healthy adult 
volunteers

1 completed Phase 3 pivotal study for the 
treatment of chorea associated with HD

1 completed Phase 3 long-term safety study 
in patients with HD
The clinical development plan for TEV-50717 to date 
includes:

7 completed Phase 1 studies in healthy adult 
subjects

2 ongoing Phase 1 studies in healthy adult 
volunteers

1 completed Phase 3 pivotal study for the 
treatment of chorea associated with HD

1 completed Phase 3 long-term safety study 
in patients with HD
The clinical development plan for 
TEV-50717 has been updated to 
reflect the most current program 
information.


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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change

2 completed Phase 2/3 and Phase 3 studies in 
patients with TD

1 ongoing Phase 3 long-term safety study in 
patients with TD

1 completed Phase 1b study in patients with 
TS

2 ongoing Phase 2/3 and Phase 3 studies in 
patients with TS

1 ongoing Phase 3 long-term safety study in 
patients with TS

2 completed Phase 2/3 and Phase 3 studies in 
patients with TD

1 ongoing Phase 3 long-term safety study in 
patients with TD

1 completed Phase 1b study in patients with 
TS

2 ongoing Phase 2/3 and Phase 3 studies in 
patients with TS

1 ongoing Phase 3 long-term safety study in 
patients with TS
Section 2.3.3 Exploratory Endpoints (other sections affected: Section 9.5.3 Exploratory Endpoints and Section 9.5.4.4 Exploratory 
Analyses)
 
 
 
 
 
 
 
 
 
 
 
 
Update on and addition of the 
exploratory endpoints evaluating 
reduction
Section 3.1.2 Screening Period
Patients may be rescreened 1 time if there is a change 
in the patient’s medical background, a 
modificationstatus of the patient regarding eligibility 
for the study entry criteria, or other relevant change.
Patients may be rescreened 1 time if there is a change 
in the status of the patient regarding eligibility for the 
study.
Provided further details about 
rescreening activities and process
Section 3.3.3 Exploratory Measures and Time Points
 
 
 
 
Update on and addition of the 
exploratory measures and time
points evaluating reduction


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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
 
 
 
 
Section 3.7.2 Blinding/Unblinding
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). However, if a patient is 
unblinded by mistake, the investigator should discuss 
with the medical monitor whether or not the patient 
should be withdrawn.
When a blind is broken, the patient will be 
withdrawn from the study, and the event will be 
recorded onto the case report form (CRF). However, 
if a patient is unblinded by mistake, the investigator 
should discuss with the medical monitor whether or 
not the patient should be withdrawn.
Provided further guidance to the 
investigator in the situation that a 
patient is unblinded by mistake
Section 3.9.1 Drug Storage and Security
The IMP (TEV-50717 and 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 3020°C (59°F and 8668°F) 
is acceptable if there is no alternative.
The IMP (TEV-50717 and 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.
Updated temperature range for 
storage of the IMP
Section 3.13.1 Procedures for Screening and Enrollment (other sections affected: Section 3.13.2 Procedures Before IMP Treatment 
(Baseline/Day 1), Section 3.13.3.1.2 Clinic Visits (Weeks 2, 4, and 6), Section 3.13.3.2.1 Week 9, Section 3.13.3.2.2 Week 12/Early 
Termination, Section 3.13.4.1 Week 13, and Section 3.13.5 Unscheduled Visits)
A signed and dated informed consent form will be 
obtained from the parent/legally acceptable 
representative (may also include an adult other than a 
parent or legal representative), and a signed and dated 
assent, depending on the child’s age, as appropriate, 
will be obtained from each patient before screening 
procedures commence, according to national laws 
and local IEC/IRB requirements. Parents/legally 
acceptable representatives will acknowledge and 
agree to the possible use of this information for the 
study by giving informed consent.
A patient who is screened but not enrolled may be 
rescreened 1 time if there is a change in the patient’s 
A signed and dated informed consent form will be 
obtained from the parent/legally acceptable 
representative, and a signed and dated assent, 
depending on the child’s age, as appropriate, will be 
obtained from each patient before screening 
procedures commence, according to national laws 
and local IEC/IRB requirements. Parents/legally 
acceptable representatives will acknowledge and 
agree to the possible use of this information for the 
study by giving informed consent.
A patient who is screened but not enrolled may be 
Updated language surrounding 
who can be involved in the 
informed consent/assent process. 
Removed a parenthetical 
expression that was inserted 
previously
Included “conduct clinic visit” 
strictly for clarity at each visit 
where patients are expected to be 
present at the clinic for 
assessment


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
medical background, a modification of study entry 
criteria, or other relevant change.status of the patient 
regarding eligibility for the study.
The screening visit will take place not more than 31 
days before the baseline visit. The screening visit 
may be conducted over 2 separate visits at the 
discretion of the investigator. The following 
procedures will be performed at screening:

conduct clinic visit
rescreened 1 time if there is a change in the status of 
the patient regarding eligibility for the study.
The screening visit will take place not more than 31 
days before the baseline visit. The screening visit 
may be conducted over 2 separate visits at the 
discretion of the investigator. The following 
procedures will be performed at screening:

conduct clinic visit
Section 4.1. Patient Inclusion Criteria (other section affected: Section 12.1 Informed Consent/Assent)
f.
Patient and caregiver/adult (may also include an 
adult other than a parent or legal representative) 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 (may also include an adult other than 
a parent or legal representative) 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 (may also include an 
adult other than a parent or legal representative)
provide written informed consent/assent, depending 
on the child’s age, as appropriate, according to local 
regulations.
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 caregiver/adult provide written 
informed consent/assent, depending on the child’s 
age, as appropriate, according to local regulations.
Updated language surrounding 
who can be involved in the 
informed consent/assent process. 
Removed a parenthetical 
expression that was inserted 
previously
Section 4.4 Withdrawal Criteria and Procedures (other section affected: Section 7.1.7 Withdrawal Due to an Adverse Event)
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 
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 
Included clarity that patients who 
experience an adverse event can 
also be withdrawn by the sponsor. 
Provided further guidance to the 


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
7.1.7)
g.
when a blind is broken due to safety concerns 
(see Section 3.7.2). If a patient is unblinded by 
mistake, theythe investigator should discuss with the 
medical monitor whether or not the patient should be 
withdrawn.
7.1.7)
g.
when a blind is broken due to safety concerns 
(see Section 3.7.2). If a patient is unblinded by 
mistake, the investigator should discuss with the 
medical monitor whether or not the patient should be 
withdrawn.
investigator in the situation that a 
patient is unblinded by mistake
Section 5.5 Dose Reduction and Temporary IMP Discontinuation
Dose Suspension
If a subject’s serum potassium or magnesium were 
tested and found to be below the lower limit of 
normal, IMP must be suspended. 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.
Dose Suspension
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 suspension text to 
provide further guidance
Section 6.2.5 Yale Global Tic Severity Scale
 
re exploratory 
measures.
 are 
exploratory measures. 
Updated to more properly capture 
the YGTSS measures
Section 7.11 Concomitant Therapy or Medication
Medications that are allowed, provided that 
conditions outlined in the table are met, are shown in 
Appendix A, Table 9. The tables of allowed and 
prohibited medications are not comprehensive and 
may not include all possible concomitant 
medications.
Medications that are allowed, provided that 
conditions outlined in the table are met, are shown in 
Appendix A, Table 9. The tables of allowed and 
prohibited medications are not comprehensive and 
may not include all possible concomitant 
medications.
Updated allowed medications to 
clarify that the list of concomitant 
medications provided is not 
comprehensive
Section 9.1 Sample Size and Power Considerations (other section affected: Figure 1: Overall Study Schema)
It is estimated that approximately 5058 patients per 
arm will enable a power of at least 90% to detect a 
beneficial standardized effect of 6.5 points63% or 
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 
Recently, a Phase 2 study 
assessing the safety and efficacy 
of valbenazine in the treatment of 


Placebo-Controlled Study–Tourette Syndrome
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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
more when the TEV-50717 arm is compared to 
placebo (difference of 6.0 in the change from 
baseline to week 12 in TTS when the TEV 50717 
arm is compared to placebo, assuming a standard 
deviation of 9.5 and 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 100 total patients (50 patients per arm) to 116 
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, respectively, are blinded and were not used to 
inform the sample size calculation.
the TEV-50717 arm is compared to placebo 
(difference of 6.0 in the change from baseline to 
week 12 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 100 total patients (50 patients per arm) to 116 
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, respectively, are blinded and 
were not used to inform the sample size calculation.
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 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.
Section 9.2.1 Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all 
randomized patients. In this population, treatment 
will be assigned based on the treatment to which 
patients were randomized, regardless of which 
treatment they actually received. Enrolled subjects 
The intent-to-treat (ITT) analysis set will include all 
randomized patients. In this population, treatment 
will be assigned based on the treatment to which 
patients were randomized, regardless of which 
treatment they actually received.
Updated the definition of the ITT 
analysis set


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Protocol Amendment 04 text with changes shown
New wording
Reason/Justification for change
who are not randomized will be summarized 
separately as “Not randomized,” and randomized 
subjects will be analyzed based on their randomized 
treatment.
Section 9.5.4.2 Sensitivity Analysis
Sensitivity analyses for missing dataand, the 
statistical model are, and the increase in sample size 
will be provided in the statistical analysis plan.
Sensitivity analyses for missing data, the statistical 
model, and the increase in sample size will be 
provided in the statistical analysis plan.
Updated the protocol to state that 
sensitivity analysis will also be 
done for the increased sample size 
and further details will be 
provided in the statistical analysis 
plan


Placebo-Controlled Study–Tourette Syndrome
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205
APPENDIX A. ALLOWED AND DISALLOWED MEDICATIONS
Medications that are allowed, provided that conditions outlined in the table are met, are shown in Table 5. Tables for allowed and 
prohibited medications are not exhaustive and may not include all possible concomitant medications. 
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving during the study) a medication that is 
associated with QTc prolongation or that is a known strong cytochrome P450 inhibitor, or if there are any questions regarding any 
medication not listed in the tables below.
Prohibited medications that are associated with QTc prolongation are listed in Table 6, while prohibited antipsychotic drugs are listed 
in Table 7.
Table 5:
Allowed Medications
Generic/Drug class
Condition
Stable medications allowed according to inclusion/exclusions criteria
Hormonal birth control
Must be receiving stable treatment (including dose) for at least 3 months before screening.
Antidepressants
Must be receiving stable treatment (including dose) for at least 6 weeks before screening.
Benzodiazepines
Primary use must not be for tics; dosing must have been stable QT for at least 4 weeks before 
screening.
Note: PRN (as needed) use is prohibited.
Topiramate 
(up to 200 mg/day)
Must be receiving stable treatment (including dose) for at least 4 weeks before screening.
Guanfacine
Allowed, regardless of indication (ie, if prescribed for tics or Tourette syndrome). Must be 
receiving stable treatment (including dose) for at least 4 weeks before screening and no 
changes to dose or frequency are anticipated during the course of the study. 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
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


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Generic/Drug class
Condition
Stable medications allowed according to inclusion/exclusions criteria
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. 
Table 5:
Allowed Medications (Continued)
Generic/Drug class
Condition
SNRIs
Includes atomoxetine. Primary use is for the treatment of ADHD; 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 preapproval from medical monitor
Albuterol, levalbuterol
Asthma
Guaifenesin
Cold symptoms
Antihistamines
Allergies
Melatonin
Insomnia
Allowed strong CYP inhibitorsa
Bupropion
Antidepressant (aminoketone)
Fluoxetine
Antidepressant (selective serotonin reuptake inhibitor)
Paroxetine
Antidepressant (selective serotonin reuptake inhibitor)
a The use of these medications will affect the maximum daily dose of IMP, as shown in Table 2.
ADHD=Attention-deficit/hyperactivity disorder; CYP=cytochrome P450; IMP=investigational medicinal product; SNRIs=serotonin-norepinephrine reuptake 
inhibitor
Note: No dosing changes can be made during the study.


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Table 6:
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 the USA
Droperidol
Sedative; anti-nausea/anesthesia adjunct, nausea
Erythromycinb
Antibiotic; GI stimulant; GI motility
Moxifloxacin
Antibiotic/bacterial infection
Sevoflurane
Anesthetic, general/anesthesia
Probucol
Antilipemic/hypercholesterolemia
Not available in the USA
Sparfloxacin
Antibiotic/bacterial infection
Not available in the USA
a Patients are allowed to take up 500 mg/day of azithromycin.
b Systemic use only. Topical use is allowed.
GI=gastrointestinal; QTc=corrected QT; USA=United States of America.
Table 7:
Prohibited Antipsychotic Drugs
Typical/first generation antipsychotics
Atypical/second generation antipsychotics
Chlorpromazine
Aripiprazole 
Haloperidol
Asenapine maleate 
Loxapine
Clozapine 
Molindone
Iloperidone 
Perphenazine
Lurasidone 
Pimozide 
Olanzapine 
Prochlorperazine 
Olanzapine/fluoxetine 
Thioridazine
Paliperidone 


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Thiothixene
Quetiapine 
Trifluoperazine
Risperidone 
Promethazine-containing compounds
Ziprasidone 
Fluphenazine
Tiapride
Note: This table does not apply in the second week of washout for patients not rolling over to the open-label extension study (Study TV50717-CNS-30047). 
Table 8:
Other Prohibited Drugs
Generic
Class/clinical use
Note
Cannabidiol oil
Cannabis
Also includes other forms of 
cannabinoids 
Valbenazine
Vesicular monoamine transporter 2 inhibitor
Ingrezza off-label
Quinidine
Class I antiarrhythmic agent
Strong CYP2D6 inhibitor
Terbinafine
Antifungal medication 
Weak CYP2D6 inhibitor 


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


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


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Placebo-Controlled Study–Tourette Syndrome
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APPENDIX D. CHILDREN’S DEPRESSION INVENTORY, SECOND 
EDITION, PARENT AND SELF-REPORT PROFILES
The sample provided in this appendix is for reference only. 
CDI-2 Parent Profile


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CDI-2 Self-Report


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APPENDIX E. CHILDREN’S COLUMBIA-SUICIDE SEVERITY RATING 
SCALE
The sample provided in this appendix is for reference only. 
Children’s Baseline/Screening


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Children’s Since Last Visit


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APPENDIX F.
CHILDREN’S YALE-BROWN OBSESSIVE-
COMPULSIVE SCALE
The sample provided in this appendix is for reference only.


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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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250


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
Study TV50717-CNS-30046
251


Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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APPENDIX G. YALE GLOBAL TIC SEVERITY SCALE
The sample provided in this appendix is for reference only. 


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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
Clinical Study Protocol with Amendment 05
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Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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264
APPENDIX H.
 
The sample provided in this appendix is for reference only.


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


Placebo-Controlled Study–Tourette Syndrome
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Placebo-Controlled Study–Tourette Syndrome
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APPENDIX J.
The sample provided in this appendix is for reference only.


Placebo-Controlled Study–Tourette Syndrome
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268
APPENDIX K.
 
 
The sample provided in this appendix is for reference only.


Placebo-Controlled Study–Tourette Syndrome
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269


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Quality of life scale for patients aged 13 to 18 years (C&A-GTS-QOL 13-18)


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Placebo-Controlled Study–Tourette Syndrome
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APPENDIX L.
 


Placebo-Controlled Study–Tourette Syndrome
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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Randomized, Double-blind, Placebo-controlled Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Tourette Syndrome in Children and 
Adolescents 
 
 
Study Number TV50717-CNS-30046 
 
 
NCT03452943 
 
 
SAP Approval Date: 02-Dec-2019 


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