Clinical trial NCT03813238
Conditions: Cerebral Palsy, Dyskinetic
Keywords: DCP
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2019-08-06; Completion date: 2022-07-21
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
CP (cerebral palsy) refers to a group of neurological disorders that appear in infancy or early childhood and permanently affect body movement and muscle coordination. CP is caused by damage to or abnormalities inside the developing brain that disrupt the brain's ability to control movement and maintain posture and balance. The signs of CP usually appear in the early months of life, although specific diagnosis may be delayed until the age of 2 years or older. TEV-50717 (deutetrabenazine, also known as SD-809) has already provided evidence for safe and effective use in 2 other hyperkinetic movement disorders, namely chorea in Huntington's disease (HD) and tardive dyskinesia (TD). Currently, there is no approved treatment available for Dyskinesia in cerebral palsy (DCP). The available treatment options address some of the manifestations of DCP. The study population will include pediatric and adolescent participants (6 through 18 years of age) with DCP with predominant choreiform movement disorder, who have had nonprogressive CP symptoms since infancy (≤2 years of age). Diagnosis of DCP is based on the Surveillance of Cerebral Palsy in Europe criteria.

This is a Phase 3 study that will evaluate the efficacy and safety of TEV-50717 administered as oral tablets at a starting dose of 6 mg once daily in participants (age 6 through 18 years, inclusive) with DCP with predominant choreiform movement disorder. The study will be conducted in multiple centers and will use 2 parallel treatment groups (ie, TEV-50717 and placebo) in which participants will be randomized in a 2:1 ratio.

"Predominant" in this instance indicates that the choreiform movement disorder is the main cause of impairment or distress.

Detailed description:

Arms: arm 1: administered as oral tablets at a starting dose of 6 mg once daily arm 2: Matching placebo
Interventions: intervention 1: TEV-50717 intervention 2: Placebo
Intervention descriptions: intervention 1: Dosage ranging from 6 mg to 48 mg. intervention 2: Dosage ranging from 6 mg to 48 mg.

Protocol documents:
Prot_002.pdf: 



&OLQLFDO6WXG\3URWRFRO


$5DQGRPL]HG'RXEOH%OLQG3ODFHER&RQWUROOHG6WXG\RI7(9
'HXWHWUDEHQD]LQHIRUWKH7UHDWPHQWRI'\VNLQHVLDLQ&HUHEUDO3DOV\LQ&KLOGUHQ
DQG$GROHVFHQWV


6WXG\1XPEHU79&16


1&7



3URWRFROZLWK$PHQGPHQW$SSURYDO'DWH0DUFK


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
1
 
Clinical Study Protocol Amendment 05
Study Number TV50717-CNS-30080
A Randomized, Double-Blind, Placebo-Controlled Study of TEV-50717 (Deutetrabenazine) 
for the Treatment of Dyskinesia in Cerebral Palsy in Children and Adolescents
Short title: Reduction of Childhood and Adolescent Abnormal Involuntary Movements in 
Patients with Dyskinetic Cerebral Palsy in Children and Adolescents (RECLAIM-DCP)
Lay person title: A Study to Test if TEV-50717 is Effective in Relieving Abnormal 
Involuntary Movements in Cerebral Palsy
Phase 3
IND Number: 139700;
NDA Number: NA; EudraCT Number: 2018-003742-17
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol Approval Date: 27 September 2018
Protocol Amendment 05 Approval Date: 24 March 2022
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
COVID-19 pandemic-related operational updates are provided in Appendix M .
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).
Confidentiality Statement
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. The recipient agrees that no information contained 
herein may be published or disclosed without written approval from the sponsor.
© 2022 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
2
AMENDMENT HISTORY
The protocol for Study TV50717-CNS-30080 (original protocol dated 27 September 2018) has 
been amended and reissued as follows:
Amendment 05
24 March 2022
63 patients enrolled to date
Administrative Letter 07
05 May 2021
Amendment 04
09 March 2021
46 patients enrolled to date
Amendment 03
08 June 2020
30 patients enrolled to date
Amendment 02
17 October 2019
0 patients randomized/enrolled to date
Letter of Clarification 06
05 August 2019
Letter of Clarification 05
16 January 2019
Amendment 01
20 December 2018
0 patients randomized/enrolled to date
Letter of Clarification 04
05 December 2018
Letter of Clarification 03
22 November 2018
Letter of Clarification 02
16 November 2018
Letter of Clarification 01
17 October 2018
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
3
INVESTIGATOR AGREEMENT
Original Protocol Dated 27 September 2018
Amendment 05 Dated: 24 March 2022
IND Number: 139700;
NDA Number: NA; EudraCT Number: 2018-003742-17
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
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 Dyskinesia in Cerebral Palsy 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


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
4
SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized 
Representative
 
Signature
Date
Executed signature pages are maintained within the Trial Master File.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
5
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 27 September 2018
Amendment 05 Dated: 24 March 2022
IND Number: 139700;
NDA Number: NA; EudraCT Number: 2018-003742-17
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
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 Dyskinesia in Cerebral Palsy in Children and Adolescents
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 and 
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 patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations 
as well as all other national and international laws and regulations. In addition, I will assume the 
responsibility of the coordinating investigator according to a separate contract.
Coordinating Investigator:
 
Title:
Address of Investigational Center:
Vanderbilt University Medical Center
Department of Neurology
1161 21st Avenue South
A-0118 MCN
Nashville, TN 37232-2551
Tel:
Coordinating Investigator
Signature
Date
Executed signature pages are maintained within the Investigator Site File and Trial Master File.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
6
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 27 September 2018
Amendment 05 Dated: 24 March 2022
IND Number: 139700;
NDA Number: NA; EudraCT Number: 2018-003742-17
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
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 Dyskinesia in Cerebral Palsy in Children and Adolescents
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 and 
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 patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations 
as well as all other national and international laws and regulations. In addition, I will assume the 
responsibility of the coordinating investigator according to a separate contract.
Coordinating Investigator:
Title:
 at Children’s of 
Alabama Hospital
Address of Investigational Center:
1600 7th Ave. S.
CHB Suite 314
Birmingham, AL 35233
Tel:
Coordinating Investigator
Signature
Date
Executed signature pages are maintained within the Investigator Site File and Trial Master File.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
7
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV50717-CNS-30080
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and 
Adolescents
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West 
Chester, Pennsylvania 19380, United States of America
Investigational New Drug (IND) Number: 139700
New Drug Application (NDA) Number: Not applicable
EudraCT Number: 2018-003742-17
Name of Active Ingredient: Deutetrabenazine
EMA Decision Number of Pediatric Investigation Plan: Does not apply
Name of Test Investigational Medicinal Product (IMP): TEV-50717 (previously SD-809)
EudraVigilance code for the IMP, if applicable: SUB179485
Type of Study: Efficacy and safety study (Phase 3)
Indication: Dyskinesia in cerebral palsy (DCP)
Is this study conducted to investigate the New Use of an approved, marketed product? Yes
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 60 investigational centers. 
Regions Planned: North America, Asia, and Europe
Planned Study Period: Fourth quarter of 2018 to fourth quarter of 2022
Number of Patients Planned (total): Approximately 65 patients are planned to be randomized 
to TEV-50717 versus placebo in a 2:1 ratio (approximately 43 in the TEV-50717 group; 
approximately 22 in the placebo group) stratified by age at baseline (6 to <12 years; 12 through 
18 years, inclusive) and region (United States [US]; non-US). 
Study Population: Male and female patients, 6 through 18 years of age (inclusive) at baseline, 
diagnosed with DCP.
Primary and Secondary Objectives and Endpoints: The primary and secondary study 
objectives and measures/endpoints are the following:
Objectives
Measures/Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of TEV-50717 to reduce the 
severity of dyskinetic 
involuntary movements 
associated with CP.
The primary efficacy endpoint is the change from baseline to 
week 15 in the MD-CRS part II total score (movement 
disorder severity, centrally read) (TEV-50717 versus placebo).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
8
Objectives
Measures/Endpoints
A secondary objective is to 
evaluate the specific efficacy 
parameters of TEV-50717 
beyond the measure of the 
primary objective.
The key secondary efficacy endpoints (TEV-50717 versus 
placebo) are the following: 

MD-CRS part I total score (general assessment, 
centrally read) change from baseline to week 15

CaGI-I Scale (global, caregiver rated) at week 15

CGI-I Scale (global, physician rated) at week 15

UHDRS-TMC (centrally read)

UHDRS-TMD (centrally read)
Other efficacy measures and endpoints (TEV-50717 versus 
placebo) include the following:

MD-CRS part I total score (general assessment, 
physician rated)

MD-CRS part II total score (general assessment, 
physician rated)

MD-CRS Global Index (calculated from MD-CRS 
parts I and II total scores)

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

PEDI-CAT (ADL, caregiver completed, content-
balanced version)

The CP module of the PedsQL (QoL, 
patient/caregiver)

PGI-I Scale (global, patient/caregiver)

CGI-S Scale (global, physician rated)

CaGI-I response, defined as patients who are 
described by the caregiver as “Much Improved” or 
“Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are 
described as “Much Improved” or “Very Much 
Improved” in the CGI-I score

CGI-S response, defined as patients who have a 
reduction of ≥1 point in the CGI-S score

PGI-I response, defined as patients who are 
described as “Much Improved” or “Somewhat 
Improved” in the PGI-I score 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
9
Objectives
Measures/Endpoints
A secondary objective of the 
study is to evaluate the safety 
and tolerability of TEV-50717.
The safety variables include adverse events (and the number of 
patients who withdraw from the study due to adverse events), 
vital signs, laboratory tests (hematology, chemistry, and 
urinalysis), ECG measurements, CBCL, ESRS, ESS, and the 
children’s C-SSRS.
ADL=activities of daily living; CaGI-I=Caregiver Global Impression of Improvement; CBCL=Child Behavior 
Checklist (for ages 6-18); CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of 
Severity; CP=cerebral palsy; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS=Epworth Sleepiness Scale (for children and 
adolescents); MD-CRS=Movement Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability 
Inventory-Computer Adapted Test; PedsQL=Pediatric Quality of Life Inventory; PGI-I=Patient Global Impression 
of Improvement; QoL=quality of life; UHDRS-TMC=Unified Huntington’s Disease Rating Scale-Total Maximal 
Chorea; UHDRS-TMD=Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia; 
UHDRS-TMS=Unified Huntington’s Disease Rating Scale-Total Motor Score.
Exploratory Objective and Endpoint: The exploratory study objective and endpoint are the 
following:
Objective
Endpoint
 
 
 
General Study Design:
This is a Phase 3, 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study to evaluate the efficacy and safety of TEV-50717 administered as oral tablets at a 
starting dose of 6 mg once daily in patients (age 6 through 18 years) with DCP with predominant 
choreiform movement disorder, who have had CP symptoms, of a non-progressive nature, since 
infancy (≤2 years of age). “Predominant” in this instance indicates that the choreiform movement 
disorder is the main cause of impairment or distress. 
The study will consist of a screening period (up to 31 days) and a double-blind treatment period 
including a titration period (7 weeks) and a maintenance period (8 weeks), followed by a 
washout period of 1 week, and a follow-up telephone contact 1 week after the washout period. 
Throughout the study, patients will interact regularly with investigational center personnel, in-
clinic and by telephone (with non-recording live video), for the evaluation of safety/tolerability, 
dyskinesia severity, and behavioral status (in-clinic only). 
For the purposes of this protocol, a caregiver is defined as an adult who is familiar with the 
patient and is responsible for daily care, enabling that person to effectively complete the protocol 
requirements. The caregiver accompanies the patient to the visits and provides input to the 
relevant scales as required by the protocol. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
10
For patients who are minors, the caregiver is typically a parent or a legally accepted 
representative. In some countries, an adult (such as grandparent or nurse) can be appointed by 
the parent or legally accepted representative (as per local regulations and laws) and would take 
over this responsibility as a caregiver. The parent or legally accepted representative only has to 
sign the parent/legally accepted representative informed consent form (ICF) and not the 
caregiver ICF.
For adult patients, a caregiver must be appointed by the patient; this can be the parent, a legally 
accepted representative, or other adult, as appropriate and according to local laws and 
regulations.
For patients who are minors, certain responsibilities in the protocol can only be completed by the 
parent/legally accepted representative, ie, informed consent, withdrawal of consent, requests for 
discontinuation of the IMP, or withdrawal from the study for any reason. To further clarify, the 
caregiver is not allowed to make decisions on the child’s health or where “parent/legally 
accepted representative” is specifically indicated in the protocol.
At the baseline visit (day 1), patients will be randomly assigned to 1 of 2 treatment groups with 
TEV-50717 IMP or placebo IMP in a 2:1 ratio stratified by age at baseline (6 to <12 years; 
12 through 18 years, inclusive) and region (US; non-US). IMP will be titrated during the 
double-blind treatment period starting with 6 mg of TEV-50717 or matching placebo IMP in the 
morning of day 2. Patients in the highest body weight group (≥40 kg/88 lbs) will start an evening 
administration from day 3 and for the remainder of the first week. TEV-50717 daily doses of 
12 mg and higher will be administered as 2 divided equal doses, approximately 8 to 10 hours 
apart during the day. The number of matching placebo IMP tablets will be increased accordingly. 
Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg/88 lbs. For patients ≥40 kg/88 lbs, the first dose increase should be performed in an 
interval less than 5 days, only once, on day 3. During the titration period, the dose of IMP will be 
adjusted according to the titrations scheme to identify a dose level that optimally reduces 
dyskinesia (as determined by the investigator, as indicated by a reduction in the Clinical Global 
Impression of Improvement [CGI-I]) and is well tolerated. If a patient experiences a “clinically 
significant” adverse event attributable to the IMP, the investigator will first determine if a dose 
reduction (to the previous dose level) or suspension is necessary and possible. After titration, 
patients will remain at their optimal dose for the length of the maintenance period.
Screening period (up to 31 days): After written informed consent/assent, 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; 12-lead electrocardiogram (ECG); along with Movement Disorder-Childhood 
Rating Scale (MD-CRS) part II (physician rated, with video recording, centrally read with video 
review, centrally read by Enrollment Adjudication Board [EAB]) to assess severity of 
dyskinesia; Clinical Global Impression of Severity (CGI-S) to assess clinical impression of DCP
severity, comorbid CP symptoms, and behavioral status; children’s Columbia-Suicide Severity 
Rating Scale (C-SSRS); assessment of drug-induced parkinsonism according to the 
Extrapyramidal Symptom Rating Scale (subscales I and II; ESRS); assessment of change in 
behavior according to the Child Behavior Checklist (for ages 6-18) (CBCL) questionnaire; and 
assessment of sedation according to the Epworth Sleepiness Scale (for children and adolescents)
(ESS) questionnaire. Screening may be conducted over 2 separate visits at the discretion of the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
11
investigator. The diagnosis of CP and DCP will be established based on clinical features as 
described in the inclusion/exclusion criteria. The EAB will also confirm, based on video 
recordings, that choreiform is clinically the predominant movement disorder of the patient’s 
DCP. EAB assessment results will be available to the investigator prior to baseline and 
randomization. The MD-CRS part II will be administered by the investigational center physician 
and video review, for central-blinded reading. In this study, the MD-CRS part II will be scored 
only based on chorea.
Titration period (7 weeks): Patients who remain eligible for participation in the study will be 
randomized at the baseline visit (day 1) and instructed to take the first dose of blinded IMP the 
following morning with food (eg, a snack) and should not be taken on an empty stomach. The 
titration scheme and maximum dose will be determined by body weight and cytochrome P450 
2D6 (CYP2D6) impairment status at baseline. Patients will be classified as CYP2D6 impaired if 
they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 poor metabolizer. At the baseline 
visit, a telephone for non-recording live video will be provided to the patient and caregiver. 
Patients and their caregiver will interact weekly with the investigator/staff, either by telephone 
contact (with non-recording live video) or clinic visit from week 1 through week 7 of the titration 
period, in order to evaluate safety/tolerability and establish a dose of IMP that optimally reduces 
the severity of dyskinetic involuntary movements (clinically meaningful reduction in dyskinesia, 
as indicated by a reduction in the CGI-I) and is well tolerated. Safety/tolerability in-clinic 
evaluations during titration include assessment of vital signs, monitoring for adverse events and 
concomitant medications, 12-lead ECGs, identifying subjects at risk for suicide according to the 
C-SSRS questionnaire, assessment of drug-induced parkinsonism according to the ESRS 
(subscales I and II), assessment of change in behavior according to the CBCL questionnaire, and 
assessment of sedation according to the ESS questionnaire. If a patient experiences a “clinically 
significant” adverse event attributable to the IMP, the investigator will first determine if a dose 
reduction (to the previous dose level) or suspension is necessary and possible. At the end of the 
titration period, the patient’s dose will be established for the maintenance period. All IMP 
adjustments are made only after a remote or in-clinic visit; if the dose is escalated, the dose 
escalation will occur with the next morning’s dose.
In-person (in-clinic) study visits will be scheduled at weeks 3 and 7, and telephone contacts (with 
non-recording live video) will be scheduled for weeks 1, 2, 4, 5, and 6 in order to assess 
dyskinesia and adverse events. The telephone contacts to the patient will be supported by live 
video stream, without recording, to provide visual confirmation to the investigator of the verbal 
information provided by the patient or caregiver. The dose of the IMP should be increased on a 
weekly basis to reach a clinically meaningful reduction in dyskinesia, as indicated by a reduction 
in the CGI-I. The IMP dose should not be increased further if either of the following occurs:

the patient experiences a protocol-defined “clinically significant” adverse event 
(defined as an adverse event that is related to IMP and is either moderate or severe in 
intensity or meets the criteria for a serious adverse event), OR

the maximum allowable dose is reached based on the patient’s weight and CYP2D6 
impairment status at baseline.
Dose adjustments can be made up to and including the week 7 in-clinic visit. If an optimal dose 
is reached before the week 7 in-clinic visit, the dose of IMP should not be increased further, but 
the patient should continue on that dose for the remainder of the titration period and throughout 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
12
the maintenance period. If a patient experiences a “clinically significant” adverse event 
attributable to the IMP, the investigator will first determine if a dose reduction (to the previous 
dose level) or suspension is necessary and possible. 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. 
Maintenance period (8 weeks): Patients will continue to receive their maintenance dose over the 
next 8 weeks, although a 1-time dose reduction (to the previous dose level for the remainder of 
the study) for adverse events is allowed. Patients will return to the clinic at weeks 9, 12, and 
15 for assessments of efficacy and safety. 
Washout period and follow-up: All patients will discontinue IMP at the week 15 visit and will 
return 1 week later for the end-of-study visit. Patients who complete the study may be eligible to 
begin participation in the open-label safety extension Study TV50717-CNS-30081 at that time. 
At the week 16 visit, patients may choose to enter Study TV50717-CNS-30081 (on that day) or 
up to 1 week later (2 weeks from the week 15 visit). Patients who complete treatment but choose 
not to participate in the open-label safety extension Study TV50717-CNS-30081 any time before 
week 17 of Study TV50717-CNS-30080 will be contacted for a safety evaluation call occurring 
2 weeks after their last dose of IMP. Additional details for patients to enter Study TV50717-
CNS-30081 are provided in the TV50717-CNS-30081 protocol.
When approximately 50 patients have completed the study (including follow-up), an independent 
Data Monitoring Committee (iDMC) will perform an unblinded non-binding interim analysis 
(IA) for futility based on centrally read MD-CRS part II total score. 
An iDMC charter will be developed for the IA, and the procedures to ensure the integrity of the 
study will be provided in the charter.
At the time of informed consent, the parent/legally accepted representative will be counseled 
that, once randomized to treatment, patients are to remain in the study and complete all study 
procedures unless the choice is made to withdraw consent. Patients who withdraw from the study 
before completing the 15-week treatment period should have an early termination (ET) visit 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 ET; evaluations will be as 
described for week 17. 
Patients who screen fail or terminate early from the study due to emergency circumstances (such 
as coronavirus disease 2019 [COVID-19]) may be allowed to re-screen/re-enter (respectively) 
the study at a later date, depending on the circumstances. Each case should be referred to the 
medical monitor and approved in advance.
There is a separate protocol for the open-label safety extension Study TV50717-CNS-30081.
Brief Summary of Study Design for the Trial Registry(s):
CP refers to a group of neurological disorders that appear in infancy or early childhood and 
permanently affect body movement and muscle coordination. CP is caused by damage to or 
abnormalities inside the developing brain that disrupt the brain’s ability to control movement and 
maintain posture and balance. The signs of CP usually appear in the early months of life, 
although specific diagnosis may be delayed until the age of 2 years or older. TEV-50717 
(deutetrabenazine, also known as SD-809) has already provided evidence for safe and effective 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
13
use in 2 other hyperkinetic movement disorders, namely chorea in Huntington’s disease (HD) 
and tardive dyskinesia (TD). Currently, there is no approved treatment available for DCP. The 
available treatment options address some of the manifestations of DCP. The study population 
will include pediatric and adolescent patients (6 through 18 years of age) with DCP with 
predominant choreiform movement disorder, who have had non-progressive CP symptoms since 
infancy (≤2 years of age). Diagnosis of DCP is based on the Surveillance of Cerebral Palsy in 
Europe criteria. 
This is a Phase 3 study that will evaluate the efficacy and safety of TEV-50717 administered as 
oral tablets at a starting dose of 6 mg once daily in patients (age 6 through 18 years, inclusive) 
with DCP with predominant choreiform movement disorder. The study will be conducted in 
multiple centers and will use 2 parallel treatment groups (ie, TEV-50717 and placebo) in which 
patients will be randomized in a 2:1 ratio.
Method of Randomization and Blinding: 
Patients will be randomly assigned to receive treatment with TEV-50717 or matching placebo in 
a 2:1 ratio using Randomization and Trial Supply Management (RTSM). Patients will be 
stratified by age at baseline (6 to <12 years; 12 through 18 years, inclusive) and region (US; 
non-US). 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 
sponsor’s clinical supply chain staff and RTSM vendor) will be blinded to the IMP identity until 
the database has been locked for analysis and the treatment assignments are revealed. 
The iDMC will perform an unblinded non-binding IA for futility and will monitor safety 
throughout the study based on unblinded data. An iDMC charter will be developed for the IA, 
and the procedures to ensure the integrity of the study will be provided in the charter.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate:
The IMPs are defined as the test IMP and placebo IMP. There is no reference IMP in this study.
Test IMP will be administered as oral tablets at a starting dose of 6 mg once daily with food (eg, 
a snack) and should not be taken on an empty stomach. Titration schemes based on body weight 
at baseline are shown in Table 1. The maximum daily dose is determined by body weight at 
baseline and CYP2D6 impairment status (Table 2). Patients will be classified as CYP2D6 
impaired if they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 poor metabolizer. 
Although dose adjustments can be made up to and including the week 7 in-clinic visit, if the 
optimal dose is reached before then, the dose of IMP should not be increased any further, but the 
patient should continue taking that dose for the remainder of the titration period and throughout 
the maintenance period. If a patient experiences a “clinically significant” adverse event that is 
attributed to the IMP, the investigator will first determine if a dose reduction (to the previous 
dose level) or suspension is necessary and possible. 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 once for the remainder of the maintenance period.
TEV-50717 tablets (test IMP) 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). Test IMP will be supplied in 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
14
20-count tablets per dose strength per bottle assembling 6, 12, 18, 24, 30, 36, 42, and 48 mg dose 
kit combinations. 
The placebo IMP tablets and packaging will match those for TEV-50717.  
All IMP adjustments are made only after a remote or in-clinic visit; if the dose is escalated, the 
dose escalation will occur with the next morning’s dose.
IMP will be administered as follows:

IMP should be swallowed whole. If the IMP is crushed or split, it should not be 
ingested; it should be replaced with a new tablet. The tablets will be taken with food 
(eg, a snack) and should not be taken on an empty stomach. Patients may be offered 
the optional use of a Medi+Straw®, which is a commercially available straw that can 
assist patients to overcome their swallowing difficulties.

Dosing will be based on body weight at the baseline visit and CYP2D6 impairment 
status, as shown in Table 1 and Table 2, respectively.

If there is only a single dose of IMP per day, the dose should be taken in the morning. 
However, patients experiencing somnolence while taking the 6-mg dose in the 
morning may switch to taking it as an evening dose for the rest of the days up to 
day 14.

The starting dose of 6 mg will be administered in the morning on day 2 and for the 
remainder of the first week. Patients in the highest body weight group (≥40 kg/88 lbs) 
will start an evening administration from day 3 and for the remainder of the first 
week. TEV-50717 daily doses of 12 mg and higher will be administered as 2 divided 
equal 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 the 
next dose, the missed dose should be skipped. 

Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg/88 lbs. For patients ≥40 kg/88 lbs, the first dose increase should be performed 
in an interval less than 5 days, only once, on day 3.

During the week 3 visit, the investigator or designee will make sure the patient 
receives the last treatment kit back so the patient can take the evening dose to 
complete the week 3 dosing for that day. Refer to the pharmacy manual for further 
details.

For any dose adjustment, the investigator or designee should confirm that patients 
have the bottle that contains the appropriate tablet strength and quantity to complete 
the recommended daily regimen.

At an in-clinic visit, a dose reduction, if required, should be made to the previously 
tolerated dose level. 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 IMP should be adjusted according to Table 1
to identify a dose level that optimally reduces dyskinesia (as determined by the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
15
investigator, as indicated by a reduction in the CGI-I) and is well tolerated. Dose 
adjustments should ONLY take place after telephone or in-clinic visit.
Table 1:
Maximum Daily Dose of IMP During the Titration Period by Week and 
Weight Category at Baseline
Daily dosea,b
Study time period
12 kg to <17 kg
(26 lbs to <37 lbs)
17 kg to <30 kg
(37 lbs to <66 lbs)
30 kg to <40 kg
(66 lbs to <88 lbs)
≥40 kg
(≥88 lbs)
Day 2 (first dose in morning)
6 mg
6 mg
6 mg
6 mg
Week 1
6 mg
6 mg
6 mg
12 mgc
Week 2
6 mg
12 mg
12 mg
18 mg
Week 3
12 mgd
18 mgd
18 mgd
24 mg
Week 4
12 mgd
18 mgd
24 mgd
30 mg
Week 5
18 mgd
24 mgd
30 mgd
36 mgd
Week 6
18 mgd
24 mgd
36 mgd
42 mgd
Week 7
24 mgd
30 mgd
42 mgd
48 mgd
a All IMP adjustments are made only after a remote or in-clinic visit; if the dose is escalated, the dose escalation will 
occur with the next morning’s dose. Dose adjustments should ONLY take place after telephone or in-clinic visit.
b Dose increases may not occur more frequently than every 5 days, except for patients ≥40 kg/88 lbs. For patients 
≥40 kg/88 lbs, the first dose increase should be performed in an interval less than 5 days, only once, on day 3. 
Refer to Table 3 for the exact visit windows at each weekly titration visit.
c Patients in this weight category will receive the 6-mg once-daily dose in the morning on day 2, followed by 
twice-daily administration of 6 mg starting on day 3.
d For those taking strong CYP2D6 inhibitors, such as paroxetine, fluoxetine, and bupropion, or those who are poor 
CYP2D6 metabolizers, the maximum daily dose for patients ≥40 kg is 36 mg/day, that for 30 to <40 kg is 
24 mg/day, that for 17 to <30 kg is 18 mg/day, and that for 12 to <17 kg is 12 mg/day (see Table 2).
CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product.
Table 2:
Maximum Daily Dose of IMP by CYP2D6 Impairment Status
Weight category
Maximum daily dose in the absence of 
CYP2D6 impairment
Maximum daily dose in the presence of 
CYP2D6 impairment
12 kg to <17 kg
(26 lbs to <37 lbs)
24 mg
12 mg
17 kg to <30 kg
(37 lbs to <66 lbs)
30 mg
18 mg
30 kg to <40 kg
(66 lbs to <88 lbs)
42 mg
24 mg
≥40 kg
(≥88 lbs)
48 mg
36 mg
CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product.
Note: Patients will be classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor or are a 
CYP2D6 poor metabolizer. Strong CYP2D6 inhibitors include paroxetine, fluoxetine, and bupropion.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
16
Test IMP: TEV-50717 (deutetrabenazine, also known as SD-809)
Reference IMP: None
Placebo IMP: Placebo tablets match TEV-50717 (deutetrabenazine, also known as SD-809)
Duration of Patient Participation and Maximal Exposure to IMP:
This study will consist of up to a 31-day screening period, a 15-week double-blind treatment 
period (a 7-week titration period followed by an 8-week maintenance period), and a 2-week 
follow-up period. Patients are expected to participate in this study for its entire duration.
Study Duration: Fourth quarter of 2018 to fourth quarter of 2022
End of Study: End of study is defined as the last visit of the last patient.
Plans for Treatment or Care After the Patient Has Ended Participation in the Study:
Patients who complete the study may be eligible to begin participation in the open-label safety 
extension Study TV50717-CNS-30081 at the end of the washout period. Patients who complete 
treatment, but choose not to participate in the open-label safety extension 
Study TV50717-CNS-30081 any time before week 17 of Study TV50717-CNS-30080 will be 
contacted for a safety evaluation call occurring 2 weeks after their last dose of IMP.
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria: 
1. Patient is 6 through 18 years of age (inclusive) at baseline. 
2. Patient weighs at least 26 pounds (12 kg) at baseline.
3. Patient has had CP symptoms since infancy (≤2 years), and CP is judged by the 
investigator to be of a non-progressive nature (Monbaliu et al 2017, 
Wimalasundera et al 2016). 
4. Patient has a diagnosis of DCP according to the Surveillance of Cerebral Palsy in Europe 
criteria (Cans 2000).
5. Patient has an MD-CRS part II total score of ≥10 at the baseline visit, based on 
investigator scoring of chorea. 
6. Patient’s symptoms are causing functional problems determined by a CGI-S score of 4 or 
greater based on investigator scoring.
7. Choreiform is the predominant (ie, the main cause of impairment or distress) movement 
disorder as assessed at screening.
8. Patient is able to swallow study medication whole.
9. Patient and caregiver are willing to adhere to the medication regimen and to comply with 
all study procedures.
10. Patient is in good general health, as indicated by medical and psychiatric history, as well 
as physical and neurological examination.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
17
11. In the investigator’s opinion, the patient and/or caregiver has the ability to understand the 
nature of the study and its procedures, and the patient is expected to complete the study 
as designed.
12. For a patient who is a minor, the parent(s)/legally accepted representative(s) provide 
written informed consent, and the patient provides assent (in accordance with local 
regulations). Adult patients provide their own written informed consent (in accordance 
with local regulations) and the legally acceptable representative will sign, if needed.
In this study, eligible patients are patients with dyskinetic cerebral palsy who may have 
some degree of mental, motor, and/or communication (eg, speech, writing, etc) 
limitations or disabilities. The patient may not be able to read the assent/consent form. 
Some patients may only be able to provide a limited assent/consent (for instance, by 
verbalizations or gestures). The investigator will determine the suitability of enrolling 
such patients in this study and will follow the local regulation to obtain the relevant 
consent/assent.
13. Caregivers provide written informed consent after being assigned the role by an adult 
patient, or if this role is delegated by the parent/legally accepted representative of a 
patient who is a minor.
14. Females who are postmenarchal or ≥12 years of age may be included only if they have a 
negative beta-human chorionic gonadotropin test at baseline or are sterile. Definitions of 
sterile, premenarchal, and postmenarchal are given in Appendix F. 
15. Females who are postmenarchal or ≥12 years of age whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the duration 
of the study (ie, starting at screening) and for 30 days after the last dose of IMP. Further 
details are included in Appendix F.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria:
1.
a. Patient has a predominant movement disorder other than dyskinesia.
b. Patient’s predominant motor symptoms are dystonic.
c. Patient’s predominant motor symptoms are spastic.
d. Patient has another movement disorder that could impair the motor assessment in the 
MD-CRS part II.
e. Patient has choreiform movement disorder that has not been consistent throughout the 
life of the patient.
2. 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 and anticipated to remain stable (dose and 
frequency) within the study duration.
3. Patient has a history of suicidal intent or related behaviors based on medical or 
psychiatric history or the C-SSRS 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


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
18

Previous suicidal preparatory acts or behavior
4. Patient has a history of a previous actual, interrupted, or aborted suicide attempt based on 
medical or psychiatric history or the C-SSRS.
5. Patient has a first-degree relative who has completed suicide.
6. Patient has received any of the following concomitant medications within the specified 
exclusionary windows of screening:

Within 30 days: tetrabenazine, deutetrabenazine, or valbenazine

Within 21 days: reserpine 

Within 14 days: levodopa, dopamine agonists, and monoamine oxidase inhibitors
7. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic 
stimulation, or transcranial direct current stimulation for treatment of abnormal 
movements or CP within 6 months of the screening visit, or the patient is not in a stable 
clinical condition. 
8. Patient has recent surgical procedure or is anticipated to have a surgical procedure during 
the study that, in the opinion of the investigator, makes the patient unsuitable for the 
study.
9. Patient has a severe mental disability or an unstable or serious medical illness (eg, 
epilepsy) at screening or baseline that, in the opinion of the investigator, could jeopardize 
or would compromise the patient’s ability to participate in this study.
10. Patient has a QT interval corrected for heart rate using Fridericia’s formula value 
>450 msec on 12-lead ECG at screening. 
11. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.
12. Patient has evidence of diminished hepatic function, as indicated by the following:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× the 
upper limit of the normal range (ULN) at screening

Alkaline phosphatase (ALP) or total bilirubin >2× ULN at screening

Note: Patients with Gilbert’s syndrome are eligible to participate if approved by 
the medical monitor. 

Note: Patients with abnormalities in 2 or more of the following clinical laboratory 
parameters must be approved for enrollment by the medical monitor: AST, ALT, 
ALP, and total bilirubin. 
13. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5 × ULN at screening. 
14. Patient has a known allergy to any of the components of the IMP.
15. Patient has participated in an investigational drug or device study and received 
IMP/intervention within 30 days or 5 drug half-lives of screening, whichever is longer.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
19
16. Patient is pregnant or breastfeeding.
17. Patient has a history of or acknowledges alcohol or other substance abuse in the 
12 months before screening.
18. Patient has a positive urine drug screen test result (with exception of medications listed in 
Table 10 of Appendix H). Any request to include a patient with a positive urine drug 
screen test result should be discussed with, and approved by, the medical monitor. Refer 
to Section 7.5.2.2 (urine drug screen) for more details.
Statistical Considerations
Primary and Secondary Estimands:
The primary estimand is the difference in means between TEV-50717 and placebo in the target 
patient population for the change from baseline to week 15 in centrally read MD-CRS part II 
total score, regardless of whether or not dose reduction, suspension, or discontinuation occurred, 
and regardless of treatment-related adverse events. 
The secondary estimands are the differences in means between TEV-50717 and placebo in the 
target patient population for (1) change from baseline to week 15 in centrally read MD-CRS 
part I total score, (2) Caregiver Global Impression of Improvement (CaGI-I) at week 15, (3) 
CGI-I at week 15, (4) change from baseline to week 15 in centrally read UHDRS-TMC, and (5) 
change from baseline to week 15 in centrally read UHDRS-TMD, regardless of whether or not 
dose reduction, suspension, or discontinuation occurred, and regardless of treatment-related 
adverse events.
The primary estimand assesses the effectiveness in the reduction of choreiform movements in 
patients with DCP with predominant choreiform movement disorder, evaluated by the central 
reviewers, focusing on the causal effects attributable to the IMP. The secondary estimands assess 
the effectiveness on patients’ ability to perform daily functions, the improvement in dyskinesia 
evaluated by the caregiver and the investigator, and the reduction in chorea and dystonia 
evaluated by the central reviewers, all with a focus on the causal effects attributable to the IMP.
The patient population for this study is patients with DCP with predominant choreiform 
movement disorder and severity of DCP represented by MD-CRS part II total score of ≥10 and 
CGI-S ≥4 at baseline. This population is expected to have the sensitivity to demonstrate 
clinically meaningful improvement following treatment with TEV-50717. Due to practical 
reasons, it is not possible to obtain a central reading of MD-CRS part II items at the time of the 
baseline visit prior to randomization; therefore, inclusion of a subject into the study is based on 
investigator scoring of MD-CRS part II items at baseline. 
Analysis of Primary Endpoint:
The primary endpoint is the change from baseline to week 15 in centrally read MD-CRS part II 
total score (TEV-50717 versus placebo). The MD-CRS part II total score is obtained by 
summing the total raw scores of MD-CRS part II items (0 to 28). 
The modified intent-to treat (mITT) analysis set (all randomized patients with at least 
1 post-baseline centrally read MD-CRS part II assessment) will be used for the primary analysis.
The primary analysis will be a mixed-model, repeated-measures with the change in MD-CRS 
part II total score as the dependent variable. The model will include fixed effects for treatment 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
20
group, week (3 levels: weeks 9, 12, and 15), and treatment group by week interaction. The 
baseline MD-CRS part II total score, age group at baseline (2 levels: 6 to <12 years; 12 through 
18 years, inclusive), and region (US; non-US) will be included as covariates. The unstructured 
covariance model will be used.
Missing data will be classified as missing at random (MAR) and missing not at random 
(MNAR). Early terminations related to tolerability, treatment-related adverse events, or lack of 
efficacy will be classified as MNAR. Intermittent missing data, early terminations for patients 
who are lost to follow-up, and early terminations due to COVID-19 will be classified as MAR. 
For all other cases and for cases classified as above, classification as MAR/MNAR will be 
done/revisited in a blinded manner on a case-by-case basis prior to the IA and prior to database 
lock for final analysis. The MAR/MNAR multiple imputation method will be applied in the 
primary analysis, where MNAR data will be imputed using the jump-to-reference method, and 
MAR data will be imputed based on the randomized treatment group. The resulting complete, 
imputed datasets will each be analyzed using the analysis model described above, and the 
resulting statistics combined using methodology presented by Rubin (1987) and Little and Rubin 
(2002).
The difference in least squares (LS) mean of the change in MD-CRS part II total score from 
baseline to week 15 (TEV-50717 versus placebo) will be compared using a 1-sided test for 
superiority at a nominal significance level of α=0.025. 
The LS mean and standard error for the treatment groups, the LS mean difference, 2-sided 95% 
confidence interval, and p-value for the comparison (TEV-50717 versus placebo) at week 15 will 
be presented.
Sample Size Rationale:
The initial sample size estimation of approximately 185 patients randomized to TEV-50717 
versus placebo in a 2:1 ratio (approximately 124 in the TEV-50717 group; approximately 61 in 
the placebo group) is the sample size required to obtain a statistically significant result in the 
primary analysis based on a 1-sided test for mean difference at a significance level of α=0.025 
with a power of approximately 90%, assuming a mean difference of 1.8 and a standard deviation 
(SD) of 3.5 in each treatment group. 
At the time of writing Amendment 05, the initially planned sample size has been reduced to 
approximately 65 patients randomized to TEV-50717 versus placebo in a 2:1 ratio 
(approximately 43 in the TEV-50717 group; approximately 22 in the placebo group).
The initial assumptions regarding the mean difference and SD are based on the change from 
baseline to month 6 in patients treated with trihexyphenidyl reported by Battini et al (2014), 
assuming an effect size of 55% for TEV-50717 versus placebo. The effect size of 55% was 
assumed based on the observed effect sizes of TEV-50717 in the pivotal studies in HD and TD. 
In the current study, these assumptions correspond to a mean difference of 2.0 in MD-CRS 
part II total score and an SD of 3.5 in each treatment group.
The rate of MNAR data for the primary analysis is expected to be 10%. MNAR data will be 
imputed in a conservative manner as if they were obtained from patients in the placebo treatment 
group, regardless of the treatment group. As a result, the mean difference is expected to be 
reduced from 2.0 to 1.8 in the primary analysis. The impact of the missing data imputation on the 
SD is negligible.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
21
Sensitivity Analysis:
To assess the robustness of the primary efficacy analysis, sensitivity analyses will include the 
following:
Sensitivity analyses for assumptions of missing data mechanism:

tipping point (MNAR)

MAR multiple imputation 
Sensitivity analysis for the statistical model:

analysis of covariance (ANCOVA)

primary model, including only the following covariates: treatment group, week, and 
treatment group by week interaction
Other:

primary model repeated for the intent-to-treat (ITT) analysis set

primary model repeated for the set of patients in the mITT analysis set that received 
at least 1 dose of IMP

primary model repeated for the set of patients that complete the study without any 
major protocol deviations that may impact efficacy (per-protocol analysis)

ANCOVA models for MD-CRS part II total score change from baseline to week 9 
and to week 12
Key Secondary Endpoints and Analysis: 
The key secondary endpoints are the following:
1. Change from baseline to week 15 in centrally read MD-CRS part I total score 
(TEV-50717 versus placebo) 
2. CaGI-I at week 15 (TEV-50717 versus placebo)
3. CGI-I at week 15 (TEV-50717 versus placebo)
4. Change from baseline to week 15 in centrally read UHDRS-TMC (TEV-50717 versus 
placebo)
5. Change from baseline to week 15 in centrally read UHDRS-TMD (TEV-50717 
versus placebo)
Each key secondary endpoint will be analyzed in the same fashion as the primary endpoint, with 
the exception that the baseline value of the given endpoint will be included as the covariate. 
Other Efficacy Measures/Endpoints: 
Other efficacy measures and endpoints (TEV-50717 versus placebo) include the following:

MD-CRS part I total score (general assessment, physician rated)

MD-CRS part II total score (general assessment, physician rated)

MD-CRS Global Index (calculated from MD-CRS parts I and II total scores)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
22

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

Pediatric Evaluation Disability Inventory-Computer Adapted Test (PEDI-CAT) 
(activities of daily living, caregiver completed, content-balanced version)

The CP module of the Pediatric Quality of Life Inventory (PedsQL) (quality of life, 
patient/caregiver)

Patient Global Impression of Improvement Scale ([PGI-I] global, patient/caregiver)

Clinical Global Impression of Severity ([CGI-S], global, physician rated)

CaGI-I response, defined as patients who are described by the caregiver as “Much 
Improved” or “Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are described as “Much Improved” or “Very 
Much Improved” in the CGI-I score

CGI-S response, defined as patients who have a reduction of ≥1 point in the CGI-S 
score

PGI-I response, defined as patients who are described as “Much Improved” or 
“Somewhat Improved” in the PGI-I score
Analysis methods will be provided in the statistical analysis plan.
Multiple Comparisons and Multiplicity:
The primary efficacy endpoint will be tested at the 1-sided significance level of α=0.025. 
If the primary endpoint is statistically significant (p-value ≤0.025), the 5 key secondary 
hypotheses will be tested using a hierarchical approach at the 1-sided significance level of 
α=0.025, in the following order: (1) MD-CRS part I total score, (2) CaGI-I, (3) CGI-I, (4) 
UHDRS-TMC centrally read, and (5) UHDRS-TMD centrally read. 
 
 
 
 
No multiplicity control will be applied to the sensitivity analysis or other endpoints.
Planned Interim Analysis:
When approximately 50 patients have completed the study (including follow-up), an iDMC will 
perform an unblinded non-binding IA for futility based on centrally read MD-CRS part II total 
score.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
23
Safety Analyses: 
Safety analyses will be performed on the safety analysis set.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to test IMP (ie, reasonable 
possibility) (defined as related or with missing relationship) (overall and by severity), 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.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. ECG and vital signs values will be compared with predefined criteria to identify 
potentially clinically significant values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
The frequency and severity of suicidal ideation or behavior according to the children’s 
Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire will be presented by visit and 
by treatment group. A shift table for children’s C-SSRS categories at baseline, compared to the 
worst (highest) category during the treatment period, will be presented. 
Assessment of drug-induced parkinsonism according to the ESRS (subscales I and II), 
assessment of change in behavior according to the CBCL questionnaire, and assessment of 
sedation according to the ESS questionnaire will be summarized descriptively.
For continuous variables, descriptive statistics will be provided for actual values and changes 
from baseline to each time point. For categorical variables, patient counts and percentages will 
be provided. Descriptive summaries of serious adverse events, patient withdrawals due to 
adverse events, and potentially clinically significant abnormal values (clinical laboratory or vital 
signs) based on predefined criteria will be provided as well.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report.
Tolerability Analysis:
If more than 15% of the patients withdraw from the study before the end of the treatment period, 
the number of days until study discontinuation will be analyzed using Kaplan-Meier 
methodology using the ITT analysis set.
Pharmacokinetic/Pharmacodynamic Analysis:
 
 
 
 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
24
 
 
Biomarker Analysis: Not applicable
Immunogenicity Analysis: Not applicable
Ancillary Studies Analysis: Not applicable


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
25
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
SPONSOR PROTOCOL APPROVAL ...........................................................................................4
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS........................................................................................................33
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................36
1.1.
Introduction.................................................................................................................36
1.1.1.
Background for TEV-50717.......................................................................................36
1.1.2.
Experience with Tetrabenazine in the Treatment of Dyskinesia in Cerebral 
Palsy and Other Hyperkinetic Movement Disorders in Children and 
Adolescents.................................................................................................................37
1.2.
Findings from Nonclinical and Clinical Studies.........................................................38
1.2.1.
Nonclinical Studies.....................................................................................................38
1.2.1.1.
Nonclinical Pharmacology..........................................................................................38
1.2.1.2.
Nonclinical Pharmacokinetics and Drug Metabolism................................................38
1.2.1.3.
Toxicology..................................................................................................................39
1.2.2.
Clinical Studies...........................................................................................................39
1.2.2.1.
Clinical Pharmacology Studies...................................................................................40
1.2.2.2.
Clinical Safety and Efficacy Studies ..........................................................................40
1.2.2.3.
Pharmacometric Analysis of TEV-50717 Active Metabolites to Support 
Dose Selection and Pharmacokinetic Characterization in a Pediatric 
Population...................................................................................................................41
1.3.
Known and Potential Benefits and Risks to Patients..................................................41
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................41
1.3.1.1.
Benefits of TEV-50717...............................................................................................41
1.3.1.2.
Potential Risks of TEV-50717....................................................................................41
1.3.2.
Overall Benefit and Risk Assessment for This Study ................................................42
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................43
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................43


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
26
2.1.1.
Justification of Primary Endpoint...............................................................................44
2.1.2.
Primary and Secondary Estimands.............................................................................45
2.2.
Exploratory Objectives and Endpoints.......................................................................46
3.
STUDY DESIGN .......................................................................................................47
3.1.
General Study Design and Study Schematic Diagram ...............................................47
3.2.
Planned Number of Patients and Regions ..................................................................52
3.3.
Justification for Study Design and Selection of Population.......................................52
3.4.
Stopping Rules for the Study......................................................................................52
3.5.
Schedule of Study Procedures and Assessments........................................................53
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................59
4.1.
Patient Inclusion Criteria ............................................................................................59
4.2.
Patient Exclusion Criteria...........................................................................................60
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................62
4.4.
Replacement of Patients .............................................................................................64
4.5.
Rescreening.................................................................................................................64
4.6.
Screening Failure........................................................................................................64
5.
TREATMENTS..........................................................................................................65
5.1.
Investigational Medicinal Products Used in the Study...............................................65
5.1.1.
Test Investigational Medicinal Product......................................................................65
5.1.1.1.
Starting Dose and Dose Levels...................................................................................65
5.1.1.2.
Dose Modification and Dose Stratification ................................................................65
5.1.2.
Placebo Investigational Medicinal Product ................................................................68
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................70
5.2.1.
Storage and Security...................................................................................................70
5.2.2.
Labeling......................................................................................................................70
5.2.3.
Accountability.............................................................................................................70
5.3.
Justification for Investigational Medicinal Products..................................................71
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................71
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................71
5.4.
Treatment after the End of the Study..........................................................................71
5.5.
Restrictions .................................................................................................................72
5.6.
Prior and Concomitant Medication.............................................................................72


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
27
5.7.
Procedures for Monitoring Patient Compliance .........................................................73
5.8.
Temporary Discontinuation of Investigational Medicinal Product ............................73
5.9.
Randomization and Blinding......................................................................................74
5.10.
Maintenance of Randomization and Blinding............................................................75
5.10.1.
Maintenance of Randomization..................................................................................75
5.10.2.
Blinding and Unblinding ............................................................................................75
5.10.3.
Independent Data Monitoring Committee..................................................................75
5.11.
Total Blood Volume ...................................................................................................76
6.
ASSESSMENT OF EFFICACY ................................................................................77
6.1.
Primary Efficacy Measure..........................................................................................77
6.2.
Key Secondary Efficacy Measures.............................................................................78
6.2.1.
Movement Disorder-Childhood Rating Scale Part I Total Score ...............................78
6.2.2.
Caregiver Global Impression of Improvement Scale .................................................79
6.2.3.
Clinical Global Impression of Improvement Scale ....................................................79
6.2.4.
Unified Huntington’s Disease Rating Scale-Total Maximal Chorea .........................80
6.2.5.
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia.......................80
6.3.
Other Efficacy Measures ............................................................................................80
6.3.1.
Movement Disorder-Childhood Rating Scale Part I and Part II Total Scores............80
6.3.2.
Movement Disorder-Childhood Rating Scale Global Index ......................................80
6.3.3.
Unified Huntington’s Disease Rating Scale-Total Motor Score ................................81
6.3.4.
Unified Huntington’s Disease Rating Scale-Total Maximal Chorea .........................81
6.3.5.
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia.......................81
6.3.6.
Pediatric Evaluation Disability Inventory-Computer Adapted Test (Activities 
of Daily Living, Caregiver Completed, Content-Balanced Version) .........................81
6.3.7.
Pediatric Quality of Life Inventory, Cerebral Palsy Module......................................81
6.3.8.
Patient Global Impression of Improvement Scale......................................................82
6.3.9.
Clinical Global Impression of Severity ......................................................................82
7.
ASSESSMENT OF SAFETY.....................................................................................84
7.1.
Adverse Events ...........................................................................................................84
7.1.1.
Definition of an Adverse Event..................................................................................84
7.1.2.
Recording and Reporting of Adverse Events .............................................................85
7.1.3.
Severity of an Adverse Event .....................................................................................86
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............86


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
28
7.1.5.
Serious Adverse Events..............................................................................................86
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................87
7.1.5.2.
Expectedness...............................................................................................................87
7.1.5.3.
Reporting a Serious Adverse Event............................................................................88
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................90
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................90
7.2.
Safety Rating Scales ...................................................................................................90
7.2.1.
Children’s Columbia-Suicide Severity Rating Scale..................................................90
7.2.2.
Child Behavior Checklist (for Ages 6-18)..................................................................90
7.2.3.
Extrapyramidal Symptom Rating Scale......................................................................91
7.2.4.
Epworth Sleepiness Scale (for Children and Adolescents) ........................................91
7.3.
Pregnancy ...................................................................................................................92
7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................93
7.5.
Clinical Laboratory Tests ...........................................................................................93
7.5.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................94
7.5.2.
Other Clinical Laboratory Tests .................................................................................95
7.5.2.1.
Beta-Human Chorionic Gonadotropin Tests ..............................................................95
7.5.2.2.
Urine Drug Screen ......................................................................................................95
7.6.
Physical Examination .................................................................................................95
7.7.
Vital Signs ..................................................................................................................96
7.8.
Electrocardiography....................................................................................................96
7.9.
Assessment of Suicidality...........................................................................................97
7.10.
Assessment of Depression..........................................................................................98
7.11.
Neurological Examinations ........................................................................................99
7.12.
Concomitant Medication or Treatment.......................................................................99
7.13.
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data...........................................................................................................................100
8.
ASSESSMENT OF PHARMACOKINETICS/ PHARMACODYNAMICS 
AND PHARMACOGENETICS...............................................................................101
8.1.
Pharmacokinetic Assessment....................................................................................101
8.2.
Assessment of Exploratory Biomarkers ...................................................................102
8.3.
Pharmacogenetics .....................................................................................................102


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
29
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics..................................................................102
9.
STATISTICS ............................................................................................................103
9.1.
Sample Size and Power Considerations ...................................................................103
9.2.
Analysis Sets.............................................................................................................103
9.2.1.
Intent-to-Treat Analysis Set......................................................................................103
9.2.2.
Modified Intent-to-Treat Analysis Set......................................................................104
9.2.3.
Safety Analysis Set...................................................................................................104
9.2.4.
Per-Protocol Analysis Set.........................................................................................104
9.3.
Data Handling Conventions......................................................................................104
9.3.1.
Handling Withdrawals and Missing Data.................................................................104
9.4.
Study Population.......................................................................................................105
9.4.1.
Patient Disposition....................................................................................................105
9.4.2.
Demographic and Baseline Characteristics ..............................................................105
9.5.
Efficacy Analysis......................................................................................................105
9.5.1.
Primary Estimand .....................................................................................................105
9.5.2.
Primary Endpoint......................................................................................................106
9.5.2.1.
Primary Efficacy Analysis........................................................................................106
9.5.2.2.
Sensitivity Analysis ..................................................................................................106
9.5.2.3.
Minimal Clinically Important Difference and Minimal Clinically Important 
Change ......................................................................................................................107
9.5.3.
Secondary Estimands................................................................................................107
9.5.4.
Key Secondary Endpoints.........................................................................................108
9.5.4.1.
Secondary Efficacy Analysis....................................................................................108
9.5.5.
Other Efficacy Endpoints .........................................................................................108
9.5.5.1.
Other Efficacy Analysis............................................................................................109
9.6.
Multiple Comparisons and Multiplicity....................................................................109
9.7.
Planned Interim Analysis..........................................................................................110
9.8.
Safety Endpoints and Analysis .................................................................................110
9.9.
Tolerability Analysis ................................................................................................111
9.10.
Pharmacokinetic/Pharmacodynamic Analysis..........................................................111
9.11.
Reporting Deviations from the Statistical Plan ........................................................111
10.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................112
11.
COMPLIANCE STATEMENT................................................................................113


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
30
12.
DATA MANAGEMENT AND RECORD KEEPING ............................................114
13.
FINANCING AND INSURANCE...........................................................................115
14.
PUBLICATION POLICY ........................................................................................116
15.
REFERENCES .........................................................................................................117
16.
SUMMARY OF CHANGES TO PROTOCOL .......................................................120
16.1.
Amendment 05 Dated 24 March 2022......................................................................120
16.2.
Administrative Letter 07 Dated 05 May 2021..........................................................142
16.3.
Amendment 04 Dated 09 March 2021......................................................................145
16.4.
Amendment 03 Dated 08 June 2020.........................................................................174
16.5.
Amendment 02 Dated 17 October 2019 ...................................................................177
16.6.
Letter of Clarification 06 Dated 05 August 2019 .....................................................195
16.7.
Letter of Clarification 05 Dated 16 January 2019 ....................................................196
16.8.
Amendment 01 Dated 20 December 2018................................................................198
16.9.
Letter of Clarification 04 Dated 05 December 2018 ................................................217
16.10.
Letter of Clarification 03 Dated 22 November 2018................................................220
16.11.
Letter of Clarification 02 Dated 16 November 2018................................................222
16.12.
Letter of Clarification 01 Dated 17 October 2018....................................................225
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................227
APPENDIX B.
INDEPENDENT DATA MONITORING COMMITTEE..............................229
APPENDIX C.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................230
APPENDIX D.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................237
APPENDIX E.
ETHICS............................................................................................................239
APPENDIX F.
BIRTH CONTROL METHODS AND PREGNANCY TESTING.................241
APPENDIX G.
LOST TO FOLLOW-UP.................................................................................242
APPENDIX H.
LIST OF ALLOWED AND PROHIBITED MEDICATIONS.......................243
APPENDIX I.
TOTAL BLOOD VOLUME.............................................................................245
APPENDIX J.
PRODUCT COMPLAINTS .............................................................................246
APPENDIX K.
DATA MANAGEMENT AND RECORD KEEPING ...................................248
APPENDIX L.
PUBLICATION POLICY................................................................................251
APPENDIX M.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19.............252


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
31
LIST OF TABLES
Table 1:
Maximum Daily Dose of IMP During the Titration Period by Week and 
Weight Category at Baseline ......................................................................................15
Table 2:
Maximum Daily Dose of IMP by CYP2D6 Impairment Status.................................15
Table 3:
Study Procedures and Assessments............................................................................54
Table 4:
Maximum Daily Dose of IMP During the Titration Period by Week and 
Weight Category at Baseline ......................................................................................67
Table 5:
Maximum Daily Dose of IMP by CYP2D6 Impairment Status.................................68
Table 6:
Investigational Medicinal Products Used in the Study...............................................69
Table 7:
The Relationship of an Adverse Event to the IMP.....................................................86
Table 8:
Clinical Laboratory Tests ...........................................................................................94
Table 9:
Blood Sampling Scenarios........................................................................................101
Table 10:
Allowed Medications................................................................................................243
Table 11:
Prohibited QTc-Prolonging Drugs............................................................................244
Table 12:
Total Blood Volumes................................................................................................245


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
32
LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................51


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
33
LIST OF ABBREVIATIONS
Abbreviation
Term
ADL
activities of daily living
AIMS
Abnormal Involuntary Movements Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BoNT
botulinum neurotoxin
CDMS
clinical data management system
CFR
Code of Federal Regulations
CaGI-I
Caregiver Global Impression of Improvement
CBCL
Child Behavior Checklist (for ages 6-18)
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clinical Global Impression of Severity
ClinRO
clinician-reported outcome
COVID-19
coronavirus disease 2019
CP
cerebral palsy
CRF
case report form
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
CYP2D6
cytochrome P450 2D6
DCP
dyskinesia in cerebral palsy
EAB
Enrollment Adjudication Board
ECG
electrocardiogram
ESRS
Extrapyramidal Symptom Rating Scale (subscales I and II)
ESS
Epworth Sleepiness Scale (for children and adolescents)
ET
early termination
EOS
end of study
EU
European Union
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
34
Abbreviation
Term
GPSP
Global Patient Safety and Pharmacovigilance
β-HCG
beta-human chorionic gonadotropin
HD
Huntington’s disease
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
iDMC
independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intent-to-treat
LS
least squares
LSO
local safety officer
MAOI
monoamine oxidase inhibitor
MAR
missing at random
MD-CRS
Movement Disorder-Childhood Rating Scale
mITT
modified intent-to-treat
MMRM
mixed-effects model repeat measurement 
MNAR
missing not at random
n
number
NDA
New Drug Application
PEDI-CAT
Pediatric Evaluation Disability Inventory-Computer Adapted Test
PedsQL
Pediatric Quality of Life Inventory
PGI-I
Patient Global Impression of Improvement
PGx
pharmacogenetics
PND
postnatal day
PP
per-protocol
QoL
quality of life
QTc
QT corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
SAP
statistical analysis plan


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
35
Abbreviation
Term
SD
standard deviation
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TD
tardive dyskinesia
TS
Tourette syndrome
UHDRS-TMC
Unified Huntington’s Disease Rating Scale-Total Maximal Chorea
UHDRS-TMD
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
UHDRS-TMS
Unified Huntington’s Disease Rating Scale-Total Motor Score
ULN
upper limit of the normal range
US
United States
USA
United States of America
VMAT2
vesicular monoamine transporter type 2
α-HTBZ
alpha-dihydrotetrabenazine
β-HTBZ
beta-dihydrotetrabenazine


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
36
1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
Cerebral palsy (CP) denotes a non-progressive disturbance of brain function that usually occurs 
in the developing fetal or infant brain (age ≤2 years) (Rosenbaum et al 2007). It is the most 
common and costly form of chronic motor disability in children, with a prevalence of 2 to 4 per 
1,000 live births in the United States (US), and the condition is more common in boys than in 
girls (Maenner et al 2016, Monbaliu et al 2017, CDC, Prevalence of Cerebral Palsy). Although 
there have been no general studies of life expectancy in people with CP, most children affected 
by CP live between 30 and 70 years, depending on the severity of the condition. In general, a 
child with a mild case of CP usually lives longer than a child with mobility and intellectual 
limitations (Cerebral Palsy Life Expectancy 2018). In the US, there are about 764,000 children 
and adults with CP, including about 500,000 children under the age of 18 years (Prevalence of 
Cerebral Palsy).
Prematurity is the most common cause of CP, but other causes include stroke, hypoxic ischemic 
injury, infection, brain malformation, and genetic abnormalities (CDC Causes and Risk Factors 
of Cerebral Palsy 2018; NINDS Cerebral Palsy: Hope Through Research 2019). Complications 
of CP may include eye movement abnormalities, communication problems, swallowing 
difficulty, poor weight gain, social isolation, hip dysplasia and dislocation, scoliosis, osteopenia 
and fractures, and pain. A variety of movement disorders are associated with CP, including 
spasticity, dyskinesia (dystonia, chorea, athetosis, and even ballismus), and ataxia. Many patients 
with CP present with mixed types of movement disorders (Monbaliu et al 2017, CDC). 
Dyskinesia is considered to result from an insult of non-progressive nature in the basal ganglia of 
the brain. Dyskinesia in cerebral palsy (DCP) is a form of CP characterized by abnormal 
involuntary movements of the dystonic and choreiform types in approximately 6% to 15% of 
patients with CP. DCP is a rare disease, and based on the above prevalence numbers of CP in the 
US, one could assume that approximately 30,000 to 75,000 children <18 years of age and 16,000 
to 40,000 adults have DCP (Monbaliu et al 2017).
There are currently no approved treatments for DCP, which is a serious disease with an unmet 
medical need. Current treatment options (off-label use) to treat dystonia and chorea include 
tetrabenazine, dopaminergic, or gamma-aminobutyric acidergic interventions, but these show 
high variability in response (Monbaliu et al 2017). Botulinum neurotoxin A is also in clinical use 
for the treatment of spasticity and dystonia and is considered modestly effective in selected 
patients, but it does not meet the full treatment need. Currently, there are very few agents with 
novel mechanisms of action in development for movement disorders in CP. 
The purpose of the study is to determine whether TEV-50717 is effective in the treatment of 
dyskinetic involuntary movements associated with CP.
1.1.1.
Background for TEV-50717
TEV-50717 (deutetrabenazine, also known as SD-809) was initially developed to provide 
patients and prescribers with an effective treatment for chorea in Huntington’s disease (HD) with 
an improved pharmacokinetic and tolerability profile compared with tetrabenazine. TEV-50717 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
37
is a vesicular monoamine transporter type 2 (VMAT2) inhibitor structurally related to 
tetrabenazine, with 2 trideuteromethoxy groups instead of the 2 methoxy groups attached to the 
positions 9 and 10 of tetrabenazine. This deuterium placement does not change the target 
pharmacology, but it attenuates metabolism through cytochrome P450 2D6 (CYP2D6). Thus, 
this deuterium placement in TEV-50717 increases the half-life of the active metabolites relative 
to those of tetrabenazine, enabling reduced dosing frequency and plasma fluctuation and thus 
potentially improving safety and tolerability.
TEV-50717 is a 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. IMP 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 investigational medicinal product (IMP) will be supplied in 20-count 
tablets per dose strength per bottle.
TEV-50717 was approved for the treatment of chorea associated with HD and for the treatment 
of tardive dyskinesia (TD) in adults on 03 April 2017 and 30 August 2017, respectively. For 
details, see also the US Prescribing Information (AUSTEDO USPI 2017).
1.1.2.
Experience with Tetrabenazine in the Treatment of Dyskinesia in Cerebral Palsy 
and Other Hyperkinetic Movement Disorders in Children and Adolescents
Tetrabenazine is another VMAT2 inhibitor that presynaptically depletes monoamines, such as 
dopamine, serotonin, norepinephrine, and histamine, from nerve terminals (Kaur et al 2016). 
Although widely known among physicians treating DCP, there is limited and rather anecdotal 
literature on the potential efficacy of tetrabenazine on the treatment of hyperkinetic movement 
disorders in patients with CP of pediatric age. 
Tetrabenazine has been studied in a pediatric population with a variety of hyperkinetic 
movement disorders. Jain et al (2006) reviewed the outcomes of 31 children at Columbia 
University Medical Center who were treated with tetrabenazine. Eighteen of these children had 
chorea, of which half had additional movement disorders, 10 had tics, and 3 had dystonia. The 
average duration of symptoms before treatment was 4 years, and the age of children in the study 
ranged from 22 months to 18 years, with a mean age of 11±4.9 years. The primary causes of the 
abnormal movements in these pediatric patients were CP in 2 patients; primary generalized 
dystonia in 2 patients; various brain injuries (intraventricular hemorrhage with developmental 
delay or post-hypoxic injury), genetic abnormalities with brain lesions (arteriovenous 
malformations with developmental delay and neurofibromatosis type I), metabolic disorders 
(propionic acidemia, Lesch-Nyhan syndrome, and Leigh’s syndrome), immune mediated 
(Sydenham’s chorea), medication effects (tardive dystonia or withdrawal-emergent syndrome), 
and unknown etiology in 5 patients. Doses of tetrabenazine ranged from 25 mg daily 
(0.9 mg/kg/day) to 350 mg daily (10 mg/kg/day), and the average dose was 107 mg daily 
(3.7 mg/kg/day). Twenty-four of these pediatric patients with hyperkinetic movement disorders 
had improved symptoms (14 out of 18 with chorea, 8 out of 10 with tics, and 2 out of 3 with 
dystonia). Adverse events and tolerability findings were present in 19 (61%) patients who had at 
least 1 side effect (sedation, 35%; behavioral changes, 19%; depression, 10%; nausea, 3%; and 
parkinsonism, 3%), and the treatment was stopped in 17 (55%) patients. 
Although not related to CP, in another study, Vuong et al (2004) evaluated the safety and 
efficacy of tetrabenazine as a potential treatment for hyperkinetic movement disorders in 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
38
10 patients with chorea, 12 patients with dystonia, and 53 patients with tics. In this study, the 
doses ranged from 6.25 to 150 mg/day. The patients with chorea had approximately 90% 
improvement at the second visit, and those with dystonia had approximately 50% improvement 
at the second visit. Adverse events included dose-dependent nausea, vomiting, drowsiness, and 
depression.
1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure (IB).
1.2.1.
Nonclinical Studies
The key nonclinical study findings are provided below, with details available in the IB.
1.2.1.1.
Nonclinical Pharmacology
TEV-50717 is a selectively deuterium-substituted VMAT2 inhibitor structurally related to 
tetrabenazine. The biologically active metabolites formed from TEV-50717 
(alpha-dihydrotetrabenazine [α-HTBZ] and beta-dihydrotetrabenazine [β-HTBZ]) are potent 
inhibitors of VMAT2 binding, with inhibition constant values of 3.8 and 22 nM, respectively, 
that are similar to previously reported values of their corresponding non-deuterated forms 
(Scherman et al 1988). Off-target binding occurs at a similar extent with deuterated and 
non-deuterated α-HTBZ and β-HTBZ. TEV-50717 and tetrabenazine in male rats at doses 
resulting in similar systemic exposure to the test articles (α-HTBZ and β-HTBZ) produced 
similar, expected, exaggerated central nervous system pharmacological effects. In particular, the 
adverse event of catalepsy, a known response in rats to drugs that reduce central nervous system 
dopamine concentrations (Fuenmayor and Vogt 1979), was similar in magnitude after 
TEV-50717 and tetrabenazine administration.
1.2.1.2.
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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
39
1.2.1.3.
Toxicology
General and Reproductive Adult Toxicology: Oral administration of TEV-50717 in rats reduced 
body weight gain, increased mammary hyperplasia, and produced estrous cycle changes, all of 
which occurred with tetrabenazine at doses that produced similar systemic exposures to test 
articles and metabolites. Mammary and estrus effects are likely consequences of reduced central 
dopamine and subsequent increased prolactin, consistent with information in the Xenazine®
(tetrabenazine) label. Oral administration of TEV-50717 in pregnant rats did not produce test 
article-related embryofetal toxicities, even at doses that led to reduced body weight gain in dams. 
Oral administration of metabolite M1 to pregnant rats from gestational days 6 to 17 produced no 
test article-related maternal or fetal toxicities.
Genetic Toxicology: TEV-50717 and its α-HTBZ and β-HTBZ metabolites were negative in in 
vitro studies for mutagenicity (bacterial reverse mutation or the Ames test) and for chromosomal 
structural aberrations in human peripheral blood lymphocytes. Oral doses of TEV-50717 were 
negative for inducing micronuclei in the bone marrow of treated mice.
Juvenile Toxicology: The effects of TEV-50717 on juvenile development was assessed in male 
and female rats with oral dosing from weaning (postnatal day [PND] 21) to PND 71, similar to 
human dosing from year 2 through early adolescence and overlapping with TEV-50717 oral 
dosing in a general adult toxicology study. The effects of M1 was assessed in male and female 
juvenile rats from PND 25 to PND 70 with a recovery phase and postdosing reproductive 
assessment.
TEV-50717 produced no test article-related effects on learning and memory functions, on 
histopathology assessments, on reproductive capacity (male and female fertility and estrus 
cyclicity), or on intrauterine survival of embryos from matings during recovery from test article 
administration. Adversely reduced body weight gain and adverse clinical observation of tremors 
and in-cage hyperactivity were all noted in previous studies with adult rats; these effects have not 
predicted adult clinical intolerance to TEV-50717. The highest dose level of M1 (50 mg/kg/day) 
produced no test article-related toxicities (clinical observations, changes in body weight gain, 
clinical pathology, histopathology, ophthalmology, and performance in learning and memory 
tests).
1.2.2.
Clinical Studies
The clinical development plan for TEV-50717 to date includes the following:

Fourteen completed Phase 1 studies in healthy adult volunteers

One completed Phase 3 pivotal study for the treatment of chorea associated with HD

One completed Phase 3 long-term safety study in patients with HD

Two completed pivotal Phase 2/3 and Phase 3 studies in patients with TD

One completed Phase 3 long-term safety study in patients with TD

One completed Phase 1b study in patients with Tourette syndrome (TS)

Two completed pivotal studies in patients with TS

One terminated Phase 3 long-term safety study in patients with TS


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
40
Further details may be found in the IB.
1.2.2.1.
Clinical Pharmacology Studies
Fourteen Phase 1 clinical pharmacology studies were conducted in healthy adult volunteers. In 
addition, sparse pharmacokinetic sampling was included in the Phase 3 studies in patients with 
HD and TD where the population pharmacokinetic analyses including these data have been 
performed to extensively evaluate both the pharmacokinetics and pharmacokinetic-
pharmacodynamic relationship of TEV-50717. A summary of the clinical pharmacology findings 
is provided in the IB.
Pharmacometric analyses of the active metabolites of TEV-50717 based on the Phase 1 clinical 
pharmacology studies in healthy adult volunteers were performed to support dose selection and 
pharmacokinetic characterization in a pediatric population. Subsequently, a further 
pharmacometric analysis of active metabolites following administration of TEV-50717 to 
adolescent patients with TS with tics (Study SD-809-C-17) was completed. The results of these 
analyses are described in Section 1.2.2.3.
1.2.2.2.
Clinical Safety and Efficacy Studies
The safety profile of TEV-50717 has been characterized to date in healthy volunteers, as well as 
in adult patients with chorea associated with HD and TD (as detailed in the IB) and in children 
and adolescents with TS. Study SD-809-C-17 also evaluated the safety of TEV-50717 in 
adolescent patients with TS. Results of the safety analyses indicate that treatment with 
TEV-50717 at doses up to 36 mg daily given in 2 divided doses is generally safe and well 
tolerated for up to 8 weeks in patients with TS. No serious treatment-emergent adverse events or 
severe treatment-emergent adverse events occurred in this study. The most frequently observed 
treatment-emergent adverse events during the entire treatment period were fatigue and headache, 
each reported in 4/23 (17.4%) patients, followed by irritability, which was reported in 3/23 
(13.0%) patients. 
Studies TV50717-CNS-30046 and TV50717-CNS-30060 evaluated children and adolescent 
patients with tics associated with TS. Neither study met the primary efficacy endpoint. In both 
studies, TEV-50717 was generally safe and well tolerated. No deaths occurred in either study. 
One patient had 2 serious adverse events. There were no trends in changes from baseline in 
serum laboratory, vital signs, ECG, and physical and neurological parameters. There was no 
evidence of a new safety signal in pediatric patients with TS treated with TEV-50717 in 
comparison to the known safety profile of this drug in adult patients with HD or TD.
The open-label, long-term Study TV50717-CNS-30047 evaluated children and adolescent 
patients with tics associated with TS. Treatment with TEV-50717 through 54 weeks resulted in 
improvement of tics. The safety profile observed in pediatric patients with TS receiving 
long-term treatment with TEV-50717 was generally comparable to the known safety profile of 
this drug in adult patients with HD or TD, with the exception of the adverse event of weight gain.
There were no clinically meaningful trends in mean changes from baseline for any clinical 
laboratory variable or any other observations related to safety.
This is the first study to assess the safety and efficacy of TEV-50717 in patients with DCP.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
41
1.2.2.3.
Pharmacometric 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 volunteers in the Phase 1 program, a 
structural population pharmacokinetic model was developed to guide dose selection for HD 
patients with chorea (Study SD-809-CLN-076) and subsequently optimized to better describe the 
absorption/bioconversion profile of -HTBZ and β-HTBZ (Study SD-809-CLN-077). 
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 total (α+β)-HTBZ exposure in 
adolescent patients (age 12 through 18 years) with TS and to simulate exposure in adolescent and 
pediatric patients (age 6 through 11 years) with and without concomitant CYP2D6 impairment 
(genetic or because of concomitant use of a strong CYP2D6 inhibitor) across a range of doses 
(Appendix H). 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 (α+β)-HTBZ exposures across a range of body weights corresponding to a pediatric and 
adolescent population according to the Centers for Disease Control growth charts. 
This analysis indicated that exposure to total (+β)-HTBZ is influenced by body weight, and a 
reduction in dose for pediatric and adolescent patients weighing <40 kg is necessary in order to 
provide comparable exposure to doses up to 48 mg/day in adults, a level previously 
demonstrated to be safe and well tolerated in treated patients with chorea associated with HD. 
This analysis provides the basis for the dosing recommendations in Section 5.1.
1.3.
Known and Potential Benefits and Risks to Patients
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)
Additional information regarding benefits and risks to patients may be found in the current IB 
and in the US prescribing information for AUSTEDO® (deutetrabenazine).
1.3.1.1.
Benefits of TEV-50717
Although the efficacy of TEV-50717 in patients with DCP has not yet been established, 
TEV-50717 has already provided evidence for safe and effective use in 2 hyperkinetic movement 
disorders, namely chorea in HD and TD.
1.3.1.2.
Potential Risks of TEV-50717
The following information is based on clinical trial experience with TEV-50717 and the US 
prescribing information for Xenazine (tetrabenazine) and Austedo (deutetrabenazine):

TEV-50717 is contraindicated in patients with HD who are actively suicidal or in 
patients with untreated or inadequately treated depression.

TEV-50717 is contraindicated in patients with impaired hepatic function.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
42

TEV-50717 is contraindicated in patients taking monoamine oxidase inhibitors 
(MAOIs). TEV-50717 should not be used in combination with a MAOI or within a 
minimum of 14 days of discontinuing therapy with a MAOI.

TEV-50717 is contraindicated in patients taking reserpine. At least 21 days should 
elapse after stopping reserpine before starting TEV-50717.

TEV-50717 is contraindicated in patients taking tetrabenazine or valbenazine. At 
least 30 days should elapse after stopping tetrabenazine or valbenazine before starting 
TEV-50717.
Additional information regarding each potential issue may be found in the current IB.
1.3.2.
Overall Benefit and Risk Assessment for This Study
There are currently no approved treatments for DCP, which is a serious disease with an unmet 
medical need. Also, there is a significant need to identify effective treatments for DCP. The 
results from studies in other study populations, such as patients with TS or HD, demonstrated no 
signal on safety scales, vital signs, laboratory parameters, or 12-lead electrocardiograms (ECGs). 
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 
the IB for details).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
43
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are the following:
Objectives
Measures/Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of TEV-50717 to reduce the 
severity of dyskinetic 
involuntary movements 
associated with CP.
The primary efficacy endpoint is the change from baseline to 
week 15 in the MD-CRS part II total score (movement 
disorder severity, centrally read) (TEV-50717 versus placebo).
A secondary objective is to 
evaluate the specific efficacy 
parameters of TEV-50717 
beyond the measure of the 
primary objective.
The key secondary efficacy endpoints (TEV-50717 versus 
placebo) are the following:

MD-CRS part I total score (general assessment, 
centrally read) change from baseline to week 15

CaGI-I Scale (global, caregiver rated) at week 15

CGI-I Scale (global, physician rated) at week 15

UHDRS-TMC (centrally read)

UHDRS-TMD (centrally read)
Other efficacy measures and endpoints (TEV-50717 versus 
placebo) include the following:

MD-CRS part I total score (general assessment, 
physician rated)

MD-CRS part II total score (general assessment, 
physician rated)

MD-CRS Global Index (calculated from MD-CRS 
parts I and II total scores)

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

PEDI-CAT (ADL, caregiver completed, 
content-balanced version)

The CP module of the PedsQL (QoL, 
patient/caregiver)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
44
Objectives
Measures/Endpoints

PGI-I Scale (global, patient/caregiver)

CGI-S Scale (global, physician rated)

CaGI-I response, defined as patients who are 
described by the caregiver as “Much Improved” or 
“Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are 
described as “Much Improved” or “Very Much 
Improved” in the CGI-I score

CGI-S response, defined as patients who have a 
reduction of ≥1 point in the CGI-S score

PGI-I response, defined as patients who are 
described as “Much Improved” or “Somewhat 
Improved” in the PGI-I score
A secondary objective of the 
study is to evaluate the safety 
and tolerability of TEV-50717.
The safety variables include adverse events (and the number of 
patients who withdraw from the study due to adverse events), 
vital signs, laboratory tests (hematology, chemistry, and 
urinalysis), ECG measurements, CBCL, ESRS, ESS, and the 
children’s C-SSRS.
ADL=activities of daily living; CaGI-I=Caregiver Global Impression of Improvement; CBCL=Child Behavior 
Checklist (for ages 6-18); CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of 
Severity; CP=cerebral palsy; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS=Epworth Sleepiness Scale (for children and 
adolescents); MD-CRS=Movement Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability 
Inventory-Computer Adapted Test; PedsQL=Pediatric Quality of Life Inventory; PGI-I=Patient Global Impression 
of Improvement; QoL=quality of life; UHDRS-TMC=Unified Huntington’s Disease Rating Scale-Total Maximal 
Chorea; UHDRS-TMD=Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia; 
UHDRS-TMS=Unified Huntington’s Disease Rating Scale-Total Motor Score.
2.1.1.
Justification of Primary Endpoint
The rationale to use a movement disorder scale as the primary endpoint to evaluate patients with 
DCP is based on a few key drivers. In prior studies, the motor scales measured and demonstrated 
a treatment benefit of TEV-50717 in patients with abnormal movements (eg, chorea and 
dyskinesia) associated with HD (Unified Huntington’s Disease Rating Scale [UHDRS]-Total 
Maximal Chorea [TMC]) and TD (Abnormal Involuntary Movements Scale [AIMS]) (Austedo 
Prescriber Information). Moreover, the use of motor scales as a primary outcome measure has 
been sufficient for TEV-50717 to gain regulatory approval to treat patients with abnormal 
movements. Conversely, the functional and global scales did not consistently show a treatment 
benefit of TEV-50717 in patients with abnormal movements. 
The Movement Disorder-Childhood Rating Scale (MD-CRS) part II is similar to UHDRS-TMC 
and AIMS in assessing the severity of abnormal hyperkinetic movement disorders in the 7 body 
regions using a 0 to 4 scale. Neither MD-CRS part II nor AIMS differentiates whether the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
45
dyskinesia is dystonic or choreiform. Experts in the field support the choice of MD-CRS part II 
to assess the severity of movement disorders in children with DCP.
The MD-CRS has 2 parts: part I for general assessment of the functioning and impact of CP on 
the activities of the patient, and part II for a specific motor assessment of the severity of the 
movement disorder. 
MD-CRS part II evaluates the severity of the movement disorder in 7 body regions, all areas in 
which dyskinesia can be seen in patients with CP. The MD-CRS part II does not differentiate 
whether the dyskinesia is of the dystonic or choreiform phenotype, and the worst dyskinesia in 
any of the regions observed during the assessment session will be taken as the score for each 
affected body region. The MD-CRS part II was developed and validated in the CP population for 
children and adolescents aged 4 to 18 years (Battini et al 2008). In addition, the scale was shown 
to be suitable for detecting a treatment effect after an intervention with trihexyphenidyl, a drug 
used to treat dyskinesia in children with CP (Battini et al 2014).
The MD-CRS was developed based on centralized readings of the video recordings of the patient 
assessments. The use of blinded centralized readings and ratings of videos of patients with 
movement disorders in clinical trials may decrease the inter-site and intra-site variability of data. 
This clinical trial will use centralized ratings of the videos to reduce data variability.
2.1.2.
Primary and Secondary Estimands
The primary estimand is the difference in means between TEV-50717 and placebo in the target 
patient population for the change from baseline to week 15 in centrally read MD-CRS part II 
total score, regardless of whether or not dose reduction, suspension, or discontinuation occurred, 
and regardless of treatment-related adverse events. 
The secondary estimands are the differences in means between TEV-50717 and placebo in the 
target patient population for (1) change from baseline to week 15 in centrally read MD-CRS 
part I total score, (2) Caregiver Global Impression of Improvement (CaGI-I) at week 15,
(3) Clinical Global Impression of Improvement (CGI-I) at week 15, (4) change from baseline to 
week 15 in centrally read UHDRS-TMC, and (5) change from baseline to week 15 in centrally
read UHDRS-TMD, regardless of whether or not dose reduction, suspension, or discontinuation 
occurred, and regardless of treatment-related adverse events.
The primary estimand assesses the effectiveness in the reduction of choreiform movements in 
patients with DCP with predominant choreiform movement disorder, as evaluated by the central 
reviewers, focusing on the causal effects attributable to the IMP. The secondary estimands assess 
the effectiveness on patients’ ability to perform daily functions, the improvement in dyskinesia 
evaluated by the caregiver and the investigator, and the reduction in chorea and dystonia 
evaluated by central reviewers, all with a focus on the causal effects attributable to the IMP.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
46
2.2.
Exploratory Objectives and Endpoints
The exploratory study objective and endpoint of this study are the following:
Objective
Endpoint
 
 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
47
3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a Phase 3, 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study to evaluate the efficacy and safety of TEV-50717 administered as oral tablets at a 
starting dose of 6 mg once daily in patients (age 6 through 18 years, inclusive) with DCP with 
predominant choreiform movement disorder, who have had CP symptoms, of a non-progressive 
nature, since infancy (≤2 years of age). “Predominant” in this instance indicates that the 
choreiform movement disorder is the main cause of impairment or distress.
The study will consist of a screening period (up to 31 days) and a double-blind treatment period 
including a titration period (7 weeks) and a maintenance period (8 weeks), followed by a 
washout period of 1 week, and a follow-up telephone contact 1 week after the washout period. 
Throughout the study, patients will interact regularly with investigational center personnel, 
in-clinic and by telephone (with non-recording live video), for the evaluation of
safety/tolerability, dyskinesia severity, and behavioral status (in-clinic only). Every effort should 
be made to utilize the same investigator to perform assessments on a patient throughout the 
duration of the study during these interactions. Under circumstances that require or encourage 
involvement of the patient’s caregiver when administering assessments, every effort should be 
made to involve the same caregiver of a patient throughout the duration of the study. Standard of 
care for treatment of CP should continue throughout the study, with some possible restrictions.
Standard of care could include any possible rehabilitation service(s), such as physiotherapy, 
occupational therapy, or sensory integration of the patient, should remain constant throughout the 
course of the study.
For the purposes of this protocol, a caregiver is defined as an adult who is familiar with the 
patient and is responsible for daily care, enabling that person to effectively complete the protocol 
requirements. The caregiver accompanies the patient to the visits and provides input to the 
relevant scales as required by the protocol. 
For patients who are minors, the caregiver is typically a parent or a legally accepted 
representative. In some countries, an adult (such as grandparent or nurse) can be appointed by 
the parent or legally accepted representative (as per local regulations and laws) and would take 
over this responsibility as a caregiver. The parent or legally accepted representative only has to 
sign the parent/legally accepted representative informed consent form (ICF) and not the 
caregiver ICF.
For adult patients, a caregiver must be appointed by the patient; this can be the parent, a legally 
accepted representative, or other adult, as appropriate and according to local laws and 
regulations.
For patients who are minors, certain responsibilities in the protocol can only be completed by the 
parent/legally accepted representative, ie, informed consent, withdrawal of consent, requests for 
discontinuation of the IMP, or withdrawal from the study for any reason. To further clarify, the 
caregiver is not allowed to make decisions on the child’s health or where “parent/legally 
accepted representative” is specifically indicated in the protocol.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
48
At the baseline visit (day 1), patients will be randomly assigned to 1 of 2 treatment groups with 
TEV-50717 IMP or placebo IMP in a 2:1 ratio stratified by age at baseline (6 to <12 years; 
12 through 18 years, inclusive) and region (US; non-US). IMP will be titrated during the 
double-blind treatment period starting with 6 mg of TEV-50717 or matching placebo IMP in the 
morning of day 2. Patients in the highest body weight group (≥40 kg/88 lbs) will start an evening 
administration from day 3 and for the remainder of the first week. TEV-50717 daily doses of 
12 mg and higher will be administered as 2 divided equal doses, approximately 8 to 10 hours 
apart during the day. The number of matching placebo IMP tablets will be increased accordingly. 
Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg/88 lbs. For patients ≥40 kg/88 lbs, the first dose increase should be performed in an 
interval less than 5 days, only once, on day 3. During the titration period, the dose of IMP will be 
adjusted according to the titrations scheme (details are given in Section 5) to identify a dose level 
that optimally reduces dyskinesia (as determined by the investigator, as indicated by a reduction 
in the clinician-reported outcome [ClinRO] of the assessment of the CGI-I) and is well tolerated. 
If a patient experiences a “clinically significant” adverse event attributable to the IMP, the 
investigator will first determine if a dose reduction (to the previous dose level) or suspension is 
necessary and possible (Section 5.8). After titration, patients will remain at their optimal dose for 
the length of the maintenance period. 
Screening period (up to 31 days): After written informed consent/assent, 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; 12-lead ECG; along with MD-CRS part II (physician rated, with video 
recording, centrally read with video review, centrally read by the Enrollment Adjudication Board 
[EAB]) to assess severity of dyskinesia; Clinical Global Impression of Severity (CGI-S) to assess 
global clinical impression of DCP severity, comorbid CP symptoms, and behavioral status; 
children’s Columbia-Suicide Severity Rating Scale (C-SSRS); assessment of drug-induced 
parkinsonism according to the Extrapyramidal Symptom Rating Scale (subscales I and II; 
ESRS); assessment of change in behavior according to the Child Behavior Checklist (for ages 
6-18) (CBCL) questionnaire; and assessment of sedation according to the Epworth Sleepiness 
Scale (for children and adolescents) (ESS) questionnaire. Screening may be conducted over 
2 separate visits at the discretion of the investigator. The diagnosis of CP and DCP will be 
established based on clinical features as described in the inclusion/exclusion criteria. The EAB 
will also confirm, based on video recordings, that choreiform is clinically the predominant 
movement disorder of the patient’s DCP. EAB assessment results will be available to the 
investigator prior to baseline and randomization. The MD-CRS part II will be administered by 
the investigational center physician and video review for central-blinded reading. In this study, 
the MD-CRS part II will be scored only based on chorea.
Titration period (7 weeks): Patients who remain eligible for participation in the study will be 
randomized at the baseline visit (day 1) and instructed to take the first dose of blinded IMP the 
following morning 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 4 and Table 5. Patients will be classified as 
CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 poor 
metabolizer. At the baseline visit, a telephone for non-recording live video will be provided to 
the patient and caregiver. Patients and their caregiver will interact weekly with the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
49
investigator/staff, either by telephone contact (with non-recording live video) or clinic visit from 
week 1 through week 7 of the titration period, in order to evaluate safety/tolerability and 
establish a dose of IMP that optimally reduces the severity of dyskinetic involuntary movements 
(clinically meaningful reduction in dyskinesia, as indicated by a reduction in the CGI-I) and is 
well tolerated. Safety/tolerability in-clinic evaluations during titration include assessment of vital 
signs, monitoring for adverse events and concomitant medications, 12-lead ECGs, identifying 
subjects at risk for suicide according to the C-SSRS questionnaire, assessment of drug-induced 
parkinsonism according to the ESRS (subscales I and II), assessment of change in behavior 
according to the CBCL questionnaire, and assessment of sedation according to the ESS 
questionnaire. If a patient experiences a “clinically significant” adverse event attributable to the 
IMP, the investigator will first determine if a dose reduction (to the previous dose level) or 
suspension is necessary and possible. At the end of the titration period, the patient’s dose will be 
established for the maintenance period. All IMP adjustments are made only after a remote or in-
clinic visit; if the dose is escalated, the dose escalation will occur with the next morning’s dose.
In-person (in-clinic) study visits will be scheduled for weeks 3 and 7, and telephone contacts 
(with non-recording live video) will be scheduled for weeks 1, 2, 4, 5, and 6 in order to assess 
dyskinesia and adverse events. The telephone contacts to the patient will be supported by live 
video stream, without recording, to provide visual confirmation to the investigator of the verbal 
information provided by the patient or caregiver. The dose of the IMP should be increased on a 
weekly basis to reach a clinically meaningful reduction in dyskinesia, as indicated by a reduction 
in the CGI-I. The IMP dose should not be increased further if either of the following events 
occurs:

the patient experiences a protocol-defined “clinically significant” adverse event 
(defined as an adverse event that is related to IMP and is either moderate or severe in 
intensity or meets the criteria for a serious adverse event), OR

the maximum allowable dose is reached based on the patient’s weight and CYP2D6 
impairment status at baseline.
Dose adjustments can be made up to and including the week 7 in-clinic visit. If an optimal dose 
is reached before the week 7 in-clinic visit, the dose of IMP should not be increased further, but 
the patient should continue on that dose for the remainder of the titration period and throughout 
the maintenance period. If a patient experiences a “clinically significant” adverse event 
attributable to the IMP, the investigator will first determine if a dose reduction (to the previous 
dose level) or suspension is necessary and possible. 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.
Maintenance period (8 weeks): Patients will continue to receive their maintenance dose over the 
next 8 weeks, although a 1-time dose reduction (to the previous dose level for the remainder of 
the study) for adverse events is allowed. Patients will return to the clinic at weeks 9, 12, and 
15 for assessments of efficacy and safety. 
Washout period and follow-up: All patients will discontinue IMP at the week 15 visit and will 
return 1 week later for the end-of-study (EOS) visit. Patients who complete the study may be 
eligible to begin participation in the open-label safety extension Study TV50717-CNS-30081 at 
that time. At the week 16 visit, patients may choose to enter Study TV50717-CNS-30081 (on 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
50
that day) or up to 1 week later (2 weeks from the week 15 visit). Patients who complete 
treatment but choose not to participate in the open-label safety extension Study 
TV50717-CNS-30081 any time before week 17 of Study TV50717-CNS-30080 will be 
contacted for a safety evaluation call occurring 2 weeks after their last dose of IMP. Additional 
details for patients to enter Study TV50717-CNS-30081 are provided in the TV50717-CNS-
30081 protocol.
When approximately 50 patients have completed the study (including follow-up), an independent 
Data Monitoring Committee (iDMC) will perform an unblinded non-binding interim analysis 
(IA) for futility based on centrally read MD-CRS part II total score. 
An iDMC charter will be developed for the IA, and the procedures to ensure the integrity of the 
study will be provided in the charter.
At the time of informed consent, the parent/legally accepted representative will be counseled 
that, once randomized to treatment, patients are to remain in the study and complete all study 
procedures unless the choice is made to withdraw consent. Patients who withdraw from the study 
before completing the 15-week treatment period should have an early termination (ET) visit 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 ET; evaluations will be as 
described for week 17.
Patients who screen fail or terminate early from the study due to emergency circumstances (such 
as coronavirus disease 2019 [COVID-19]) may be allowed to re-screen/re-enter (respectively) 
the study at a later date, depending on the circumstances. Each case should be referred to the 
medical monitor and approved in advance.
There is a separate protocol for the open-label safety extension Study TV50717-CNS-30081.
The end of study is defined as last visit of the last patient.
The study schematic diagram is presented in Figure 1.
For coronavirus disease 2019 (COVID-19) updates, refer to Appendix M.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
51
Figure 1: Overall Study Schematic Diagram
Screening
Titration Period
Investigator, in consultation with the patient and caregiver, will 
determine if a dose increase is warranted to achieve optimal dyskinesia 
reduction
Maintenance Therapy
Wash 
out
Follow Up
≥ 40 kg
30 < 40 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (24) 
mg
30 (24) 
mg
36 (24) 
mg
42 (24) 
mg
Stable maintenance dose 
42 (24) mg/day
17 < 30 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (18) 
mg
30 (18) 
mg
Stable maintenance dose 
30 (18) mg/day
6 (6) 
mg
12 (12) 
mg
24 (24) 
mg
30 (30) 
mg
36 (36) 
mg
42 (36) 
mg
48 (36) 
mg
Stable maintenance dose 
48 (36) mg/day
18 (18) 
mg
12 < 17 kg
6 (6)
mg
12 (12) 
mg
18 (12) 
mg
24 (12) 
mg
Stable maintenance dose 
24 (12) mg/day
In-clinic visit
Telephone call
Telephone call with 
non recorded video
Video recording
Option of 
participation in 
long-term safety 
study
Up to 31 
days
Week 
15/ ET
end-of-
study visit
Week 
1
Week 
3
Week 
16
Baseline
Day 
1
Week 
12
Week 
7
Week  
9
Week 
2
Day 
2
Week 
4
Week 
5
Week 
17
Week 
6
Day
3
Week 
15
1 
week
AE=adverse event; CGI=Clinical Global Impression; CYP2D6=cytochrome P450 2D6; ET=early termination; max=maximum.
Note: If a patient is CYP2D6-impaired, the dose administered is indicated in parentheses. The dose of the IMP should be increased on a weekly basis until any of 
the following events occur: clinically meaningful reduction in dyskinesia (ie, CGI-I) as determined by the investigator, clinically significant AE, or the maximum 
allowable dose is reached after remote or in-clinic visits.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
52
3.2.
Planned Number of Patients and Regions
Approximately 65 patients are planned to be randomized to TEV-50717 versus placebo in a 
2:1 ratio (approximately 43 in the TEV-50717 group; approximately 22 in the placebo group) 
stratified by age at baseline (6 to <12 years; 12 through 18 years) and region (US; non-US). 
Details on sample size are given in Section 9.1.
This study is planned to be conducted in approximately 60 investigational centers in North 
America, Asia, and Europe. 
3.3.
Justification for Study Design and Selection of Population
Currently, there is no approved treatment available for DCP. The available treatment options 
address some of the manifestations of DCP, which is hyperkinetic motor impairment due to a 
non-progressive disturbance of brain function that occurred in the developing fetal or infant 
brain, generally before the age of 2 years, and will therefore have a major debilitating impact on 
the ability of the child with CP to further develop motor skills. Therefore, the study population 
will include pediatric and adolescent patients (6 through 18 years of age) with DCP with 
predominant choreiform movement disorder, who have had non-progressive CP symptoms since 
infancy (≤2 years of age). Diagnosis of DCP is based on the Surveillance of Cerebral Palsy in 
Europe criteria (Cans 2000).
Consequently, the placebo-controlled, double-blind study design (TEV-50717 versus placebo in 
a 2:1 ratio) was chosen for this Phase 3 study to determine whether treatment with study 
medication results in a statistically significant effect on dyskinetic involuntary movements of 
patients with DCP.
3.4.
Stopping Rules for the Study
When approximately 50 patients have completed the study (including follow-up), an iDMC will 
perform an unblinded non-binding IA for futility based on the primary endpoint, the centrally 
read MD-CRS part II total score. Based on the results of the IA, the study may be stopped for 
futility.
During the conduct of the study, serious adverse events will be reviewed (Section 7.1.5), as they 
are reported from the investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of the following:

new toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment

discontinuation of the development of the IMP
If the study will be stopped, the patients who are terminated early will be followed according to 
Withdrawal Criteria and Procedures for the Patient (Section 4.3).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
53
3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 3. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetic and other 
assessments). Study procedures and assessments by visit are listed in Appendix C.
For COVID-19 updates, refer to Appendix M.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
54
Table 3:
Study Procedures and Assessments
Screening
BLa
Titration
Maintenance
Follow-up
U
Study weekb
-31 days
Day 1
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
(Day 
84)
15c/
ETd
(Day 
105)
16/EOS 
(7 days 
from 
week 15 
visit)
17e
(14 days 
from 
week 15 
visit)
Visit window (days)
0
+1
-1 and 
+3 
±3 days from day 1/baseline and ≥5 days from last dose 
change
±2 days from 
week 15 visit
In-clinic visit
Xf
X
X
X
X
X
X
X
X
Telephone contactg
X
X
X
X
X
X
Xh
Evaluate/adjust IMPi
Xj
Xj
Xj
Xj
Xj
Xj
Xj
X
Informed consent/assentk
X
Eligibility criteria
X
X
Medical history and psychiatric 
history
X
Demographics
X
Vital signs and weightl
X
Xm
X
X
X
X
Xm
X
X
Physical examination
X
X
X
Xh
Neurological examination
X
X
X
Xh
Height
X
X
12-lead ECGn
X
X
X
X
Xo
Xh
Xp
Xq
Chemistry/hematology/urinalysis
X
X
Xr
Xh
Urine drug screen
X
X
X
X
X
Xh
CYP2D6 genotypes
X
β-HCG testt
X
X
X
X
X
X
X
Xh


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
55
Screening
BLa
Titration
Maintenance
Follow-up
U
Study weekb
-31 days
Day 1
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
(Day 
84)
15c/
ETd
(Day 
105)
16/EOS 
(7 days 
from 
week 15 
visit)
17e
(14 days 
from 
week 15 
visit)
Visit window (days)
0
+1
-1 and 
+3 
±3 days from day 1/baseline and ≥5 days from last dose 
change
±2 days from 
week 15 visit
Randomization
X
MD-CRS part I (physician rated, 
with video recording)u
X
X
X
X
X
Xh
MD-CRS part I (centrally read, 
with video review)u
X
X
X
X
X
Xh
MD-CRS part II (physician rated, 
with video recording)u
X
X
X
X
X
X
Xh
MD-CRS part II (centrally read, 
with video review)u
X
(EAB)
X
X
X
X
X
Xh
CaGI-Iv
X
X
X
X
X
X
Xh
CGI-I (global, physician rated)w
X
X
X
X
X
X
X
X
X
X
X
Xh
CGI-S (global, physician rated)
X
X
X
X
X
X
X
X
Xh
PEDI-CAT (ADL, caregiver 
completed, content-balanced 
version)
X
X
Xh
PedsQL (QoL, patient/caregiver)
X
X
Xh
PGI-I (global, patient/caregiver)v
X
X
X
X
X
X
Xh
UHDRS-TMC (centrally read)
X
X
X
X
Xh
UHDRS-TMD (centrally read)
X
X
X
X
Xh
UHDRS-TMS (physician rated)
X
X
X
X
Xh


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
56
Screening
BLa
Titration
Maintenance
Follow-up
U
Study weekb
-31 days
Day 1
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
(Day 
84)
15c/
ETd
(Day 
105)
16/EOS 
(7 days 
from 
week 15 
visit)
17e
(14 days 
from 
week 15 
visit)
Visit window (days)
0
+1
-1 and 
+3 
±3 days from day 1/baseline and ≥5 days from last dose 
change
±2 days from 
week 15 visit
Children’s C-SSRS (Baseline/ 
Screening)x
X
Children’s C-SSRS (Since Last 
Visit)x
X
X
X
X
X
X
X
Xh
ESRS subscales I and II
X
X
X
X
X
X
X
X
Xh
CBCLy
X
X
X
X
X
X
X
X
Xh
ESS
X
X
X
X
X
X
X
X
Xh
Dispense IMP
Xz
Xz
Xaa
Xaa
Xaa
Xh
Collect IMP
X
X
X
X
X
Xh
Assess IMP accountability/ 
compliance/supplybb
Xcc
Xcc
Xdd
Xcc
Xcc
Xcc
X
X
X
X
Xh
Assess adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Xee
Contact RTSM
X
X
X
X
X
X
a
The BL visit will occur (day 1), and the first dose of the IMP will be taken the next morning (day 2).
b
Assessment is to occur at the end of study week, unless stated otherwise.
c
The date and time of the last dose of study medication before the week 15 visit should be reported to the investigator/staff by the patient or caregiver. The 
investigational center will document the date and time of the sample collection.
d
For patients who withdraw prematurely, an ET 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 ET visit; evaluations will be as described for week 17.
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 for 
TV50717-CNS-30081.
f
The screening visit may be conducted over 2 separate visits at the discretion of the investigator.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
57
g
Telephone contacts at weeks 1, 2, 4, 5, and 6 will be conducted with non-recording live video. Telephone contact at week 17 is a phone contact only (ie, no 
live video streaming).
h
Assessment to be completed at investigator’s discretion.
i
Dose increases may not occur more frequently than every 5 days, except for patients ≥40 kg/88 lbs. For patients ≥40 kg/88 lbs, the first dose increase should
be performed in an interval less than 5 days, only once, on day 3.  
j
Dose adjustment will be made by the investigator after telephone contact with the patient and caregiver or in-clinic visit to evaluate dyskinesia reduction and 
adverse events. If the dose is escalated, the dose escalation will occur with the next morning’s dose.
k
l
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 3 minutes (the same position and arm or leg should be used each time vital signs are measured for a given patient).
m
Orthostatic BP and pulse will be measured after the patient is in a standing position for at least 3 minutes (for patients who are able to stand); for patients who 
find standing difficult or do not allow for a reliable BP and pulse measurement, alternative methods to collect orthostatic BP and pulse should be discussed 
with the medical monitor.
n
All ECGs will be performed after at least 5 minutes rest in a supine or semi-supine position.
o
Perform ECG if there was a significant abnormality at the ET visit.
p
 
 
 
q
 
 
r
Patients with clinically significant laboratory abnormalities at week 15 will have those laboratory evaluations repeated at the week 16 visit.
s
The patient’s CYP2D6 genotype results will be provided to the RTSM, which drives each patient’s dose regimen, and the patient’s CYP2D6 genotype will 
remain blinded during the conduct of the study.
t
For females who are postmenarchal or aged ≥12 years of childbearing potential. Serum test will be administered at screening and week 15, whereas a urine 
test will be administered at baseline and all other in-clinic visits where this test is administered.
u
MD-CRS parts I and II assessments are done locally at the investigational center, by the investigator, and video recorded. An EAB will confirm, at the 
screening visit, that choreiform movement disorder is the predominant dyskinetic movement disorder and that DCP severity represented by an MD-CRS part 
II score is ≥10. The EAB will inform the local rater if their assessment is different than the local rater’s assessment; however, it is the investigator who 
determines the subject’s eligibility. All the subsequent MD-CRS ratings will be performed by the investigator and video recorded and then centrally read, in a 
blinded manner.
v
CaGI-I and PGI-I are to be completed before all other investigator-rated scales during visits where CaGI-I and PGI-I are collected.
w
During telephone contact, the CGI-I scale can only be done if non-recording video is available, allowing the investigator to complete the required assessment.
x
The children’s C-SSRS questionnaire will be presented to patients who have reached ≥12 years of age at screening or 11 years of age at screening but will 
turn 12 years of age during the study. Children 13 years of age and under must be interviewed in conjunction with the caregiver. For children over 13 years of 
age, parent/legally accepted representative involvement is strongly encouraged. Questions should be directed to the child, but the parent/legally accepted 
representative should be encouraged to add relevant information. 
y
A full CBCL assessment (Competence Scale [Parts I to VII] and a Syndrome Scale [behavioral items]) will be performed at screening and week 15/ET. The 
Syndrome Scale part of the CBCL assessment only will be performed at baseline and weeks 3, 7, 9, 12, and 16/EOS.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
58
z
IMP will be dispensed in the clinic. At the baseline visit, patients will receive IMP kits of increasing doses sufficient for 3 weeks. At the week 3 visit, 
4 additional kits of increasing doses will be dispensed to cover the following 4 weeks until the end of the titration period at week 7. These supplies will allow 
the patient to maintain their titration scheme between clinic visits by way of remote caregiver/patient telephone contacts. Dose adjustments can be made up to 
and including the week 7 in-clinic visit. If an optimal dose is reached before then, the dose of IMP should not be increased any further, but the patient should 
continue on that same dose for the remainder of the titration period and throughout maintenance dosing. The investigational center will determine titration (ie, 
starting the next dose) for the patient by telephone. See Table 4 for baseline weight-based dosing titration. For any dose adjustment, the investigator or 
designee should confirm that patients have the bottle that contains the appropriate tablet strength and quantity to complete the recommended daily regimen.
aa Patients will receive doses for 3 weeks (±3 days) of maintenance treatment.
bb Study drug accountability will be assessed during in-clinic visits only. A check for compliance with TEV-50717 intake will be performed during each 
in-clinic visit and telephone contact after TEV-50717 has been dispensed.
cc The study staff needs to discuss the drug status during the telephone contacts to ensure that the patients have adequate tablets, inform the patients if they 
should titrate, and remind them to bring used and unused IMP bottles to the next in-clinic visit.
dd During the week 3 visit, the investigator or designee will make sure the patient receives the last treatment kit back so the patient can take the evening dose to 
complete the week 3 dosing for that day. Refer to the pharmacy manual for further details.
ee Caregivers and patients will be instructed during the course of the study to notify the investigator if any new medication is prescribed/administered (other than 
TEV-50717) or if there is any change in current medications, including over-the-counter medications. Any new and/or any change in current medications 
should be reviewed with the investigator.
β-HCG=beta human chorionic gonadotropin; ADL=activities of daily living; BL=baseline visit; BP=blood pressure; CaGI-I=Caregiver Global Impression of 
Improvement; CBCL=Child Behavior Checklist (for ages 6-18); CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of 
Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; CYP2D6=cytochrome P450 2D6; DCP=dyskinesia in cerebral palsy; EAB=Enrollment 
Adjudication Board; ECG=electrocardiogram; EOS=end of study visit; ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS =Epworth 
Sleepiness Scale (for children and adolescents); ET=early termination visit; 
; IMP=investigational medicinal product; 
MD-CRS=Movement Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability Inventory-Computer Adapted Test; PedsQL=Pediatric 
Quality of Life Inventory; PGI-I=Patient Global Impression of Improvement; 
; QoL=quality of life; RTSM=Randomization and Trial 
Supply Management; U=unscheduled visit; UHDRS-TMC=Unified Huntington’s Disease Rating Scale-Total Maximal Chorea; UHDRS-TMD=Unified 
Huntington’s Disease Rating Scale-Total Maximal Dystonia; UHDRS-TMS=Unified Huntington’s Disease Rating Scale-Total Motor Score.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
59
4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix D).
Standard of care for treatment of CP should continue throughout the study, with some possible 
restrictions related to concomitant medication, for example, as outlined in Section 5.5 . Standard 
of care could include any possible rehabilitation service(s), such as physiotherapy, occupational 
therapy, or sensory integration of the patient, which should remain constant throughout the 
course of the study.
4.1.
Patient Inclusion Criteria
Patients may be randomized/enrolled in this study only if they meet all of the following criteria:
1. Patient is 6 through 18 years of age (inclusive) at baseline. 
2. Patient weighs at least 26 pounds (12 kg) at baseline.
3. Patient has had CP symptoms since infancy (≤2 years), and CP is judged by the 
investigator to be of a non-progressive nature (Monbaliu et al 2017, 
Wimalasundera et al 2016).
4. Patient has a diagnosis of DCP according to the Surveillance of Cerebral Palsy in Europe 
criteria (Cans 2000).
5. Patient has an MD-CRS part II total score of ≥10 at the baseline visit, based on 
investigator scoring of chorea.
6. Patient’s symptoms are causing functional problems determined by a CGI-S score of 4 or 
greater based on investigator scoring.
7. Choreiform is the predominant (ie, the main cause of impairment or distress) movement 
disorder as assessed at screening.
8. Patient is able to swallow study medication whole.
9. Patient and caregiver are willing to adhere to the medication regimen and to comply with 
all study procedures.
10. Patient is in good general health, as indicated by medical and psychiatric history, as well 
as physical and neurological examination.
11. In the investigator’s opinion, the patient and/or caregiver has the ability to understand the 
nature of the study and its procedures, and the patient is expected to complete the study 
as designed.
12. For a patient who is a minor, the parent(s)/legally accepted representative(s) provide 
written informed consent, and the patient provides assent (in accordance with local 
regulations). Adult patients provide their own written informed consent (in accordance 
with local regulations) and the legally acceptable representative will sign, if needed.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
60
In this study, eligible patients are patients with dyskinetic CP who may have some degree 
of mental, motor, and/or communication (eg, speech, writing, etc) limitations or 
disabilities. The patient may not be able to read the assent/consent form. Some patients 
may only be able to provide a limited assent/consent (for instance, by verbalizations or 
gestures). The investigator will determine the suitability of enrolling such patients in this 
study and will follow the local regulation to obtain the relevant assent/consent. 
13. Caregivers provide written informed consent after being assigned the role by an adult 
patient, or if this role is delegated by the parent/legally accepted representative of a 
patient who is a minor.
14. 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, premenarchal, and postmenarchal are given in Appendix F. 
15. Females who are postmenarchal or ≥12 years of age whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the duration 
of the study (ie, starting at screening) and for 30 days after the last dose of IMP. Further 
details are included in Appendix F.
4.2.
Patient Exclusion Criteria
Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
1. a. Patient has a predominant movement disorder other than dyskinesia.
b. Patient’s predominant motor symptoms are dystonic.
c. Patient’s predominant motor symptoms are spastic.
d. Patient has another other movement disorder that could impair the motor assessment in 
the MD-CRS part II.
e. Patient has choreiform movement disorder that has not been consistent throughout the 
life of the patient.
2. 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 and anticipated to remain stable (dose and 
frequency) within the study duration.
3. Patient has a history of suicidal intent or related behaviors based on medical or 
psychiatric history or the C-SSRS 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
4. Patient has a history of a previous actual, interrupted, or aborted suicide attempt based on 
medical or psychiatric history or the C-SSRS.
5. Patient has a first-degree relative who has completed suicide.
6. Patient has received any of the following concomitant medications within the specified 
exclusionary windows of screening:


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
61

Within 30 days: tetrabenazine, deutetrabenazine, or valbenazine

Within 21 days: reserpine

Within 14 days: levodopa, dopamine agonists, and MAOIs
7. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic 
stimulation, or transcranial direct current stimulation for treatment of abnormal 
movements or CP within 6 months of the screening visit, or the patient is not in a stable 
clinical condition. 
8. Patient has recent surgical procedure or is anticipated to have a surgical procedure during 
the study that, in the opinion of the investigator, makes the patient unsuitable for the 
study.
9. Patient has a severe mental disability or an unstable or serious medical illness (eg, 
epilepsy) at screening or baseline that, in the opinion of the investigator, could jeopardize 
or would compromise the patient’s ability to participate in this study.
10. Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) value 
>450 msec on 12-lead ECG at screening. 
11. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.
12. Patient has evidence of diminished hepatic function, as indicated by the following:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the 
upper limit of the normal range (ULN) at screening

Alkaline phosphatase (ALP) or total bilirubin >2 × ULN at screening

Note: Patients with Gilbert’s syndrome are eligible to participate if approved by 
the medical monitor. 

Note: Patients with abnormalities in 2 or more of the following clinical laboratory 
parameters must be approved for enrollment by the medical monitor: AST, ALT, 
ALP, and total bilirubin. 
13. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5 × ULN at screening. 
14. Patient has a known allergy to any of the components of the IMP.
15. Patient has participated in an investigational drug or device study and received 
IMP/intervention within 30 days or 5 drug half-lives of screening, whichever is longer.
16. Patient is pregnant or breastfeeding.
17. Patient has a history of or acknowledges alcohol or other substance abuse in the 
12 months before screening.
18. Patient has a positive urine drug screen test result (with exception of medications listed in 
Table 10 of Appendix H). Any request to include a patient with a positive urine drug 
screen test result should be discussed with, and approved by, the medical monitor. Refer 
to Section 7.5.2.2 (urine drug screen) for more details.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
62
4.3.
Withdrawal Criteria and Procedures for the Patient
Patients are expected to participate in this study for its entire duration and perform the scheduled 
visits and procedures. 
During the titration period, an optimal dose should be sought for each patient. Throughout the 
maintenance period, patients will continue to receive the optimal dose determined during 
titration. If a patient experiences a “clinically significant” adverse event attributable to the IMP, 
the investigator will first determine if a dose reduction (to the previous dose level) or suspension 
is necessary and possible (Section 5.8). Each patient is free to withdraw from the study or 
discontinue from IMP at any time, without prejudice to their continued care, but every effort 
should be made to determine the reason for discontinuation. 
Every effort should be made to ensure that patients comply with study visits and procedures, as 
detailed in the protocol. Patients must be withdrawn from the study if any of the following events 
occur:
1. Patient or parent(s)/legally acceptable representative withdraws consent or requests 
discontinuation from the IMP or withdrawal from the study for any reason.
2. Patient develops an illness that would interfere with his/her continued participation.
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator.
4. Patient takes prohibited concomitant medications as defined in this protocol 
(see Appendix H).
5. Patient engages in alcohol or other substance abuse.
6. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test.
7. The sponsor requests withdrawal of the patient.
8. Patient experiences an adverse event or other medical condition that indicates to the 
investigator that continued participation is not in the best interest of the patient.
9. The patient experiences a serious adverse event or pregnancy, or in cases when the 
investigator deems it necessary to unblind the patient’s IMP assignment to make 
treatment decisions.
10. Patient has evidence of diminished hepatic function based on the following liver function 
laboratory test results:
a.
AST or ALT >2.5 × ULN
b. ALP or total bilirubin >2 × ULN
11. Patient develops Neuroleptic Malignant Syndrome (NMS)
12. If a post-baseline QTcF value >500 msec or change from screening >60 msec is found, 
the investigator should repeat the ECG assessment twice more and compare the average 
of these 3 post-screening QTcF values to the pre-treatment QTcF values at screening. The 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
63
IMP must be stopped for any confirmed post-baseline QTcF average value >500 msec or 
average increase from screening >60 msec. 
13. In patients who experience signs of suicidal ideation or behavior (Section 7.9), the 
investigator should consult with the medical monitor to determine whether the patient 
should continue in the study.
In addition, a patient may be withdrawn from the study as described in Sections 3.4, 3.5, 
and 5.10 and Appendix C.
Because the statistical analysis of the primary endpoint of this study includes the assessment of 
randomness of missing data (Section 9.5.2.1), the most accurate as possible determination of the 
reason for ET is very important. Investigators should make every effort to obtain accurate 
information on patients in the case of withdrawal from the study or discontinuation from IMP. 
Results of any evaluations and observations, together with a narrative describing the reason(s) 
for withdrawal from the study or discontinuation from IMP, must be recorded in the source 
documents. The case report form (CRF) must document the primary reason for withdrawal from 
the study or discontinuation from IMP.
See Appendix G for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If the reason for withdrawal from the study or discontinuation from IMP is an adverse event 
and/or clinically significant abnormal laboratory test result, monitoring will be continued as 
applicable (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). If a patient is withdrawn wholly or in part because of an adverse event, the 
specific event or test result (including repeated test results, as applicable) must be recorded both 
on the source documentation and in the adverse events page and termination page of the CRF.
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 also include adverse events, the 
relevant 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” and not the adverse event.
All assessments should be performed according to the protocol on the last day the patient takes 
IMP, or as soon as possible thereafter.
For COVID-19 updates, refer to Appendix M.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
64
4.4.
Replacement of Patients
A patient who is enrolled but does not complete the treatment period will not be replaced.
4.5.
Rescreening
A patient who is screened but not enrolled (eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time) may be considered for rescreening 
1 time if there is a change in the patient’s medical background or other relevant change. (Note: 
the medical monitor should approve rescreening after review of the enabling reasons.)
Patients may have individual parameters retested at the discretion of both the investigator and the 
sponsor.
If the patient is rescreened, an informed consent form (ICF) will need to be re-signed.
For COVID-19 updates, refer to Appendix M.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. Minimal information includes, but is not limited 
to, demography, screening failure details, eligibility criteria, and any serious adverse events.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
65
5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
IMP is defined as the test IMPs and matching placebo IMPs to the respective test IMPs. There is 
no reference IMP in this study.
5.1.1.
Test Investigational Medicinal Product
Test IMP (TEV-50717 [deutetrabenazine, previously SD-809]) will be administered as oral 
tablets with food (eg, a snack) and should not be taken on an empty stomach. The IMP is coated 
with a white polymer coating to aid in swallowing. TEV-50717 tablets have been manufactured 
according to current Good Manufacturing Practice (GMP) regulations. TEV-50717 tablets will 
be supplied as 6-, 9-, 12-, 15-, and 18-mg tablets by bottle and labeled according to applicable 
regulatory guidelines. Each bottle pack (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 may be found in Table 6, the IB for TEV-50717, and the Prescribing 
Information for TEV-50717.
5.1.1.1.
Starting Dose and Dose Levels
Test IMP will be administered as oral tablets at a starting dose of 6 mg once daily with food (eg, 
a snack) and should not be taken on an empty stomach. Titration schemes based on body weight 
at baseline are shown in Table 4. The maximum daily dose is determined by body weight at 
baseline and CYP2D6 impairment status (see Table 5). Patients will be classified as CYP2D6 
impaired if they are receiving a strong CYP2D6 inhibitor or are a CYP2D6 poor metabolizer. 
Dose adjustments can be made up to and including the week 7 in-clinic visit. If an optimal dose 
is reached before the week 7 in-clinic visit, the dose of IMP should not be increased further, but 
the patient should continue on that dose for the remainder of the titration period and throughout 
the maintenance period. If a patient experiences a “clinically significant” adverse event that is 
attributed to the IMP, the investigator will first determine if a dose reduction (to the previous 
dose level) or suspension is necessary and possible. 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 once for the remainder of the maintenance period.
TEV-50717 tablets (test IMP) 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). Test IMP will be supplied in 
20-count tablets per dose strength per bottle assembling 6, 12, 18, 24, 30, 36, 42, and 48 mg dose 
kit combinations. The placebo IMP tablets and packaging will match those for TEV-50717.
5.1.1.2.
Dose Modification and Dose Stratification
All IMP adjustments are made only after a remote or in-clinic visit; if the dose is escalated, the 
dose escalation will occur with the next morning’s dose.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
66
IMP will be administered as follows:

IMP should be swallowed whole. If the IMP is crushed or split, it should not be 
ingested; it should be replaced with a new tablet. The tablets will be taken with food 
(eg, a snack) and should not be taken on an empty stomach. Patients may be offered 
the optional use of a Medi+Straw®, which is a commercially available straw that can 
assist patients to overcome their swallowing difficulties.

Dosing will be based on body weight at the baseline visit and CYP2D6 impairment 
status, as shown in Table 4 and Table 5, respectively.

If there is only a single dose of IMP per day, the dose should be taken in the morning. 
However, patients experiencing somnolence while taking the 6-mg dose in the 
morning may switch to taking it as an evening dose for the rest of the days up to 
day 14.

The starting dose of 6 mg will be administered in the morning on day 2 and for the 
remainder of the first week. Patients in the highest body weight group (≥40 kg/88 lbs) 
will start an evening administration from day 3 and for the remainder of the first 
week. TEV-50717 daily doses of 12 mg and higher will be administered as 2 divided 
equal 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 the 
next dose, the missed dose should be skipped. 

Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg/88 lbs. For patients ≥40 kg/88 lbs, the first dose increase should be performed 
in an interval less than 5 days, only once, on day 3.

During the week 3 visit, the investigator or designee will make sure the patient 
receives the last treatment kit back so the patient can take the evening dose to 
complete the week 3 dosing for that day. Refer to the pharmacy manual for further 
details.

For any dose adjustment, the investigator or designee should confirm that patients 
have the bottle that contains the appropriate tablet strength and quantity to complete 
the recommended daily regimen.

At an in-clinic visit, a dose reduction, if required, should be made to the previously 
tolerated dose level. 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 IMP should be adjusted according to Table 4
to identify a dose level that optimally reduces dyskinesia (as determined by the 
investigator, as indicated by a reduction in the CGI-I) and is well tolerated. Dose 
adjustments should ONLY take place after telephone or in-clinic visit.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
67
Table 4:
Maximum Daily Dose of IMP During the Titration Period by Week and 
Weight Category at Baseline
Study time period
Daily dosea,b
12 kg to <17 kg
(26 lbs to <37 lbs)
17 kg to <30 kg
(37 lbs to <66 lbs)
30 kg to <40 kg
(66 lbs to <88 lbs)
≥40 kg
(≥88 lbs)
Day 2 (first dose in morning)
6 mg
6 mg
6 mg
6 mg
Week 1
6 mg
6 mg
6 mg
12 mgc
Week 2
6 mg
12 mg
12 mg
18 mg
Week 3
12 mgd
18 mgd
18 mgd
24 mg
Week 4
12 mgd
18 mgd
24 mgd
30 mg
Week 5
18 mgd
24 mgd
30 mgd
36 mgd
Week 6
18 mgd
24 mgd
36 mgd
42 mgd
Week 7
24 mgd
30 mgd
42 mgd
48 mgd
a All IMP adjustments are made only after a remote or in-clinic visit; if the dose is escalated, the dose escalation will 
occur with the next morning’s dose. Dose adjustments should ONLY take place after telephone or in-clinic visit.
b Dose increases may not occur more frequently than every 5 days, except for patients ≥40 kg/88 lbs. For patients 
≥40 kg/88 lbs, the first dose increase should be performed in an interval less than 5 days, only once, on day 3. 
Refer to Table 3 for the exact visit windows at each weekly titration visit.
c Patients in this weight category will receive the 6-mg once-daily dose in the morning on day 2, followed by 
twice-daily administration of 6 mg starting on day 3.
d For those taking strong CYP2D6 inhibitors, such as paroxetine, fluoxetine, and bupropion, or those who are poor 
CYP2D6 metabolizers, the maximum daily dose for patients ≥40 kg is 36 mg/day, that for 30 to <40 kg is 
24 mg/day, that for 17 to <30 kg is 18 mg/day, and that for 12 to <17 kg is 12 mg/day (see Table 5).
CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
68
Table 5:
Maximum Daily Dose of IMP by CYP2D6 Impairment Status
Weight category
Maximum daily dose in the absence of 
CYP2D6 impairment
Maximum daily dose in the presence of 
CYP2D6 impairment
12 kg to <17 kg
(26 lbs to <37 lbs)
24 mg
12 mg
17 kg to <30 kg
(37 lbs to <66 lbs)
30 mg
18 mg
30 kg to <40 kg
(66 lbs to <88 lbs)
42 mg
24 mg
≥40 kg
(≥88 lbs)
48 mg
36 mg
CYP2D6=cytochrome P450 2D6; IMP=investigational medicinal product.
Note: Patients will be classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor or are a 
CYP2D6 poor metabolizer. Strong CYP2D6 inhibitors include paroxetine, fluoxetine, and bupropion.
5.1.2.
Placebo Investigational Medicinal Product
Placebo tablets match TEV-50717 tablets. Additional details may be found in Table 6.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
69
Table 6:
Investigational Medicinal Products Used in the Study
IMP Name
TEV-50717 Test IMP
Placebo IMP
Company-assigned number
TEV-50717 (SD-809, AUSTEDO®, 
deutetrabenazine)
Not applicable
Formulation
Modified release solid oral dosage form (tablet with 
film coating)
Modified release solid oral dosage form (tablet with 
film coating)
Unit dose strength(s)/Dosage level(s)
TEV-50717 tablets are available in the following 
dose strengths: 6, 9, 12, 15, and 18 mg, all of which 
are identical in size, shape, and color (white). Test 
IMP will be supplied in 20-count tablets per dose 
strength per bottle.
Not applicable
Route of administration
Oral
Oral
Packaging
Test IMP will be provided in bottles.
Placebo IMP will be provided in bottles.
Manufacturer
Norwich Pharmaceuticals Inc., New York, United 
States
(Referenced as NPI or Norwich)
6826 State Highway 12
Norwich, NY 13815
Anesta LLC
4745 Wiley Post Way 
Salt Lake City, UT 84116
Norwich Pharmaceuticals Inc., New York, United 
States
(Referenced as NPI or Norwich)
6826 State Highway 12
Norwich, NY 13815
Anesta LLC
4745 Wiley Post Way 
Salt Lake City, UT 84116
Storage conditionsa
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F)
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F)
a For additional information related to the IMP storage condition, refer to Section 11 of the Pharmacy Manual.
IMP=investigational medicinal product.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
70
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products
5.2.1.
Storage and Security
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The IMPs (TEV-50717 and placebo IMP) must be stored at a controlled room temperature, 20ºC 
to 25ºC (68ºF to 77ºF), in a securely locked, substantially constructed cabinet or enclosure with 
access limited to authorized staff. For additional information related to the IMP storage 
condition, refer to Section 11 of the Pharmacy Manual.
5.2.2.
Labeling
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation guidelines on Good Clinical Practice (GCP) and GMP and will include any 
locally required statements. If necessary, labels will be translated into the local language.
5.2.3.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment and any 
applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and 
used in accordance with this protocol.
Only patients enrolled in the study may receive IMPs, and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator (or designee) will instruct the patient to store the IMP according to the 
instructions on the label, if applicable, or will give instructions in an appropriate form.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Any used (partially used or empty) bottles and 
unused kits/bottles that are not destroyed at the site are returned to the sponsor or designee, as 
agreed with the sponsor (including expired and damaged kits). 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
71
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
Based on the feedback from the external experts, the optimal dose of tetrabenazine in the 
treatment of DCP in a pediatric population is individualized and not related to any specific dose 
per body weight. Also, the 2 published studies (Jain et al 2006, Vuong et al 2004) on the use of 
tetrabenazine in the treatment of hyperkinetic movement disorders (including DCP) (see 
Section 1.1.2) introduce a wide range of doses of tetrabenazine that were found to be effective. 
As variability in optimal dose of tetrabenazine might be due to its highly variable metabolism of 
the active (+β)-HTBZ, it is also conceivable that the patients with hyperkinetic movement 
disorders would require an individually optimized dose. Therefore, this uses a flexible dose 
design, where maximal dose is limited based on body weight and CYP2D6 impairment status. 
Based on modeling and simulations of the exposure (area under the plasma concentration-time 
curve) and maximum observed concentration in adults and adolescents, it is possible to design 
dosing regimens in alternative body weight categories depending on their CYP2D6 impairment 
status, which would give comparable exposure and maximum observed concentration across the 
range of strata. This approach is analogous to what has also been adopted in the ongoing 
TV50717-CNS-30046 Phase 2/3 and TV50717-CNS-30060 Phase 3 studies of TEV-50717 in 
TS.
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
A standard placebo-controlled, double-blind study design (TEV-50717 versus placebo in a 
2:1 ratio) was chosen to determine whether TEV-50717 treatment results in a statistically 
significant effect on the motor system of patients with CP. As CP is not a progressive 
neurological disorder, and available treatments are for symptomatic control, the use of placebo is 
justified in a short-term study where safety is carefully monitored. Moreover, a placebo control is 
ideal for characterizing the efficacy and safety of an experimental agent in a new study 
population.
5.4.
Treatment after the End of the Study
All patients will discontinue IMP at the week 15 visit and will return 1 week later for the EOS 
visit.
 
Patients will not receive the evening 
IMP dose on this day. 
Patients who complete the study may be eligible to begin participation in the open-label safety 
extension Study TV50717-CNS-30081. At the week 16 visit, patients may choose to enter Study 
TV50717-CNS-30081 (on that day) or up to 1 week later (2 weeks from the week 15 visit). 
Patients who complete treatment but choose not to participate in the open-label safety extension 
Study TV50717-CNS-30081 before week 17 of Study TV50717-CNS-30080 will be contacted 
for a safety evaluation call occurring 2 weeks after their last dose of IMP. Additional details for 
patients to enter Study TV50717-CNS-30081 are provided in the TV50717-CNS-30081 protocol. 
Note: Patients can also roll over to the extension study within 2 to 4 weeks after the week 15 visit 
but will be required to complete additional scales and tests as part of Study TV50717-CNS-30081. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
72
5.5.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.6. 
While patients receiving a strong CYP2D6 inhibitor (such as paroxetine, fluoxetine, or 
bupropion) at baseline may be enrolled into this study, the removal of strong CYP2D6 inhibitors 
during treatment is discouraged, as this would have an effect on exposure to active circulating 
drug. If the removal of a strong CYP2D6 inhibitor is required from a clinical perspective, the 
medical monitor should be contacted so that an appropriate change in IMP dosing can be made. 
The addition of a strong CYP2D6 inhibitor is prohibited during the study.
Restrictions in regard to sexual activity and required laboratory values are provided in the 
inclusion and exclusion criteria. 
As with other VMAT2 inhibitors (tetrabenazine and 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. 
Patients should be advised not to drive a car or operate dangerous machinery until they 
understand how TEV-50717 affects them.
Use of non-approved drugs (per protocol) is prohibited from the time of signing of the ICF and 
throughout study participation.
Patients may not donate blood from the time of signing of the informed consent, while taking the 
IMP, and for 14 days after the last dose.
5.6.
Prior and Concomitant Medication
Any prior or concomitant medication a patient has had within 3 months prior to baseline and up 
to the end of study, including follow-up, will be recorded on the CRF. Generic or trade name, 
indication, dose, and start and end dates of the administered medication will be recorded. The 
sponsor will encode all medication according to the World Health Organization drug dictionary.
At each clinic visit after the screening visit, the investigator will ask patients and/or caregiver 
whether the patient has taken any medications (other than IMP), including over-the-counter 
medications, vitamins, or herbal or nutritional supplements, since the previous visit. Caregivers 
and patients will be instructed during the course of the study to notify the investigator if any new 
medication is prescribed/administered (other than TEV-50717) or if there is any change in 
current medications, including over-the-counter medications. Any prescribed new and/or any 
change in current medication should be reviewed with the investigator. Indication, dosage, and 
start and end dates should be entered on the CRF. 
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving 
during the study) a medication that is associated with QT prolongation or that is a known strong 
CYP inhibitor. Allowed strong CYP inhibitors at baseline are shown in Appendix H, Table 10. 
The addition of a strong CYP inhibitor is prohibited during the study.
Prohibited medications that are associated with QT prolongation are listed in Appendix H, 
Table 11. 
Concomitant medication will be monitored throughout the study. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
73
5.7.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance until completion of the 
IMP administration according to the protocol or discontinuation from IMP. A check of 
compliance with IMP intake will be performed during each in-clinic visit after the used IMP has 
been returned, and IMP accountability records will be completed. At week 3, IMP administration 
compliance can be calculated only for weeks 1 and 2, as the last kit at week 3 is returned to the 
patient so that the patient can complete the week 3 dosing for that evening.
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. Based on pill counts at in-clinic visits, poor compliance with study 
drug intake (ie, <80%) or overdose (ie, >105%) is to be recorded as an important deviation and 
expeditiously reported to the medical monitor.
Patients are expected to participate in this study for its entire duration. Exposure to IMP will be 
assessed as required (Section 5.1).
5.8.
Temporary Discontinuation of Investigational Medicinal Product
Refer to Table 3 for data to be collected at the time of IMP discontinuation and follow-up and for 
any further evaluations that need to be completed.
If a patient experiences a “clinically significant” adverse event that is attributed to IMP, the 
investigator will first determine if a dose reduction (to the previous dose level) or suspension is 
necessary and possible. Dose adjustments should be made based on all available information, 
including the patient’s and parent’s/caregiver’s reports of adverse events and motor function 
improvement, 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 should be notified. Suspension of IMP treatment for up to 1 week, if 
warranted, is allowed. If the patient restarts IMP within 7 days of suspension, the full dose of 
IMP may be resumed without titration at the same dose level or 1 dose lower (last tolerated 
dose). Suspension of IMP treatment for adverse events must be reviewed with the medical 
monitor before IMP treatment is restarted. Suspensions for more than 7 days must be reviewed 
by the medical monitor before therapy is restarted, and also to determine if there is adequate time 
for patients to be reinstated and complete study evaluations. The reason for a dose reduction or 
suspension must be clearly documented in the related adverse event form.
Dose reduction or suspension is allowed once during the titration period and once during the 
maintenance period. Patients who restart IMP treatment will remain at the current dose 
throughout that period with no further dose changes and will, otherwise, follow the visit schedule 
as outlined in the protocol. If a dose reduction occurs before a scheduled clinic visit, the clinic 
visit will be postponed so that efficacy evaluations can be performed at least 7 days after the 
change. 
If a dose suspension occurs before a scheduled clinic visit, an unscheduled visit should be 
scheduled as soon as possible so that efficacy evaluations can be performed at least 7 days after 
the change. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
74
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.
If a patient’s serum potassium or magnesium level falls below the lower limit of normal, IMP 
should be suspended. Since TEV-50717 does not have any known effect on potassium and 
magnesium levels, the reference to potassium and magnesium is in the context of other factors 
related to any current underlying condition, such as severe diarrhea or intake of drugs that lower
serum potassium and magnesium. The investigator will be responsible to manage the patient’s 
condition per the site’s standard of care and assess continuation of treatment. The medical 
monitor should be contacted to discuss the suspension and possible resumption of the IMP. IMP 
treatment may only be restarted once serum potassium and/or magnesium levels have 
normalized.
Patients who restart IMP treatment will follow the visit schedule as outlined in Table 3. Patients 
who withdraw from the study will proceed as described in Section 4.3.
5.9.
Randomization and Blinding
This is a double-blind study. Patients will be randomized to either TEV-50717 or matching 
placebo in a 2:1 ratio using Randomization and Trial Supply Management (RTSM). Patients will 
be stratified by age at baseline (6 to <12 years; 12 through 18 years, inclusive) and region (US; 
non-US). 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 
sponsor’s clinical supply chain staff and RTSM vendor) will be blinded to the IMP identity until 
the database has been locked for analysis and the treatment assignments are revealed.
The iDMC will perform an unblinded non-binding IA for futility and will monitor safety 
throughout the study based on unblinded data. An iDMC charter will be developed for the 
interim analyses, and the procedures to ensure the integrity of the study will be provided in the 
charter (see Section 5.10.3 for more details).
In the event of an emergency, it will be possible to determine to which treatment group and dose 
the patient has been allocated by accessing the RTSM system. All investigational centers will be 
provided with details of how to access the system for code breaking at the start of the study. The 
medical monitor or equivalent should be notified following unblinding. Any unblinding of the 
IMP performed by the investigator must be recorded in the source documents.
Patients re-entering the study will be manually assigned to their initial treatment group by the 
RTSM unblinded vendor. Blinding will be maintained for the patient, investigator, and sponsor 
as described above; the only information that will be available is that the patient was assigned to 
the same treatment group previously. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider (eg, via an RTSM system). The generation of the randomization list and 
management of the RTSM system will be done by a qualified service provider under the 
oversight of the responsible function at Teva.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
75
5.10.
Maintenance of Randomization and Blinding
5.10.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of analysis (after the end of study or at the IA), after 
receiving unblinding request from a Teva statistician, the service provider will provide the 
unblinded IMP assignment according to the processes defined in the relevant standard operating 
procedure. For the IA and iDMC closed sessions, the codes will be provided to an independent 
statistician who will perform the IA.
5.10.2.
Blinding and Unblinding
For information about personnel who may be aware of IMP assignments, see Section 5.9. 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, 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, through specialized 
access in the RTSM system. Breaking of the treatment code may always be performed by the 
investigator without prior approval by the sponsor; however, the sponsor should be notified that 
the code was broken, but the patient treatment assignment should not be revealed to the sponsor.
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the blind code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study and analysis and 
reporting of the data.
5.10.3.
Independent Data Monitoring Committee
There will be an iDMC in this study. 
When approximately 50 patients have completed the study (including follow-up), the iDMC will 
perform an unblinded non-binding IA for futility based on centrally read MD-CRS part II total 
score.
Details on how the iDMC chairperson will communicate with the sponsor in regard to issues 
resulting from the conduct and clinical aspects of the study are described in the iDMC charter. 
The iDMC charter will be developed for the IA, and the procedures to ensure the integrity of the 
study will be provided in the charter. The sponsor will work closely with the iDMC to provide 
the necessary safety and efficacy data for review. In addition, results of the IA will be 
communicated to the sponsor as outlined in the iDMC charter.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
76
Details are given in Appendix B.
5.11.
Total Blood Volume
The total blood volume to be collected for each patient in this study is approximately 40 mL (at 
maximum), as detailed in Appendix I.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
77
6.
ASSESSMENT OF EFFICACY
Efficacy in this study will be evaluated using MD-CRS part I total score, MD-CRS part II total 
score, CaGI-I, CGI-I, CGI-S, PEDI-CAT, UHDRS-TMS, UHDRS-TMC, UHDRS-TMD, and 
PGI-I. It is recommended that the same order of administration/completion of the scales be kept 
per patient throughout the study, as best as possible (refer to the Study TV50717-CNS-30080 
RECLAIM-DCP: Order of scales administration/completion document). At all relevant visits 
where collected, PGI-I and CaGI-I are to be completed before all other investigator-rated scales.
The investigator should review all scales and questionnaires in a timely manner for any potential 
reporting of adverse events and document this review accordingly. At each study visit, as 
applicable, the investigator should compare the current scores to the baseline scores.
For COVID-19 updates, refer to Appendix M.
6.1.
Primary Efficacy Measure
The primary efficacy measure is centrally read MD-CRS part II total score, which is part of the 
MD-CRS for the age group 4 to 18 years. MD-CRS part II was shown to be suitable for detecting 
a treatment effect after an intervention with trihexyphenidyl, a drug used to treat dyskinesia in 
children with CP (Battini et al 2014).
The MD-CRS was developed as a child-oriented instrument aimed to describe various types of 
movement disorders (dystonia, chorea, athetosis, ballismus, and hypokinetic-rigid) and to 
compare changes during natural history and/or pharmacological treatments or to monitor
interventions (Battini et al 2008 and Battini et al 2014). MD-CRS reliability (eg, inter- and 
intra-rater reliability) has been evaluated when used by clinicians and professionals of 
rehabilitation after a 1-day training on its scoring (Sgandurra et al 2018). The version “MD-CRS 
4-18” has been designed to evaluate various movement disorders in children and adolescents, 
aged 4 to 18 years, and their influence on daily living activities or motor function in different 
body regions at rest and during specific tasks (Battini et al 2008). 
The MD-CRS has 2 parts: part I for general assessment of the functioning and impact of CP on 
the activities of the patient and part II for a specific motor assessment of severity of the 
movement disorder. MD-CRS part II evaluates the severity of the movement disorder in a scale 
of 0 to 4 in 7 body regions, all areas in which dyskinesia can be seen in patients with CP. In 
rating the movement disorder of the body part, 0 refers to absence of a movement disorder and 
4 refers to a situation where movement disorder is present during all of the tasks for the region 
examined and/or involves 3 or more of the other regions, making completion impossible. The 
7 body regions are (i) eye and periorbital region, (ii) face, (iii) tongue and perioral region, (iv) 
neck, (v) trunk, (vi) upper limb, and (vii) lower limb. The MD-CRS part II does not differentiate 
whether the dyskinesia is of the dystonic or choreiform phenotype, and the worst dyskinesia in 
any of the regions observed during the assessment session will be taken as the score for each 
affected body region. The minimum score is 0 (absent) and the maximum score is 28 
(marked/prolonged).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
78
The MD-CRS part II will be administered by the investigational center physician, or other 
appropriately trained study team member, and video-recorded at screening, baseline, week 9, 
week 12, week 15/ET, and week 16/EOS visits.
The MD-CRS has been updated to version 2 with changes to the scoring language. This version 
should be used when available. However, a patient will complete all study visits using the same 
version.
Assessment of MD-CRS part II items will be based solely on chorea in this study and performed 
as follows: 

Local assessment (all time points): the investigational center physician will 
administer the MD-CRS part II and complete the assessment of item scores. Note: the 
physicians will receive training on MD-CRS scoring prior to the study.

EAB review (screening): EAB will review the MD-CRS part II at the screening visit 
to confirm that dyskinesia severity is aligned with the protocol criteria for inclusion 
into the study. The review will include determination of the predominant dyskinesia 
type and scoring of MD-CRS part II items. The EAB will inform the site prior to the 
baseline visit if there are any discrepancies between the local and central assessments, 
and offer to discuss with the investigator. Ultimately, it is the investigator who 
determines the patient’s eligibility. EAB assessment of screening MD-CRS part II 
total score will not be included in the statistical analysis.

Central reading (baseline, week 9, week 12, week 15/ET, and week 16/EOS): Video 
review of MD-CRS part II will be assessed periodically in a blinded manner (ie, visit, 
investigator site rating, and other study-related information) by a central review 
board. Central reading results performed by the central raters, who are also the EAB 
members, will not be disclosed to the investigational site. Central reading details will 
be provided in a separate charter.
The primary efficacy endpoint is the change from baseline to week 15 in the MD-CRS part II 
total score (TEV-50717 versus placebo), assessed by central reading.
6.2.
Key Secondary Efficacy Measures
6.2.1.
Movement Disorder-Childhood Rating Scale Part I Total Score
The MD-CRS part I evaluates impact of DCP on the activities of the patient and provides a 
general assessment of the movement disorder of motor function (7 items), oral/verbal function 
(3 items), self-care (3 items), and attention/alertness (2 items) on a scale of 0 (present) to 
4 (absent) (Battini et al 2008, Battini et al 2014). The minimum score is 0 and the maximum 
score is 60.
The MD-CRS part I will be administered at baseline, week 9, week 12, week 15/ET, and 
week 16/EOS visits. The MD-CRS part I will be administered by the investigational center 
physician and video recorded for central blinded review. The protocol refers to MD-CRS as a 
physician-rated scale, but in certain instances, based on the experience of the rater, certain 
non-physicians may be approved to rate the MD-CRS.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
79
6.2.2.
Caregiver Global Impression of Improvement Scale
The CaGI-I is single item questionnaire to assess the caregiver’s impression of improvement in 
dyskinesia symptoms after initiating therapy. The scale is a caregiver-reported outcome that aims 
to evaluate all aspects of patients’ health and determine if there has been an overall improvement 
or not in dyskinesia symptoms. The CaGI-I is to be completed before all other investigator-rated 
scales during visits where CaGI-I is collected (Table 3). The caregiver has to select the 
1 response from the response options that gives the most accurate description of change in 
dyskinesia symptoms of the patient they care for from the beginning of the study: 
1=very much improved (since the initiation of treatment);
2=much improved;
3=minimally improved;
4=no change from baseline (symptoms remain essentially unchanged);
5=minimally worse;
6=much worse;
7=very much worse (since the initiation of treatment). 
The CaGI-I is administered at week 3, week 7, week 9, week 12, week 15/ET, and week 16/EOS 
visits. 
6.2.3.
Clinical Global Impression of Improvement Scale
Each time the patient is seen during the treatment period (ie, at each in-clinic visit or during 
telephone contacts with non-recording live video), the investigator compares the patient’s 
improvement in overall dyskinesia symptoms to the 1-week period just prior to the baseline visit 
(Busner and Targum 2007). The CGI-S score obtained at the baseline visit (see Section 6.3.9) 
serves as a good basis for making this assessment. The CGI-I is a ClinRO that uses a 7-point 
Likert scale that allows the clinician to compare the patient’s condition at the visit to the baseline 
condition as follows (with anchor points for choosing the most appropriate improvement level):
1=very much improved since the initiation of treatment (nearly all better; good level of 
functioning; minimal symptoms; represents a very substantial change);
2=much improved (notably better with significant reduction of symptoms; increase in the 
level of functioning but some symptoms remain);
3=minimally improved (slightly better with little or no clinically meaningful reduction of 
symptoms; represents very little change in basic clinical status, level of care, or functional 
capacity); 
4=no change from baseline (symptoms remain essentially unchanged);
5=minimally worse (slightly worse but may not be clinically meaningful; may represent very 
little change in basic clinical status or functional capacity); 
6=much worse (clinically significant increase in symptoms and diminished functioning); 
7=very much worse since the initiation of treatment (severe exacerbation of symptoms and 
loss of functioning).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
80
The CGI-I administered at the in-clinic visits (week 3, week 7, week 9, week 12, week 15/ET, 
and week 16/EOS) will be included in the analysis of the key secondary endpoint. Patients will 
also be assessed for CGI-I during telephone contacts (with non-recording live video) at week 1, 
week 2, week 4, week 5, and week 6.
6.2.4.
Unified Huntington’s Disease Rating Scale-Total Maximal Chorea
The UHDRS-TMC is part of the UHDRS-TMS assessment and assesses the severity of chorea in 
the face, mouth, trunk, and the 4 extremities. The minimum score is 0 (absent) and the maximum 
score is 28 (marked/prolonged) (Huntington Study Group 1996).
A central reading of the UHDRS-TMC will be performed at baseline and at weeks 9, 12, 15/ET, 
and 16/EOS visits. The central rating will be done for all patients, based on the videos collected 
for the central rating of MD-CRS. Video review will be assessed periodically in a blinded 
manner (eg, visit and investigator site rating) by a central review board. Central reading results 
performed by the central raters will not be disclosed to the investigational site. Central reading 
details will be provided in a separate charter.
6.2.5.
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
The UHDRS-Total Maximal Dystonia (TMD) is part of the UHDRS-TMS assessment and 
assesses the severity of dystonia in the trunk and the 4 extremities. The minimum score 
is 0 (absent) and the maximum score is 20 (marked/prolonged) (Huntington Study Group 1996). 
When rating dystonia (question #11), buccal-oral-lingual and facial dystonia (blepharospasm, 
jaw opening and closing) should be included in the assessment of the truncal region. 
A central reading of the UHDRS-TMD will be performed at baseline and at weeks 9, 12, 15/ET, 
and 16/EOS visits. The central rating will be done for all patients, based on the videos collected 
for the central rating of MD-CRS. Video review will be assessed periodically in a blinded 
manner (eg, visit and investigator site rating) by a central review board. Central reading results 
performed by the central raters will not be disclosed to the investigational site. Central reading 
details will be provided in a separate charter.
6.3.
Other Efficacy Measures
6.3.1.
Movement Disorder-Childhood Rating Scale Part I and Part II Total Scores
The MD-CRS part I and part II total scores will be evaluated by the investigator at baseline, 
week 9, week 12, week 15/ET, and week 16/EOS visits. See Section 6.1 and Section 6.2.1 for 
description of these rating scales.  
6.3.2.
Movement Disorder-Childhood Rating Scale Global Index
The MD-CRS Global Index is a global measure of the MD-CRS that consolidates the 
information from parts I and II using the method of weighted means of the 2 normalized indexes 
obtained from each part (Battini et al 2008). The minimum score is 0 and the maximum score 
is 1.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
81
6.3.3.
Unified Huntington’s Disease Rating Scale-Total Motor Score
The UHDRS comprises a broad assessment of features associated with HD. It is a research tool 
that has been developed to provide a uniform assessment of the clinical features and course of 
HD. The Total Motor Score assessment of the UHDRS (UHDRS-TMS) comprises 15 items and 
assesses eye movements, speech, alternating hand movements, dystonia, chorea, and gait. The 
UHDRS-TMS is calculated as the sum of the 31 motor assessments; each of which range 
between 0 to 4. The minimum score is 0 (absent) and the maximum score is 124 (worst) 
(Huntington Study Group 1996).
The protocol refers to UHDRS-TMS as a physician-rated scale, but in certain instances, based on 
the experience of the rater, certain non-physicians may be approved to rate the UHDRS-TMS.
The UHDRS-TMS is administered at baseline, week 9, week 12, and week 15/ET visits, and will 
be rated by the investigator.
6.3.4.
Unified Huntington’s Disease Rating Scale-Total Maximal Chorea
The UHDRS-TMC is administered at baseline, week 9, week 12, and week 15/ET visits, and will 
be rated by the investigator.
6.3.5.
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
The UHDRS-TMD is administered at baseline, week 9, week 12, and week 15/ET visits, and will 
be rated by the investigator.
6.3.6.
Pediatric Evaluation Disability Inventory-Computer Adapted Test (Activities of 
Daily Living, Caregiver Completed, Content-Balanced Version)
The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a 
clinical assessment for children and youth. The PEDI-CAT comprises a comprehensive item 
bank of 276 functional activities acquired throughout infancy, childhood, and young adulthood. 
This study will use only the caregiver report. The PEDI-CAT is recommended for use with 
children approaching 1 year of age and adults up to 21 years of age.
The PEDI-CAT (activities of daily living [ADL], caregiver completed, content-balanced version) 
measures function in 4 domains: (1) Daily Activities; (2) Mobility; (3) Social/Cognitive, and (4) 
Responsibility. Each domain is self-contained and can be used separately or with other domains. 
This study will use only the content-balanced version of the Daily Activities domain (Dumas and 
Fragala-Pinkham 2012). The content-balanced version presents a balance of items from each of 
the Daily Activities domain’s content areas (Getting Dressed, Keeping Clean, Home Tasks, and 
Eating & Mealtime). A total of approximately 30 items are administered (total number of items 
administered is dependent upon the responses and decision tree path).
The PEDI-CAT (ADL, caregiver completed, content-balanced version) is administered at 
baseline and at week 15/ET visits. 
6.3.7.
Pediatric Quality of Life Inventory, Cerebral Palsy Module
The Pediatric Quality of Life Inventory (PedsQL™) is a health-related quality-of-life instrument 
that consists of a well-validated generic core measure and some condition and disease-specific 
modules (Varni et al 2006). The 35-item PedsQL 3.0 CP module encompasses 7 scales: (1) Daily 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
82
Activities (9 items); (2) School Activities (4 items); (3) Movement and Balance (5 items); 
(4) Pain and Hurt (4 items); (5) Fatigue (4 items); (6) Eating Activities (5 items); and (7) Speech 
and Communication (4 items).
The scales comprise parallel child self-report and parent proxy-report formats. For children ages 
6 and 7 years and 8 to 12 years, a child self-report and a parent proxy report are completed. The 
parent proxy report assesses parents’ perceptions of their child’s health-related quality of life 
(QoL). For children ages 13 to 18 years, no parent proxy report is required. The instructions ask 
how much of a problem each item has been during the past 1 month. A 5-point response scale is 
utilized across child self-report and parent proxy report as follows:
0=never a problem; 
1=almost never a problem;
2=sometimes a problem; 
3=often a problem; 
4=almost always a problem.
The PedsQL is administered at baseline and at week 15/ET visits. Input from the caregiver is 
permitted.
6.3.8.
Patient Global Impression of Improvement Scale
The Patient Global Impression of Improvement (PGI-I) is single item questionnaire to assess the 
patient’s impression of improvement in dyskinesia symptoms after initiating therapy. The scale 
is a patient-reported outcome that aims to evaluate all aspects of patients’ health and determine if 
there has been an overall improvement or not in dyskinesia symptoms. The PGI-I is to be 
completed before all other investigator-rated scales during visits where PGI-I is collected 
(Table 3). The patient has to select the 1 response from the visual response options (“emojis”) 
that gives the most accurate description of his/her state of health and overall status: 
1=much improved (since the initiation of treatment);
2=somewhat improved;
3=no change;
4=somewhat worse;
5=much worse (since the initiation of treatment). 
The PGI-I is administered at week 3, week 7, week 9, week 12, week 15/ET, and week 16/EOS 
visits. Input from the caregiver is permitted.
6.3.9.
Clinical Global Impression of Severity
The investigator uses all available information and total clinical experience with this particular 
population to assess dyskinesia severity over the past 1-week period prior to the CGI-S 
assessment on the patient (Busner and Targum 2007). The CGI-S uses a 7-point Likert scale to 
assess dyskinesia severity as follows (with anchor points for choosing the most appropriate 
severity level caused by DCP):
1=normal (not at all ill, symptoms of disorder not present past 7 days);
2=borderline (subtle or suspected pathology);


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
83
3=mild (clearly established symptoms with minimal, if any, distress or difficulty in social 
and/or occupational function);
4=moderate (overt symptoms causing noticeable, but modest, functional impairment or 
distress; symptom level may warrant medication);
5=marked (intrusive symptoms that distinctly impair social/occupational function or cause 
intrusive levels of distress);
6=severe (disruptive symptoms, behavior and function are frequently influenced by 
symptoms, may require assistance from others);
7=extreme (symptoms drastically interferes in many life functions; may be hospitalized).
The CGI-S is administered at screening, baseline, week 3, week 7, week 9, week 12, week 
15/ET, and week 16/EOS visits. Input from the caregiver is permitted. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
84
7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel and will include the evaluation 
of adverse events (and the number of patients who withdraw from the study due to adverse 
events), vital signs, laboratory tests (hematology, chemistry, and urinalysis), ECG measurements, 
CBCL, ESRS, ESS, and the children’s C-SSRS. The investigator should review all scales and 
questionnaires in a timely manner for any potential reporting of adverse events and document 
this review accordingly.
For COVID-19 updates, refer to Appendix M.
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 that 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 TEV-50717. A new condition or the worsening of a pre-existing condition 
will be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during this study will not be considered adverse events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions
(Note: A condition recorded as pre-existing that is intermittently symptomatic [eg, 
headache] and that occurs during this study should be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures or during any washout 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, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
85
(Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.)
7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the follow-up period. The follow-up period of recording 
of adverse events is defined as 2 weeks after the last dose of IMP or up to baseline/day 1 in the 
open-label extension Study TV50717-CNS-30081 (whichever comes first) or 2 weeks after the 
ET visit for patients who terminate early from the study.
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the serious adverse event form must be completed, and 
the serious adverse event must be reported immediately (Section 7.1.5.3.1). The investigator 
does not need to actively monitor patients for adverse events after the defined periods.
At each contact with the patient, the investigator or designee must question the patient and/or 
parent(s)/caregiver (as applicable) 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. 
Adverse events of patients rolling over to the open-label extension Study TV50717-CNS-30081 
will continue to be monitored as part of the open-label extension study. 
To enable the assessment of the potential relationship of an adverse event and plasma 
concentration of IMP and metabolites, blood samples will be collected based on the scenarios 
described in Table 9. 
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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
86
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as one of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of an adverse event to the IMP is characterized in Table 7 as follows:
Table 7:
The Relationship of an Adverse Event to the IMP
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:
1.
It does not follow a reasonable temporal sequence 
from the administration of the IMP.
2.
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.
3.
It does not follow a known pattern of response to the 
IMP.
4.
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:
1.
It follows a reasonable temporal sequence from 
administration of the IMP.
2.
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.
3.
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.
4.
It follows a known pattern of response to the IMP.
IMP=investigational medicinal product.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as that time 
period from signature of the ICF to the end of the follow-up period as defined in Section 7.1.2. 
Serious adverse events occurring in a patient after the end of the follow-up period should be 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
87
reported to the sponsor if the investigator becomes aware of them, following the procedures 
described in Section 7.1.5.3.1.
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

results in death

is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event that 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 ICF 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:

ALT or AST increase of >3× ULN

total bilirubin increase of >2× ULN

absence of initial findings of cholestasis (ie, no substantial increase of ALP)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
88
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 to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 
about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for adverse events once this study has ended.
Serious adverse events occurring to a patient after the 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 [CRO] in a country without a sponsor LSO) (contact information 
is in the Clinical Study Personnel Contact Information section); the LSO will forward the report 
to the sponsor’s GPSP.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility)
Additional information includes:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
89

concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data

medical and psychiatric 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 diseases.
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 form/Extensible Markup Language file to the LSO/CRO for submission to 
the competent authorities, Independent Ethics Committees (IECs)/Institutional Review Boards 
(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 an SUSAR, only the 
LSO/CRO will receive the unblinded report for regulatory submission; the others will receive a 
blinded report.
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of TEV-50717 and the appropriate competent authorities (and IEC/IRB, as 
appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-50717


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
90
7.1.6.
Protocol-Defined Adverse Events of Special Interest
No protocol-defined adverse events of special interest for expedited reporting were identified for 
this study. Events of drug-induced parkinsonism, changes in behavior, and sleepiness will be 
monitored using standardized scores and presented as part of safety analysis (see Section 7.2).
7.1.7.
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 
(Section 4.3).
7.2.
Safety Rating Scales
Site-administered safety scales include the children’s C-SSRS (Posner et al 2011), CBCL, ESRS
(Chouinard and Margolese 2005), and ESS (Janssen et al 2017). The investigator should review 
all scales and questionnaires in a timely manner for any potential reporting of adverse events and 
document this review accordingly. At each study visit, as applicable, the investigator should 
compare the current scores to the baseline scores.
7.2.1.
Children’s Columbia-Suicide Severity Rating Scale
The children’s C-SSRS Baseline/Screening scale assesses past and current suicidal ideation and 
behaviors to determine suicide risk and is administered at screening. The children’s C-SSRS 
Since Last Visit scale is administered at baseline, weeks 3, 7, 9, 12, 15/ET, and 16. The 
children’s C-SSRS questionnaire will be presented to patients ≥12 years of age at screening or 11
years of age at screening but will turn 12 years of age during the study. Children 13 years of age 
and under must be interviewed in conjunction with the caregiver as appropriate or defined by the 
scale. For children over 13 years of age, parent/legally accepted representative involvement is 
strongly encouraged. Questions should be directed to the child, but the caregiver parent/legally 
accepted representative should be encouraged to add relevant information.
The children’s C-SSRS is an interview by trained study personnel. 
The frequency and severity of suicidal ideation or behavior according to the children’s C-SSRS 
questionnaire will be presented by visit and by treatment group. A shift table for children’s 
C-SSRS categories at baseline, compared to the worst (highest) category during the treatment 
period, will be presented. 
7.2.2.
Child Behavior Checklist (for Ages 6-18)
The CBCL assesses behavioral and emotional status in children ages 6 through 18 years of age as 
reported by the caregiver (Achenbach and Ruffle 2000; Achenbach 2005). The full CBCL has 
two parts, a Competence Scale (Parts I to VII) and a Syndrome Scale (behavioral items).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
91
The Competence Scale (Parts I to VII) assesses various activities (eg, sports, hobbies, games, 
organizations, clubs, teams, groups, jobs, and chores), interpersonal relationships, and academic 
performance. 
The Syndrome Scale comprises 113 questions related to problem behaviors. This study will use a 
recall period of “now or within the last week,” representing a modification from the original 
scale, which was “now or within the last 6 months”. For each item, the caregiver will circle 0 if 
the item is not true of their child, 1 if the item is somewhat or sometimes true, and 2 if the item is 
very true or often true. 
The CBCL is part of the Achenbach System of Empirically Based Assessment that identifies 
syndromes that are behavioral clusters that indicate certain types of behavioral, social, or 
emotional problems (Achenbach and Rescorla 2004). The problem behaviors are scored on the 
following 8 empirically based syndromes: anxious/depressed, withdrawn/depressed, somatic 
complaints, social problems, thought problems, attention problems, rule-breaking behavior, and 
aggressive behavior. 
The Competence and Syndrome Scales are displayed on profiles in relation to gender and age-
specific percentiles and T scores based on national normative samples. 
The full CBCL assessment (Competence and Syndrome Scales) will be completed at screening 
and at week 15/ET. Only the CBCL Syndrome scale will be completed at baseline, weeks 3, 7, 9, 
12, and 16/EOS.
7.2.3.
Extrapyramidal Symptom Rating Scale
The ESRS was designed to assess 4 types of drug-induced movement disorders: parkinsonism, 
akathisia, dystonia, and TD (Chouinard and Margolese 2005). In this study, parkinsonism and 
akathisia will be evaluated with subscales I (subjective questionnaire) and II (evaluation for 
parkinsonism/akathisia). The ESRS is administered at screening; baseline; and weeks 3, 7, 9, 12, 
15/ET, and 16/EOS.
The subscale I of the ESRS questionnaire rates subjective parkinsonism/akathisia at periods other 
than the day of examinations during the last 7 days. It is scored on a 4-point scale (0=Absent, 
1=Mild, 2=Moderate, or 3=Severe). The evaluation takes into account the verbal report of the 
patient on: 1) the frequency and duration of the symptom during the day, 2) the number of days 
the symptom was present during the last week, and 3) the subjective evaluation of the intensity 
of the symptom by the patient. 
The subscale II of the ESRS questionnaire for evaluation of parkinsonism and akathisia includes 
17 items with scores ranging from 0-102 to assess the following: tremor (0–48), gait and posture 
(0–6), postural stability (0-6), rigidity (0–24), expressive automatic movements (0–6), 
bradykinesia (0-6), and akathisia (0–6).
7.2.4.
Epworth Sleepiness Scale (for Children and Adolescents)
The ESS is a self-administered questionnaire composed of 8 questions that provide a measure of 
a patient’s general level of daytime sleepiness (Johns 1991). Johns (2015) proposed the ESS as 
the official modified version of the ESS for children and adolescents. In 2017, Janssen et al
published results of their validation analysis and concluded that the ESS developed for children 
and adolescents is a reliable and internally valid measure of daytime sleepiness in adolescents 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
92
12 to 18 years of age, but further studies are needed to establish the internal validity of the 
questionnaire for children under 12 years and the external validity and accuracy of cut-off points 
for children and adolescents. 
For patients 6 to 12 years of age, the ESS will be completed by the caregiver. For patients 
≥13 years of age, the ESS will be completed by the patient. Input from the caregiver is permitted.
The ESS is administered at screening; baseline; and weeks 3, 7, 9, 12, 15/ET, and 16/EOS. The 
ESS asks respondents to rate, on a 4-point Likert scale (0–3), their usual chances of dozing off or 
falling asleep in different situations or activities that most people engage in as part of their daily 
lives. The total ESS score is the sum of 8 item scores and can range between 0 and 24 with the
higher the score indicating a higher level of daytime sleepiness. Most people can complete the 
ESS without assistance in 2 or 3 minutes.
Categories

0=would never fall asleep

1=slight chance of falling asleep

2=moderate chance of falling asleep

3=high chance of falling asleep
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 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 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 
(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.
Note: Female partners’ pregnancies of male participants are not required to be proactively 
monitored.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
93
If the pregnancy in the female patient participating in the study does not continue to term, one of 
the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event and also complete the 
pregnancy form.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event and also complete the pregnancy form.

For an elective abortion not due to developmental anomalies, complete the pregnancy 
form; do not report as an adverse event.
7.4.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study protocol should be reported 
in the CRF and in the patient’s source documents as a deviation if the event meets the deviation 
criteria specified in the protocol (Appendix D), regardless of whether or not an adverse event 
occurs as a result.
The following are types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively, which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, or placebo IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP, which is accompanied by 
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
7. Breastfeeding: Suspected adverse reactions that occur in infants following exposure to a 
medicinal product from breast 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


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
94

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event and monitored as described 
in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that results in the withdrawal of the patient from the study, the 
temporary or permanent withdrawal of IMP or medical treatment, or further diagnostic work-up. 
(Note: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient 
from entering the study or receiving IMP are not considered adverse events.)
Table 8:
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Creatinine
Glucose
Magnesium
Blood urea nitrogen
Total cholesterol
Triglycerides
Uric acid
Alanine aminotransferase
Aspartate aminotransferase
Lactate dehydrogenase
Alkaline phosphatase
Bicarbonate or carbon dioxide
Protein
Albumin
Bilirubin
Direct bilirubin
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leucocytes
Neutrophils
Lymphocytes
Eosinophils
Monocytes
Basophils
Lymphocytes atypical
Prothrombin International Normalized 
Ratio
Protein
Glucose
Ketones
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
Casts
7.5.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology and coagulation, and urinalysis) will be 
performed at screening, week 15, and week 16, as detailed in Table 3. Clinical laboratory tests 
will be performed using the central laboratory. Specific laboratory tests to be performed are 
provided in Table 8. Laboratory tests performed at screening may be repeated to determine 
patient eligibility.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
95
7.5.2.
Other Clinical Laboratory Tests
7.5.2.1.
Beta-Human Chorionic Gonadotropin Tests
β-HCG tests in urine will be performed for all female patients aged 12 years or older of 
childbearing potential at baseline and other in-clinic visits as detailed in Table 3. The β-HCG 
tests in serum will be performed for all female patients aged 12 years or older of childbearing 
potential at screening and week 15 and if clinically indicated.
For COVID-19 updates, refer to Appendix M.
7.5.2.2.
Urine Drug Screen
A urine drug screen will be performed at the time points specified in Table 3. A urine drug 
screen performed at screening may be repeated to determine patient eligibility.
The urine drug screen detects the presence of drugs of abuse. Additionally, the urine drug screen 
will detect the presence of drugs prohibited according to the laboratory manual. If a given 
parameter cannot be tested using urine, or if the investigator considers that additional testing is 
needed, an alternative matrix (eg, serum) may be considered acceptable. Such tests may be 
performed locally. 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 drugs of abuse or their metabolites or drugs prohibited according to the 
laboratory manual, without medical explanation, will preclude the patient from 
randomization/enrollment or continued participation in the study. Some of the drugs listed in this 
urine drug screen may be permitted in certain cases when the particular medication is being used 
under a physician’s or clinician’s guidance and in compliance with the physician’s or clinician’s 
recommendation for a specific condition (for example, phenobarbital [barbiturates] for seizures, 
stimulant medications [including amphetamine, methylphenidate, and lisdexamfetamine] for 
attention deficit hyperactivity disorder, and opiates or oxycodone for pain) and 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. Such cases should be discussed with the medical 
monitor. Patients who either are using these medications or have a positive drug screen for these 
substances or derivatives should be submitted to the medical monitor for consideration of 
participation in this study. Patients with a substance use disorder are excluded from this clinical 
trial. However, if per the investigator’s judgment, a patient does not meet the criteria for 
substance use disorder, a positive drug screen result for these medications or derivatives, without 
medical explanation, should be discussed on a case-by-case basis with the medical monitor to 
determine the patient’s eligibility, based on the information available.
For COVID-19 updates, refer to Appendix M.
7.6.
Physical Examination
Physical examinations, including height and weight, general appearance, skin, head, eyes, ears, 
nose, throat, neck, lymph nodes, cardiovascular, respiratory, musculoskeletal, abdominal, and 
extremities will be performed at the time points detailed in Table 3. 
Weight must be measured with shoes and outerwear off.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
96
Any new physical examination finding (ie, since the screening visit) that is judged by the 
investigator as clinically significant will be considered an adverse event, recorded on the CRF, 
and monitored as described in Section 7.1.2. 
Investigators should pay special attention to clinical signs related to previous serious diseases.
7.7.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at the time points detailed in Table 3. All abnormal vital signs will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
Before blood pressure and pulse are measured, the patient must rest in a supine or 
semi-erect/seated position for at least 3 minutes. (The same position and arm or leg should be 
used each time vital signs are measured for a given patient.) Orthostatic blood pressure and pulse 
will be measured after the patient is in a standing position for at least 3 minutes (for patients who 
are able to stand). For patients who find standing difficult or do not allow for a reliable blood 
pressure and pulse measurement, alternative methods to collect orthostatic blood pressure and 
pulse should be discussed with the medical monitor. For any abnormal vital sign value, the 
measurement should be repeated as soon as possible. Any vital sign value that is judged by the 
investigator as clinically significant will be recorded both on the source documentation and the 
CRF as an adverse event and monitored as described in Section 7.1.2.
7.8.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 3. All ECGs will be 
performed after at least 5 minutes rest in a supine or semi-supine position. 
The ECG types are defined as follows:

A “standard ECG” is a “standard” 10-second 12-lead ECG.

A “summary ECG” is a continuously recorded ECG of longer than 30 seconds. For a 
“summary ECG,” the minimal recommended duration is 2 minutes or longer, and the 
preferred duration is 5 minutes (as it provides the most robust result). If a “summary 
ECG” is less than 2 minutes, data will still be captured and analyzed to the extent 
possible.
The investigator should review the ECG at screening to determine patient eligibility 
for the study and subsequent ECGs for the patient’s continuation in the study. All 
ECGs should be reviewed by the investigator for any clinically significant findings 
during the visit and before the patient leaves the clinic. A qualified physician at a 
central diagnostic center will be interpreting the ECG.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
97
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.
The criteria for an abnormal post-baseline QTcF are a value >500 msec or change from 
screening >60 msec. If one of these criteria is met, the investigator must further evaluate the 
QTcF as follows: 

If a standard ECG is abnormal and meets the above protocol criteria, 
o
A 5-minute summary ECG recording should be performed at the research site,
and a repeat standard ECG is not required. The site should follow the process to 
have these ECGs read by Spaulding. 
o
If a 5-minute summary ECG cannot be performed (for instance, if patient is 
evaluated at a facility other than the research site, and the summary ECG is not 
available), the investigator should obtain 2 repeat standard ECGs and determine 
the average of these 3 post-screening QTcF values. The site should follow the 
process to have these ECGs read by Spaulding.  

The investigator should then compare the post-screening QTcF values to the 
pre-treatment QTcF values at screening. As noted above, the post-screening QTcF 
values will use either the average QTcF from the 3 post-screening standard ECGs or 
the QTcF from the summary ECG. The IMP must be stopped for any confirmed 
post-baseline QTcF average value >500 msec or average increase from screening 
>60 msec.
Note: Abnormal ECG results at week 3 and week 7 or at an unscheduled visit may result in 
patient withdrawal from the study as detailed in Section 4.3.
7.9.
Assessment of Suicidality
TEV-50717 is considered to be central nervous system-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 central nervous system-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 with TEV-50717 should be monitored appropriately 
and observed closely for suicidal ideation and behavior or any other unusual changes in 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
98
behavior. Consideration should be given to discontinuing TEV-50717 in patients who experience 
signs of suicidal ideation or behavior.
Families and caregivers of patients being treated with TEV-50717 should be instructed to 
monitor patients 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 children’s C-SSRS described in 
Section 7.2.
Patients with a positive children’s C-SSRS suicidal ideation score on either items 1 or 2 must be 
1) discussed with the study 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/adolescent psychiatrist or licensed child/adolescent mental health provider is advised, 
followed by close ongoing monitoring.
If patients endorse or report a children’s C-SSRS suicidal ideation score of 3, 4, or 5, the patients 
will be evaluated immediately by the investigator and referred for psychiatric evaluation. The 
medical monitor will be immediately consulted. If it is determined by the investigator, the 
medical monitor, and consulting psychiatrist that exposure to the IMP may have contributed to a 
change in children’s C-SSRS and/or increased depressive symptoms, study medication will be 
immediately discontinued and the patient will be terminated from the study. In cases where it is 
determined that IMP did not contribute to changes in depression or suicidality, the investigator 
will consult with the medical monitor, consulting psychiatrist, and/or sponsor to determine 
whether the patient should continue in the study.
If patients report any suicidal behavior that is an actual attempt as assessed in the children’s
C-SSRS, they will be evaluated immediately by the investigator, referred for psychiatric 
evaluation, and terminated from the study.
If patients report any suicidal behavior that is interrupted, aborted, or preparatory as assessed in 
the children’s C-SSRS, they will be evaluated immediately by the 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, consulting psychiatrist, and/or sponsor to determine whether the patient should continue 
in the study.
7.10.
Assessment of Depression
Families and caregivers of patients are instructed to monitor the patients for any changes in or 
new onset of depressive symptoms and unusual changes in mood, cognition, or behavior, and to 
report such symptoms immediately to the investigator. Telephone contacts (with non-recording 
live video) and clinic visits also allow opportunities for the investigator to assess adverse events.
If a relevant change in status is identified, patients will be seen immediately for an unscheduled 
visit by the investigator and discussed with the medical monitor. The patient will be referred for 
further psychiatric evaluation if there is any suspicion of experiencing depression. The 
investigator will record these symptoms as an adverse event of depression. If it is determined by 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
99
the investigator, after consultation with the medical monitor and consulting psychiatrist, that 
exposure to the IMP may have contributed to the adverse event of depression, study medication 
will be immediately discontinued and the patient will be terminated from the study. Follow-up 
with a pediatric psychiatrist or licensed child/adolescent mental health provider will be arranged.
In cases where it is determined that IMP did not contribute to the adverse event of depression, 
the investigator will consult with the medical monitor and/or sponsor to determine whether the 
patient should continue in the study.
7.11.
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 3. Any neurological examination finding that is judged by the 
investigator as a potentially clinically significant change (worsening) compared with the baseline 
value will be considered an adverse event, recorded on the CRF, and monitored as described in 
Section 7.1.2.
7.12.
Concomitant Medication or Treatment
Concomitant therapy or medication usage will be monitored throughout the study according to 
time points detailed in Table 3. Parents/patients will be instructed during the course of the study 
to notify the investigator if any new medication is prescribed/administered (other than 
TEV-50717) or if there is any change in current medications, including over-the-counter 
medications. Any new prescribed/administered medication and/or any change in current 
prescribed/administered medication should be reviewed with the investigator. 
Patients may be included in this study if they are using cannabis or formulations or derivatives of 
cannabis in relatively stable amounts, for medical purposes (where applicable according to local 
regulation), under the guidance, supervision, or prescription of a clinician and anticipated to 
remain stable (dose and frequency) within the study duration. Patients who are either using 
cannabis or its derivatives or formulations or patients who have a positive drug screen for 
cannabis or its derivatives or formulations can be submitted to the medical monitor for 
consideration of participation in this study. Patients with a substance use disorder are excluded 
from this clinical trial. If per the investigator’s judgment, however, a patient does not meet the 
criteria for substance use disorder, a positive drug screen for cannabis or its metabolites, without 
medical explanation, will be discussed on a case-by-case basis between the research site, the 
Medical Monitor, and the sponsor to determine the patient’s eligibility, based on the information 
available. Patients should be advised that the recreational use of cannabis or its derivatives or 
formulations should be avoided during this study. 
Medications that are allowed, provided that conditions outlined in the table are met, are shown in 
Appendix H, Table 10. Certain considerations mentioned in the table require the review of the 
medical monitor. Changes to the allowed medications may be permitted in the context of this 
study and should be discussed with the medical monitor. If the wellbeing of the patient and the 
urgency of the clinical decision do not allow discussion with the medical monitor prior to the 
medication change, the investigator should notify the medical monitor in a timely manner 
following this decision.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
100
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 QT prolongation or that is a known strong 
CYP2D6 inhibitor. Prohibited medications that are associated with QT prolongation are listed in 
Appendix H, Table 11.
7.13.
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data
All adverse events will be reviewed on a periodic basis by the clinical project physician/medical 
monitor according to the safety monitoring plan (eg, scheduled safety reviews for TEV-50717) 
as preliminary safety databases become available. In addition, the iDMC will perform the 
unblinded IA and take part in safety monitoring throughout the study.
Methods and time points of assessing safety data are discussed in Section 3.4. Procedures for 
recording safety data are discussed in Appendix K, and methods of analyses are discussed in
Section 9.8.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
101
8.
ASSESSMENT OF PHARMACOKINETICS/
PHARMACODYNAMICS AND PHARMACOGENETICS
8.1.
Pharmacokinetic Assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 9:
Blood Sampling Scenarios
Scenario
Action
 
 
 
 
 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
102
8.2.
Assessment of Exploratory Biomarkers
8.3.
Pharmacogenetics
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics
At the screening visit, a mandatory blood sample (3.0 to 5.0 mL) will be obtained for analysis of 
CYP2D6 genotype from all patients in the study at the time point detailed in Table 3. The 
CYP2D6 genotype results will be provided to the RTSM, which drives each patient’s dose 
regimen, and the patient’s genotype for CYP2D6 will remain blinded during the conduct of the 
study. 
 
 
 
 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
103
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 (SAP). After finalization of the SAP, any additional analyses or changes to 
analyses that may be required will be fully disclosed in the CSR.
For COVID-19 updates, refer to Appendix M.
9.1.
Sample Size and Power Considerations
The initial sample size estimation of approximately 185 patients randomized to TEV-50717 
versus placebo in a 2:1 ratio (approximately 124 in the TEV-50717 group; approximately 61 in 
the placebo group) is the sample size required to obtain a statistically significant result in the 
primary analysis based on a 1-sided test for mean difference at a significance level of α=0.025 
with a power of approximately 90%, assuming a mean difference of 1.8 and a standard deviation 
(SD) of 3.5 in each treatment group. 
At the time of writing Amendment 05, the initially planned sample size has been reduced to 
approximately 65 patients randomized to TEV-50717 versus placebo in a 2:1 ratio 
(approximately 43 in the TEV-50717 group; approximately 22 in the placebo group).
The initial assumptions regarding the mean difference and SD are based on the change from 
baseline to month 6 in patients treated with trihexyphenidyl reported by Battini et al (2014), 
assuming an effect size of 55% for TEV-50717 versus placebo. The effect size of 55% was 
assumed based on the observed effect sizes of TEV-50717 in the pivotal studies in HD and TD. 
In the current study, these assumptions correspond to a mean difference of 2.0 in MD-CRS 
part II total score and an SD of 3.5 in each treatment group.
The rate of missing not at random (MNAR) data for the primary analysis is expected to be 10%. 
MNAR data will be imputed in a conservative manner as if they were obtained from patients in 
the placebo treatment group, regardless of the actual treatment group. As a result, the mean 
difference is expected to be reduced from 2.0 to 1.8 in the primary analysis. The impact of the 
missing data imputation on the SD is negligible.
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 the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
For patients who discontinue the study and re-enter it (repeating the study from baseline), only 
the data from the repeated participation will be included in the ITT analysis set.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
104
9.2.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including all 
randomized patients with at least 1 post-baseline centrally read MD-CRS part II assessment.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.
9.2.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
Rules for assignment of treatment in case of mixed actual treatments will be provided in the 
SAP.
Rules for handling safety data for patients who discontinue the study and re-enter it will be 
provided in the SAP.
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
who meet the following criteria:

compliant with study medication (80% to 105%)

complete the study without any major protocol deviations that may impact efficacy 

centrally read baseline MD-CRS part II total score of ≥10
Rules for excluding patients from the PP analysis set will be provided in the SAP. Evaluation of 
exclusion from the PP analysis set will be discussed on a case-by-case basis and documented 
prior to database lock and unblinding of the study for final analysis.
9.3.
Data Handling Conventions
9.3.1.
Handling Withdrawals and Missing Data
For this study design and population, it is unlikely that patients who withdraw from IMP will be 
willing to attend the remaining scheduled study visits and, in particular, the week 15 visit. 
Therefore, patients will not be required to return to the clinic at week 15 for efficacy evaluations, 
and the primary analysis will be based on a multiple imputation method for missing data.
For efficacy analysis, missing data will be classified as missing at random (MAR) and MNAR. 
The following cases will be considered as MNAR: 

early terminations related to tolerability

treatment-related adverse events

early terminations related to lack of efficacy 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
105
The following cases will be considered as MAR:

intermittent missing data

early termination for patients who are lost to follow-up 

early terminations due to COVID-19
For all other cases, and for cases classified as above, classification as MAR/MNAR will be 
done/revisited in a blinded manner on a case-by-case basis prior to the IA for futility and prior to 
database lock for final analysis.
Multiple imputation methods will be used in the primary and secondary efficacy analyses. See 
Section 9.5 for details.
9.4.
Study Population
The ITT analysis set (Section 9.2) will be used for all study population summaries, unless 
otherwise specified. 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; patients re-randomized; 
patients in the ITT, mITT, safety, and PP analysis sets; patients who complete the treatment 
period; patients who complete the EOS visit; 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 and psychiatric history, prior 
medications and therapies, 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 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 Estimand
The primary estimand is the difference in means between TEV-50717 and placebo in the target 
patient population for the change from baseline to week 15 in centrally read MD-CRS part II 
total score, regardless of whether or not dose reduction, suspension, or discontinuation occurred, 
and regardless of treatment-related adverse events. 
The primary estimand assesses the effectiveness in the reduction of choreiform movements in 
patients with DCP with predominant choreiform movement disorder, evaluated by the central 
reviewers, focusing on the causal effects attributable to the IMP.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
106
The target patient population for this study is patients with DCP with predominant choreiform 
movement disorder and severity of DCP represented by the following:
a.
total score of ≥10 in centrally read MD-CRS part II items at baseline, and 
b. CGI-S ≥4 at baseline.
This population is expected to have the sensitivity to demonstrate clinically meaningful 
improvement following treatment with TEV-50717.
Due to practical reasons, it is not possible to obtain a central reading of MD-CRS part II items at 
the time of the baseline visit prior to randomization; therefore, inclusion of the subject to the 
study is based on investigator scoring of MD-CRS part II items at baseline (Section 9.2.2).
9.5.2.
Primary Endpoint
The primary efficacy endpoint is the change from baseline to week 15 in the MD-CRS part II 
total score (movement disorder severity, centrally read) (TEV-50717 versus placebo).
9.5.2.1.
Primary Efficacy Analysis
The primary analysis will be a mixed-model, repeated-measures with the change in MD-CRS 
part II total score as the dependent variable. The model will include fixed effects for treatment 
group, week (3 levels: weeks 9, 12, and 15), and treatment group by week interaction. The 
baseline MD-CRS part II total score, age group at baseline (2 levels: 6 to <12 years; 12 through 
18 years, inclusive), and region (US; non-US) will be included as covariates. The unstructured 
covariance model will be used.
Missing data will be classified as MAR and MNAR, as described in Section 9.3.1. The 
MAR/MNAR multiple imputation method will be applied in the primary analysis, where MNAR 
data will be imputed using the jump-to-reference method, and MAR data will be imputed based 
on the randomized treatment group. The resulting complete, imputed datasets will each be 
analyzed using the analysis model described above, and the resulting statistics combined using 
methodology presented by Rubin (1987) and Little and Rubin (2002).
The difference in least squares (LS) mean of the change in MD-CRS part II total score from 
baseline to week 15 (TEV-50717 versus placebo) will be compared using a 1-sided test for 
superiority at a nominal significance level of α=0.025. 
The LS mean and standard error for the treatment groups, the LS mean difference, 2-sided 95% 
confidence interval, and p-value for the comparison (TEV-50717 versus placebo) at week 15 will 
be presented.
9.5.2.2.
Sensitivity Analysis
To assess the robustness of the primary efficacy analysis, sensitivity analyses will include the 
following:
Sensitivity analyses for assumptions of missing data mechanism:

tipping point (MNAR)

MAR multiple imputation 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
107
Sensitivity analysis for the statistical model:

analysis of covariance (ANCOVA)

primary model, including only the following covariates: treatment group, week, and 
treatment group by week interaction
Other:

primary model repeated for the ITT analysis set

primary model repeated for the set of patients in the mITT analysis set that received 
at least 1 dose of IMP 

primary model repeated for the PP analysis set

ANCOVA models for MD-CRS part II total score change from baseline to week 9 
and to week 12
9.5.2.3.
Minimal Clinically Important Difference and Minimal Clinically Important 
Change
To support the evaluation of the clinical impact of the change in dyskinesia as assessed by the 
primary endpoint, the minimal clinically important difference (MCID) and the minimal clinically 
important change (MCIC) will be calculated. The MCID and MCIC analyses will be performed 
based on 3 global impression of improvement anchors: caregiver (CaGI-I), investigator (CGI-I), 
and patient (PGI-I). 
The MCID and MCIC analysis will be performed separately for each anchor (CaGI-I, CGI-I, and 
PGI-I) yielding a set of thresholds, each reflecting the perspective of the caregiver, the clinician, 
or the patient, depending on the anchor used.
The MCID and MCIC analyses will be based on the methods described by Hauser et al 2014 and 
Hauser et al 2022. Details will be provided in the statistical analysis plan.
9.5.3.
Secondary Estimands
The secondary estimands are the differences in means between TEV-50717 and placebo in the 
target patient population for (1) change from baseline to week 15 in centrally read MD-CRS 
part I total score, (2) CaGI-I at week 15, (3) CGI-I at week 15, (4) change from baseline to 
week 15 in centrally read UHDRS-TMC, (5) change from baseline to week 15 in centrally read 
UHDRS-TMD, regardless of whether or not dose reduction, suspension, or discontinuation 
occurred, and regardless of treatment-related adverse events.
The secondary estimands assess the effectiveness on patients’ ability to perform daily functions, 
the improvement in dyskinesia evaluated by the caregiver and the investigator, and the reduction 
in chorea and dystonia evaluated by the central reviewers, all with a focus on the causal effects 
attributable to the IMP.  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
108
9.5.4.
Key Secondary Endpoints
The key secondary endpoints are the following:
1. Change from baseline to week 15 in centrally read MD-CRS part I total score 
(TEV-50717 versus placebo) 
2. CaGI-I at week 15 (TEV-50717 versus placebo)
3. CGI-I at week 15 (TEV-50717 versus placebo)
4. Change from baseline to week 15 in centrally read UHDRS-TMC (TEV-50717 versus 
placebo)
5. Change from baseline to week 15 in centrally read UHDRS-TMD (TEV-50717 versus 
placebo)
9.5.4.1.
Secondary Efficacy Analysis
Analyses of the key secondary endpoints will be performed as follows: 
1. MD-CRS part I total score change from baseline to week 15 will be analyzed using a 
mixed-effects model repeat measurement (MMRM) in the same fashion as the primary 
analysis, with the exception that the baseline value of MD-CRS part I total score will be 
included as the covariate instead of MD-CRS part II total score.
2. CaGI-I at week 15 will be analyzed using an MMRM model in the same fashion as the 
primary analysis, with the exceptions that the baseline value of CGI-S will be included as 
the covariate instead of MD-CRS part II total score and that week will include 5 levels 
(weeks 3, 7, 9, 12, and 15).
3. CGI-I at week 15 will be analyzed using an MMRM model in the same fashion as the 
primary analysis, with the exceptions that the baseline value of CGI-S will be included as 
the covariate instead of MD-CRS part II total score and that week will include 5 levels 
(weeks 3, 7, 9, 12, and 15). 
4. UHDRS-TMC (centrally read) change from baseline to week 15 will be analyzed using 
an MMRM model in the same fashion as the primary analysis, with the exception that the 
baseline value of UHDRS-TMC (centrally read) will be included as the covariate instead 
of MD-CRS part II total score.
5. UHDRS-TMD (centrally read) change from baseline to week 15 will be analyzed using 
an MMRM model in the same fashion as the primary analysis, with the exception that the 
baseline value of UHDRS-TMD (centrally read) will be included as the covariate instead 
of MD-CRS part II total score.
In addition, sensitivity analyses for the key secondary endpoints will be performed in the same 
fashion as the primary endpoint.
9.5.5.
Other Efficacy Endpoints
Other efficacy endpoints (change from baseline to week 15/proportion at week 15; TEV-50717 
versus placebo) are the following:

MD-CRS part I total score (general assessment, physician rated)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
109

MD-CRS part II total score (general assessment, physician rated)

MD-CRS Global Index (calculated from MD-CRS parts I and II total scores)

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

PEDI-CAT (ADL, caregiver completed, content-balanced version)

The CP module of the PedsQL (QoL, patient/caregiver)

PGI-I Scale (global, patient/caregiver)

CGI-S Scale (global, physician rated)

CaGI-I response, defined as patients who are described by the caregiver as “Much 
Improved” or “Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are described as “Much Improved” or “Very 
Much Improved” in the CGI-I score

CGI-S response, defined as patients who have a reduction of ≥1 point in the CGI-S 
score

PGI-I response, defined as patients who are described as “Much Improved” or 
“Somewhat Improved” in the PGI-I score
9.5.5.1.
Other Efficacy Analysis
Analysis methods will be provided in the SAP.
9.6.
Multiple Comparisons and Multiplicity
The primary efficacy endpoint will be tested at the 1-sided significance level of α=0.025. 
If the primary endpoint is statistically significant (p-value ≤0.025), the 5 key secondary 
hypotheses will be tested using a hierarchical approach at the 1-sided significance level of 
α=0.025, in the following order: (1) MD-CRS part I total score, (2) CaGI-I, (3) CGI-I, 
(4) UHDRS-TMC (centrally read), and (5) UHDRS-TMD (centrally read). 
 
 
 
 
No multiplicity control will be applied to the sensitivity analysis or other endpoints.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
110
9.7.
Planned Interim Analysis
This is the first study to evaluate the efficacy of TEV-50717 to reduce the severity of dyskinetic 
involuntary movements associated with CP in pediatric patients with DCP. Moreover, limited 
data are available on the effect of active treatment on MD-CRS part II total score in DCP that 
can support sample size calculations. Therefore, an IA for futility is planned.
When approximately 50 patients have completed the study (including follow-up), an iDMC will 
perform an unblinded non-binding IA for futility based on centrally read MD-CRS part II total 
score. 
The rules for futility recommendation (eg, definition of the promising zone) will be included in 
the iDMC charter and the SAP. The iDMC charter will also provide the wording that will be 
used to communicate the iDMC recommendation. The SAP will be finalized before the IA will 
be performed.
9.8.
Safety Endpoints and Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.3).
Safety assessments and time points are provided in Table 3.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to test IMP (ie, reasonable possibility; 
see Section 7.1.4) (defined as related or with missing relationship) (overall and by severity), 
serious adverse events, and adverse events causing withdrawal from the study. 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.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. ECG and vital signs values will be compared with predefined criteria to identify 
potentially clinically significant values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
The frequency and severity of suicidal ideation or behavior according to the children’s C-SSRS 
questionnaire will be presented by visit and by treatment group. A shift table for children’s C-
SSRS categories at baseline, compared to the worst (highest) category during the treatment 
period, will be presented.
Assessment of drug-induced parkinsonism according to the ESRS (subscales I and II), 
assessment of change in behavior according to the CBCL questionnaire, and assessment of 
sedation according to the ESS questionnaire will be summarized descriptively.
For continuous variables, descriptive statistics will be provided for actual values and changes 
from baseline to each time point. For categorical variables, patient counts and percentages will 
be provided. Descriptive summaries of serious adverse events, patient withdrawals due to 
adverse events, and potentially clinically significant abnormal values (clinical laboratory or vital 
signs) based on predefined criteria will be provided as well.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
111
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
9.9.
Tolerability Analysis
If more than 15% of the patients withdraw from the study before the end of the treatment period, 
the number of days until study discontinuation will be analyzed using Kaplan-Meier 
methodology using the ITT analysis set.
9.10.
Pharmacokinetic/Pharmacodynamic Analysis
 
 
 
 
 
9.11.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the SAP, the CSR, or any combination of these, as appropriate, and in 
accordance with applicable national, local, and regional requirements and regulations.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
112
10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix D for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
Refer to Appendix J for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.
For COVID-19 updates, refer to Appendix M.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
113
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the International Council for Harmonisation 
Harmonised Tripartite Guideline, Guideline for 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 trials on medicinal products for 
human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of the investigator to conduct and administer this clinical 
study in accordance with the protocol will be documented in separate clinical study agreements 
with the sponsor and other forms as required by national competent authorities in the country 
where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMPs as described in the IB or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities.
See Appendix E for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
114
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix K for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
115
13.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered.
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are, for example, damages to health and worsening of 
previous existing diseases 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 21CFR Part 54), the investigator will provide the sponsor with 
financial information required to complete the Food and Drug Administration 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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
116
14.
PUBLICATION POLICY
See Appendix L for information regarding the publication policy.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
117
15.
REFERENCES 
Achenbach TM, Ruffle TM. The Child Behavior Checklist and related forms for assessing 
behavioral/emotional problems and competencies. Pediatr Rev 2000;21(8):265-71.
Achenbach TM, Rescorla Leslie. Practical Applications of the Achenbach System of Empirically 
Based Assessment (ASEBA) for Ages 1.5 to 90+ Years. 2004:64-7. 
http://research.acer.edu.au/research_conferenceITU_2004/2
Achenbach TM. Advancing assessment of children and adolescents: commentary on evidence-
based assessment of child and adolescent disorders. J Clin Child Adolesc Psychol 
2005;34:541-7.
AUSTEDO® (deutetrabenazine) tablets (US prescribing information). Teva Pharmaceuticals 
USA, Inc; 2021. Available at: https://austedo.com/hd/pi.
Battini R, Casarano M, Sgandurra G, Olivieri I, Di Pietro R, Romeo DM, et al. Responsiveness 
of the MD-Childhood Rating Scale in dyskinetic cerebral palsy patients undergoing 
anticholinergic treatment. Eur J Paediatr Neurol 2014;18(6):698-703.
Battini R, Sgandurra G, Petacchi E, Guzzetta A, Di Pietro R, Giannini MT, et al. Movement 
Disorder-Childhood Rating Scale: reliability and validity. Pediatr Neurol 2008;39(4):259-65.
Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in 
Clinical Practice. Psychiatry (Edgmont) 2007;4(7):28-37.
Cans, C. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and 
registers. Developmental Medicine & Child Neurology 2000;42:816-24.
Center for Disease Control and Prevention (CDC). Data & Statistics for Cerebral Palsy. 
Available at: https://www.cdc.gov/ncbddd/cp/data.html
Center for Disease Control and Prevention (CDC). Causes and Risk Factors of Cerebral Palsy. 
Available at: https://www.cdc.gov/ncbddd/cp/causes.html
Cerebral Palsy Life Expectancy. Available at: https://www.birthinjuryguide.org/cerebral-
palsy/life-expectancy/. Accessed 22 May 2018.
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophrenia Research 2005;76:247-65.
Dumas HM, Fragala-Pinkham MA. Concurrent Validity and Reliability of the Pediatric 
Evaluation of Disability Inventory-Computer Adaptive Test Mobility Domain. Pediatric Physical
Therapy 2012;24:171-76.
Fuenmayor LD, Vogt M. The influence of cerebral 5-hydroxytryptamine on catalepsy induced by 
brain-amine depleting neuroleptics or by cholinomimetics. B J Pharmacol 1979;67(2):309-18.
Hauser RA, Barkay H, Wilhelm A, Wieman M, Savola J-M, Gordon MF. Minimal clinically 
important change in abnormal involuntary movement scale score in tardive dyskinesia as 
assessed in pivotal trials of deutetrabenazine. Parkinsonism Relat Disord.  2022;97:47-51.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
118
Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, et al. Minimal clinically 
important difference in Parkinson’s disease as assessed in pivotal trials of pramipexole extended 
release. Parkinsons Dis. 2014;2014:467131.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Huntington Study Group. Mov Disord 1996;11(2):136-42.
Jain S, Greene PE, Frucht SJ. Tetrabenazine therapy of pediatric hyperkinetic movement 
disorders. Mov Disord 2006;21(11):1966-72.
Janssen KC, Phillipson S, O’Connor J, Johns MW. Validation of the Epworth Sleepiness Scale 
for children and adolescents using Rasch analysis. Sleep Med 2017;33:30-5.
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. 
Sleep 1991;14(5):540-5.
Johns MW. The assessment of sleepiness in children and adolescents. Sleep Biol Rhythm 
2015;13(Suppl. 1): 97.
Kaur N, Kumar P, Jamwal S, Deshmukh R, Gauttam V. Tetrabenazine: Spotlight on Drug 
Review. Annals of Neurosciences 2016;23(3):176-85.
Little RJA, Rubin DB. Statistical Analysis with Missing Data, Second Edition. 2002, New York: 
John Wiley & Sons.
Maenner MJ, Blumberg SJ, Kogan MD, Christensen D, Yeargin-Allsopp M, Schieve LA. 
Prevalence of cerebral palsy and intellectual disability among children identified in two U.S. 
National Surveys, 2011-2013. Ann Epidemiol. 2016;26(3):222-6.
Monbaliu E, Himmelmann K, Lin JP, Ortibus E, Bonouvrié L, Feys H, et al. Clinical 
presentation and management of dyskinetic cerebral palsy. Lancet Neurol 2017;16(9):741-9.
National Institute of Neurological Disorders and Stroke (NINDS). Cerebral Palsy: Hope Through 
Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-
Through-Research/Cerebral-Palsy-Hope-Through-Research. Accessed 27 February 2020.
Posner K, Brown G, Stanley B, Brent, D, Yershova K, Oquendo M, et al. The Columbia–Suicide 
Severity Rating Scale: initial validity and internal consistency findings from three multisite 
studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
Prevalence of Cerebral Palsy. Available at: http://www.cerebralpalsy.org/about-cerebral-
palsy/prevalence-and-incidence. Accessed 11 June 2018.
Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the 
definition and classification of cerebral palsy April 2006. Dev Med Child Neurol 
2007;49(s109):8-14.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & 
Sons.
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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
119
Sgandurra G, Olivieri I, Casarano M, Di Pietro R, Menici V, Velli C, et al. Inter and intra-rater 
reliability and minimal detectable difference of Movement Disorder-Childhood Rating Scale. 
Eur J Phys Rehabil Med 2018;54(1):48-57.
Varni, JW, Burwinkle, TM, Berrin, SJ, Sherman, SA, Artavia, K, Malcarne, VL, et al. The 
PedsQL™ in pediatric cerebral palsy: Reliability, validity, and sensitivity of the Generic Core 
Scales and Cerebral Palsy Module. Developmental Medicine and Child Neurology 2006;48:442-
49.
Vuong K, Hunter C, Mejia N, Jankovic J. Safety and efficacy of tetrabenazine in childhood 
hyperkinetic movement disorders. Mov Disord 2004;19(Suppl. 9):S422.
Wimalasundera N, Stevenson VL. Cerebral palsy. Pract Neurol 2016;16:184–194.
Xenazine: Highlights of Prescribing Information. 2018. Available at: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac768bab-8afa-4446-bc7f-
caeeffec0cda. Accessed 05 Aug 2019.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
120
16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Amendment 05 Dated 24 March 2022
The reasons for this amendment are to adjust the sample size and to add new endpoints.
All major changes to the protocol body are listed below in the table and are reflected in the 
synopsis, as applicable. Minor editorial changes (typographical errors, punctuation, etc) have 
been made to the protocol (and protocol synopsis, as appropriate).
Table 3 (Study Procedures and Assessments) and Figure 1 (Overall Study Schematic Diagram) 
have been revised to reflect changes described below.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
121
Protocol text with changes shown
New wording
Reason/justification for change
1. INTRODUCTION
There are currently no approved treatments for DCP, which 
is a serious disease with an unmet medical need. Current 
treatment options (off-label use) to treat dystonia and chorea 
include tetrabenazine, dopaminergic, or gamma-
aminobutyric acidergic interventions, but these show high 
variability in response (Monbaliu et al 2017). Botulinum 
neurotoxin A is also in clinical use for the treatment of 
spasticity and dystonia and is considered modestly effective 
in selected patients, but it does not meet the full treatment 
need. Naxibimols, a non smoked cannabis derivative, was 
approved to treat spasticity associated with multiple 
sclerosis in the United Kingdom in 2010 and is being 
investigated to treat spasticity in CP (ClinicalTrials.gov 
Identifier: NCT01898520). Currently, there are very few 
agents with novel mechanisms of action in development for 
movement disorders in CP. Dalfampridine, a small molecule 
potassium channel blocker thought to restore conduction in 
central demyelinated axons, is approved for use in multiple 
sclerosis but has failed to demonstrate functional 
improvement in patients with CP (Bethoux et al 2017).
There are currently no approved treatments for DCP, which 
is a serious disease with an unmet medical need. Current 
treatment options (off-label use) to treat dystonia and chorea 
include tetrabenazine, dopaminergic, or gamma-
aminobutyric acidergic interventions, but these show high 
variability in response (Monbaliu et al 2017). Botulinum 
neurotoxin A is also in clinical use for the treatment of 
spasticity and dystonia and is considered modestly effective 
in selected patients, but it does not meet the full treatment 
need. Currently, there are very few agents with novel 
mechanisms of action in development for movement 
disorders in CP. 
New information indicates 
Naxibimols and Dalfampridine 
will not be used for DCP and 
therefore not relevant to this 
protocol.
1.1.1. Background for TEV-50717
TEV 50717 IMP tablets are available in the following 
dose strengths:…
IMP tablets are available in the following dose strengths:…
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
122
Protocol text with changes shown
New wording
Reason/justification for change
1.2.2. Clinical Studies
The clinical development plan for TEV-50717 to date 
includes the following:
•
FourteenThirteen completed Phase 1 studies in healthy 
adult volunteers
•
Two completed pivotal Phase 2/3 and Phase 3 studies in 
patients with TD
•
One ongoingcompleted Phase 3 long-term safety study 
in patients with TD
•
Two completed pivotal studies in patients with TS with 
clinical conduct and analysis concluded and clinical 
study report (CSR) finalization pending
•
One terminated Phase 3 long-term safety study in 
patients with TS with analysis of results ongoing
The clinical development plan for TEV-50717 to date 
includes the following:
•
Fourteen completed Phase 1 studies in healthy adult 
volunteers
•
Two completed pivotal Phase 2/3 and Phase 3 studies in 
patients with TD
•
One completed Phase 3 long-term safety study in 
patients with TD
•
Two completed pivotal studies in patients with TS
•
One terminated Phase 3 long-term safety study in 
patients with TS
Updated the status of the 
TEV-50717 studies that have been 
conducted/completed since the 
last amendment.
1.2.2.1. Clinical Pharmacology Studies
FourteenThirteen Phase 1 clinical pharmacology studies 
were conducted in healthy adult volunteers.
Fourteen Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers.
Updated the status of the 
TEV-50717 studies that have been 
conducted/completed since the 
last amendment.
1.2.2.2. Clinical Safety and Efficacy Studies
The safety profile of TEV-50717 has been characterized to 
date in healthy volunteers, as well as in adult patients with 
chorea associated with HD and TD (as detailed in the IB)
and in children and adolescents with TS.
The safety profile of TEV-50717 has been characterized to 
date in healthy volunteers, as well as in adult patients with 
chorea associated with HD and TD (as detailed in the IB) 
and in children and adolescents with TS.
Text updated to include the TS 
studies as part of the safety profile 
for TEV-50717
See new wording column
The open-label, long-term Study TV50717-CNS-30047 
evaluated children and adolescent patients with tics 
associated with TS. Treatment with TEV-50717 through 54 
weeks resulted in improvement of tics. The safety profile 
observed in pediatric patients with TS receiving long-term 
treatment with TEV-50717 was generally comparable to the 
known safety profile of this drug in adult patients with HD 
or TD, with the exception of the adverse event of weight 
gain.
Text added for the recently 
completed long-term TS study


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
123
Protocol text with changes shown
New wording
Reason/justification for change
1.3.1.2. Potential Risks of TEV-50717
The following information is based on clinical trial 
experience with TEV-50717 and the US prescribing 
information for Xenazine (tetrabenazine) and Austedo 
(deutetrabenazine):
The following information is based on clinical trial 
experience with TEV-50717 and the US prescribing 
information for Xenazine (tetrabenazine) and Austedo 
(deutetrabenazine):
Clarification
See new wording column
• TEV-50717 is contraindicated in patients taking 
tetrabenazine or valbenazine. At least 30 days should 
elapse after stopping tetrabenazine or valbenazine before 
starting TEV-50717.
Updated per the current 
prescribing info of Austedo
2.1. Primary and Secondary Study Objectives and Endpoints
See new wording column
• UHDRS-TMC (centrally read)
• UHDRS-TMD (centrally read)
New key secondary endpoint
2.1.2. Primary and Secondary Estimands
The secondary estimands are the differences in means 
between TEV-50717 and placebo in the target patient 
population for (1) change from baseline to week 15 in 
centrally read MD-CRS part I total score; (2) Caregiver 
Global Impression of Improvement (CaGI-I) at week 15;  
(3) Clinical Global Impression of Improvement (CGI-I) at 
week 15; (4) change from baseline to week 15 in centrally-
read UHDRS-TMC; and (5) change from baseline to week 
15 in centrally-read UHDRS-TMD, regardless of whether or 
not dose reduction, suspension, or discontinuation occurred, 
and regardless of treatment-related adverse events.
The primary estimand assesses the effectiveness in the 
reduction of choreiform movements in patients with DCP 
with predominant choreiform movement disorder, as 
evaluated by the central reviewers, focusing on the causal 
effects attributable to the IMP. The secondary estimands 
assess the effectiveness on patients’ ability to perform daily 
functions, the improvement in dyskinesia evaluated by the 
caregiver and the investigator, and the reduction in chorea 
and dystonia evaluated by central reviewers, all with a focus 
on the causal effects attributable to the IMP.
The secondary estimands are the differences in means 
between TEV-50717 and placebo in the target patient 
population for (1) change from baseline to week 15 in 
centrally read MD-CRS part I total score, (2) Caregiver 
Global Impression of Improvement (CaGI-I) at week 15, (3) 
Clinical Global Impression of Improvement (CGI-I) at week 
15, (4) change from baseline to week 15 in centrally-read 
UHDRS-TMC, and (5) change from baseline to week 15 in 
centrally-read UHDRS-TMD, regardless of whether or not 
dose reduction, suspension, or discontinuation occurred, and 
regardless of treatment-related adverse events.
The primary estimand assesses the effectiveness in the 
reduction of choreiform movements in patients with DCP 
with predominant choreiform movement disorder, as 
evaluated by the central reviewers, focusing on the causal 
effects attributable to the IMP. The secondary estimands 
assess the effectiveness on patients’ ability to perform daily 
functions, the improvement in dyskinesia evaluated by the 
caregiver and the investigator, and the reduction in chorea 
and dystonia evaluated by central reviewers, all with a focus 
on the causal effects attributable to the IMP.
Text revised to account for new 
key secondary endpoints


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
124
Protocol text with changes shown
New wording
Reason/justification for change
3.1. General Study Design and Study Schematic Diagram
… the first dose increase mayshould be performed in an 
interval less than 5 days, only once, on day 3.
… the first dose increase should be performed in an interval 
less than 5 days, only once, on day 3.
Revised to match other instances 
in protocol
The following was deleted:
When approximately 90 patients have completed the study 
(including follow up), an iDMC will perform an unblinded 
IA for futility and sample size re estimation based on 
centrally read MD CRS part II total score. Based on the 
results of the IA, the study may be stopped or the sample 
size may be kept as planned (approximately 185 total 
patients) or increased (up to approximately 230 total 
patients) (Section 9.7).
Text deleted to account for the 
change in sample size and the 
removal of the second IA for 
sample size reassessment
There is a separate protocol will be issued for the open-label 
safety extension Study TV50717-CNS-30081, as applicable.
There is a separate protocol for the open-label safety 
extension Study TV50717-CNS-30081.
The open-label extension has been 
approved for use.  
Figure 1:Overall Study Schematic Diagram
See new wording column
Figure 1 has been revised as described below:

Footnote was edited to clarify dose increases 
should be performed after remote or in-clinic 
visits.
Clarification
3.2. Planned Number of Patients and Regions
Approximately 18565 patients are planned to be randomized 
to TEV-50717 versus placebo in a 2:1 ratio (approximately 
12443 in the TEV-50717 group; approximately 6122 in the 
placebo group) stratified by age at baseline (6 to <12 years; 
12 through 18 years) and region (US; non-US). The sample 
size will be re estimated in an interim analysis and may be 
adjusted up to a total of approximately 230 patients.
Approximately 65 patients are planned to be randomized to 
TEV-50717 versus placebo in a 2:1 ratio (approximately 43
in the TEV-50717 group; approximately 22 in the placebo 
group) stratified by age at baseline (6 to <12 years; 12 
through 18 years) and region (US; non-US).
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis
This study is planned to be conducted in approximately 70
60 investigational centers in North America, Asia, and 
Europe. The study is expected to start by end of 2018 and 
last until the fourth quarter of 2022.
This study is planned to be conducted in approximately 60 
investigational centers in North America, Asia, and Europe. 
The expected end of the study 
changed to account for current 
pace of enrollment


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
125
Protocol text with changes shown
New wording
Reason/justification for change
3.4. Stopping Rules for the Study
The following was deleted:
When approximately 90 patients have completed the study 
(including follow up), an iDMC will perform an unblinded 
IA for futility and sample size re estimation based on the 
primary endpoint, the centrally read MD CRS part II total 
score. Based on the results of the IA, the study may be 
stopped for futility. For further details, see Section 9.
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis
Table 3: Study Procedures and Assessments
See new wording column
Table 3 has been revised as described below:
•
The time for the follow-up visits 16 and 17 was clarified.
•
The new endpoints (UHDRS-TMC and UHDRS-TMD) 
were added.
•
For the efficacy endpoints, assessments were added for 
possible unscheduled visits.
•
For the telephone contact visits, “Contact RTSM” was 
removed.
•
The footnotes were revised to make consistent with the 
changes to the table and the body of the protocol.
Revised to clarify and align the 
schedule of events and its 
corresponding footnotes against 
the updates included throughout 
the study design and body of the 
protocol
4.1. Patient Inclusion Criteria
11. In the investigator’s opinion, the patient and/or
caregiver havehas the ability to understand the nature of 
the study and its procedures, and the patient is expected 
to complete the study as designed.
11. In the investigator’s opinion, the patient and/or 
caregiver has the ability to understand the nature of the 
study and its procedures, and the patient is expected to 
complete the study as designed.
Revised to clarify the caregiver’s 
role in understanding the nature of 
the study.
4.3. Withdrawal Criteria and Procedures for the Patient
See new wording column
13. In patients who experience signs of suicidal ideation or 
behavior (Section 7.9), the investigator should consult 
with the medical monitor to determine whether the 
patient should continue in the study.
Added to align with Section 7.9


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
126
Protocol text with changes shown
New wording
Reason/justification for change
Table 4: Maximum Daily Dose of IMP During the Titration Period by Day and Weight Category at Baseline
See new wording column
Table 4 has been revised as described below:
•
The first column for study visit was changed from days 
to weeks.
•
The footnotes were revised to make consistent with the 
changes to the table and the body of the protocol.
Revised for clarity
5.1.1.2. Dose Modification and Dose Stratification
See new wording column
All IMP adjustments are made only after a remote or in-
clinic visit; if the dose is escalated, the dose escalation will 
occur with the next morning’s dose.
Revised to match similar change 
in Administrative Letter #07
•
Dose increases may not occur more frequently than 
every 5 days, except for patients ≥40 kg/88 lbs. For 
patients ≥40 kg/88 lbs, the first dose increase mayshould
be performed in an interval less than 5 days, only once, 
on day 3.
•
Dose increases may not occur more frequently than 
every 5 days, except for patients ≥40 kg/88 lbs. For 
patients ≥40 kg/88 lbs, the first dose increase should be 
performed in an interval less than 5 days, only once, on 
day 3.
Revised for clarity
•
At an in-clinic visit, a Adose reduction, if required, 
should be made to the previously tolerated dose level. If 
more than 1 dose reduction is required for an adverse 
event, the medical monitor should be notified.
•
At an in-clinic visit, a dose reduction, if required, should 
be made to the previously tolerated dose level. If more 
than 1 dose reduction is required for an adverse 
event, the medical monitor should be notified.
Revised for clarity
•
During the titration period, the dose of IMP should be 
adjusted according to Table 4 to identify a dose level that 
optimally reduces dyskinesia (as determined by the 
investigator, as indicated by a reduction in the CGI-I) 
and is well tolerated.  Dose adjustments should ONLY 
take place after telephone or in-clinic visit.
•
During the titration period, the dose of IMP should be 
adjusted according to Table 4 to identify a dose level 
that optimally reduces dyskinesia (as determined by the 
investigator, as indicated by a reduction in the CGI-I) 
and is well tolerated. Dose adjustments should ONLY 
take place after telephone or in-clinic visit.
Revised for clarity


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
127
Protocol text with changes shown
New wording
Reason/justification for change
Table 4: Maximum Daily Dose of IMP During the Titration Period by Week and Weight Category at Baseline
See new wording column
Table 4 has been revised as described below:
•
The title was changed from “by Day” to “by Week”.
•
Study day column was changed from “Study day” to 
“Study time period”, and the time periods were changed 
to weeks.
•
The footnotes were revised to make consistent with the 
changes to the table and the body of the protocol.
Clarification
5.4. Treatment after the End of the Study
All patients will discontinue IMP at the week 15 visit and 
will return 1 week later for the EOS visit. 
 
 
Patients will not receive the evening IMP dose 
on this day.
 
All patients will discontinue IMP at the week 15 visit and 
will return 1 week later for the EOS visit.
 
 
atients will not receive the evening IMP 
dose on this day.
Revised for clarity
Note: Patients can also roll over to the extension study 
within 2 to 4 weeks after the week 15 visit but will be 
required to complete additional scales and tests as part of 
Study TV50717-CNS-30081. Patients will further be 
allowed to roll over to Study TV50717 CNS 30081 between 
4 weeks and up to 6 months from the week 15 visit and will 
be subject to the full screening process. More details are 
presented in the TV50717 CNS 30081 protocol.
Note: Patients can also roll over to the extension study 
within 2 to 4 weeks after the week 15 visit but will be 
required to complete additional scales and tests as part of 
Study TV50717-CNS-30081.
Text deleted to loosening 
restrictions regarding COVID-19
5.7. Procedures for Monitoring Patient Compliance
See new wording column
Based on pill counts at in-clinic visits, poor compliance 
with study drug intake (ie, <80%) or overdose (ie, >105%) 
is to be recorded as an important deviation and 
expeditiously reported to the medical monitor.
Added to define compliance


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
128
Protocol text with changes shown
New wording
Reason/justification for change
5.9. Randomization and Blinding
In addition, the sponsor’s clinical personnel and all vendors 
(with the exception of the sponsor’s clinical supply chain 
staff and RTSM vendor) will be blinded to the IMP identity 
until the database has been locked for analysis and the 
treatment assignments are revealed.
In addition, the sponsor’s clinical personnel and all vendors 
(with the exception of the sponsor’s clinical supply chain 
staff and RTSM vendor) will be blinded to the IMP identity 
until the database has been locked for analysis and the 
treatment assignments are revealed.
Clarification
The iDMC will perform onean unblinded non-binding IA for 
futility, another unblinded IA for futility and sample size 
reassessment and will monitor safety throughout the study 
based on unblinded data. 
The iDMC will perform an unblinded non-binding IA for 
futility and will monitor safety throughout the study based 
on unblinded data. 
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis
5.10.3. Independent Data Monitoring Committee
The following was deleted:
When approximately 90 patients have completed the study 
(including follow up), the iDMC will perform an unblinded 
IA for futility and sample size re estimation based on 
centrally read MD CRS part II total score. Based on current 
initial assumptions, the study may be stopped or the sample 
size may be kept as planned (approximately 185 total 
patients) or increased (up to approximately 230 total 
patients). The iDMC will also perform regular safety 
monitoring throughout the study.
Text deleted to account for the 
change in sample size and the 
removal of the second interim 
analysis
6.2.Key Secondary Efficacy Measures
See new wording column
6.2.4.
Unified Huntington’s Disease Rating Scale-Total 
Maximal Chorea
New section added to account for 
the addition of a new key 
secondary endpoint
See new wording column
6.2.5.
Unified Huntington’s Disease Rating Scale-Total 
Maximal Dystonia
New section added to account for 
the addition of a new key 
secondary endpoint


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
129
Protocol text with changes shown
New wording
Reason/justification for change
6.2.4.Unified Huntington’s Disease Rating Scale-Total Maximal Chorea
The following text was moved from a later section to this 
new section: 
The UHDRS TMC is part of the UHDRS-TMS assessment 
and assesses the severity of chorea in the face, mouth, trunk, 
and the 4 extremities. The minimum score is 0 (absent) and 
the maximum score is 28 (marked/prolonged) (Huntington 
Study Group 1996).
Text moved as this is the first 
mention of UHDRS-TMC rather 
than later 
See new wording column
A central reading of the UHDRS-TMC will be performed at 
baseline and at weeks 9, 12, 15/ET, and 16/EOS visits. The 
central rating will be done for all patients, based on the 
videos collected for the central rating of MD-CRS. Video 
review will be assessed periodically in a blinded manner 
(eg, visit and investigator site rating) by a central review 
board. Central reading results performed by the central 
raters will not be disclosed to the investigational site. 
Central reading details will be provided in a separate 
charter.
Text added to account for the 
addition of the new endpoint
6.2.5. Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
The following text was moved from a later section to this 
new section: 
The UHDRS-Total Maximal Dystonia (TMD) is part of the 
UHDRS-TMS assessment and assesses the severity of 
dystonia in the trunk and the 4 extremities. The minimum 
score is 0 (absent) and the maximum score is 20 
(marked/prolonged) (Huntington Study Group 1996). When 
rating dystonia (question #11), buccal-oral-lingual and facial 
dystonia (blepharospasm, jaw opening and closing) should 
be included in the assessment of the truncal region.
Text moved as this is not the first 
mention of UHDRS-TMD rather 
than in the later section


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
130
Protocol text with changes shown
New wording
Reason/justification for change
See new wording column
A central reading of the UHDRS-TMD will be performed at 
baseline and at weeks 9, 12, 15/ET, and 16/EOS visits. The 
central rating will be done for all patients, based on the 
videos collected for the central rating of MD-CRS. Video 
review will be assessed periodically in a blinded manner 
(eg, visit and investigator site rating) by a central review 
board. Central reading results performed by the central 
raters will not be disclosed to the investigational site. 
Central reading details will be provided in a separate 
charter.
Text added to account for the 
addition of a new endpoint
6.3. Other Efficacy Measures
See new wording column
6.3.1.
Movement Disorder-Childhood Rating Scale Part I 
and Part II Total Scores
New section added for 
clarification – the numbering for 
the rest of the subsections were 
increased by one but this change 
was not noted here.  
6.3.1. Movement Disorder-Childhood Rating Scale Part I and Part II Total Scores
See new wording column
The MD-CRS part I and part II total scores will be 
evaluated by the investigator at baseline, week 9, week 12, 
week 15/ET, and week 16/EOS visits. See Section 6.1 and 
Section 6.2.1 for description of these rating scales.  
New text added for clarification
6.3.3. Unified Huntington’s Disease Rating Scale-Total Motor Score
See new wording column
The protocol refers to UHDRS-TMS as a physician-rated 
scale, but in certain instances, based on the experience of 
the rater, certain non-physicians may be approved to rate the 
UHDRS-TMS.
Text added to clarify the role of 
physicians for this efficacy 
measure 
6.3.4. Unified Huntington’s Disease Rating Scale-Total Maximal Chorea
See new wording column
The UHDRS-TMC is administered at baseline, week 9, 
week 12, and week 15/ET visits, and will be rated by the 
investigator.
New text added for clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
131
Protocol text with changes shown
New wording
Reason/justification for change
6.3.5. Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
See new wording column
The UHDRS-TMD is administered at baseline, week 9, 
week 12, and week 15/ET visits, and will be rated by the 
investigator.
New text added for clarification
7.2.1. Children’s Columbia-Suicide Severity Rating Scale
See new wording column
The children’s C-SSRS questionnaire will be presented to 
patients ≥12 years of age at screening or 11 years of age at 
screening but will turn 12 years of age during the study.
Clarification
7.2.4. Epworth Sleepiness Scale (for Children and Adolescents)
See new wording column
For patients 6 to 12 years of age, the ESS will be completed 
by the caregiver. For patients ≥13 years of age, the ESS will 
be completed by the patient. Input from the caregiver is 
permitted.
Clarification
7.8. Electrocardiography
See new wording column
The ECG types are defined as follows:
•
A “standard ECG” is a “standard” 10-second 12-lead 
ECG.
•
A “summary ECG” is a continuously recorded ECG of 
longer than 10 seconds. For a “summary ECG,” the 
minimal recommended duration is 2 minutes or longer, 
and the preferred duration is 5 minutes (as it provides the 
most robust result). If a “summary ECG” is less than 2 
minutes, data will still be captured and analyzed to the 
extent possible.
The investigator should review the ECG at screening to 
determine patient eligibility for the study and subsequent 
ECGs for the patient’s continuation in the study. All 
ECGs should be reviewed by the investigator for any 
clinically significant findings during the visit and before 
the patient leaves the clinic. A qualified physician at a 
central diagnostic center will be interpreting the ECG.
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
132
Protocol text with changes shown
New wording
Reason/justification for change
See new wording column
The criteria for an abnormal post-baseline QTcF are a value 
>500 msec or change from screening >60 msec. If one of 
these criteria is met, the investigator must further evaluate 
the QTcF as follows: 
•
If a standard ECG is abnormal and meets the above 
protocol criteria, 
o
A 5-minute summary ECG recording should be 
performed at the research site, and a repeat standard 
ECG is not required. The site should follow the 
process to have these ECGs read by Spaulding. 
o
If a 5-minute summary ECG cannot be performed 
(for instance, if patient is evaluated at a facility other 
than the research site, and the summary ECG is not 
available), the investigator should obtain 2 repeat 
standard ECGs and determine the average of these 3 
post-screening QTcF values. The site should follow 
the process to have these ECGs read by Spaulding.  
•
The investigator should then compare the post-screening 
QTcF values to the pre-treatment QTcF values at 
screening. As noted above, the post-screening QTcF 
values will use either the average QTcF from the 3 post-
screening standard ECGs or the QTcF from the summary 
ECG. The IMP must be stopped for any confirmed post-
baseline QTcF average value >500 msec or average 
increase from screening >60 msec.
Clarification
Note: Abnormal ECG results at week 3 and week 7 or at an 
unscheduled visit may result in patient withdrawal from the 
study as detailed in Section 4.3.
Note: Abnormal ECG results at week 3 and week 7 or at an 
unscheduled visit may result in patient withdrawal from the 
study as detailed in Section 4.3.
Clarification
9.1. Sample Size and Power Considerations
See new wording column
At the time of writing Amendment 05, the initially planned 
sample size has been reduced to approximately 65 patients 
randomized to TEV-50717 versus placebo in a 2:1 ratio 
(approximately 43 in the TEV-50717 group; approximately 
22 in the placebo group).
Text added to explain for the 
change in sample size due to 
study feasibility 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
133
Protocol text with changes shown
New wording
Reason/justification for change
The following was deleted:
The sample size may be adjusted in the IA to a maximal 
number of approximately 230 patients. The maximal sample 
size was chosen based on practical considerations, given the 
limited population of patients with DCP. 
Simulations for the study, including the IA for futility and 
sample size re estimation, and the corresponding statistical 
methods to control the Type I error rate were performed. 
The overall power was approximately 83% under the initial 
assumptions and the overall Type I error rate of less than 
0.025 for the primary analysis was confirmed. Further 
simulations were performed to evaluate the power and 
additional operating characteristics of the study under 
different assumptions of the effect size.
Text deleted to account for the 
change in sample size and the 
removal of the second interim 
analysis
9.3.1. Handling Withdrawals and Missing Data
For all other cases, and for cases classified as above, 
classification as MAR/MNAR will be done/revisited in a 
blinded manner on a case-by-case basis prior to the IA for 
futility, the IA for futility and sample size reassessment and 
prior to database lock for final analysis.
For all other cases, and for cases classified as above, 
classification as MAR/MNAR will be done/revisited in a 
blinded manner on a case-by-case basis prior to the IA for 
futility and prior to database lock for final analysis.
Text revised to account for the 
removal of the second interim 
analysis
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; patients re-
randomized; patients in the ITT, mITT, safety, and PP 
analysis sets; patients who complete the treatment period; 
patients who complete the EOS visit; patients who intend to 
enroll into the open label extension study; patients who do 
not intend to be enrolled into the open label extension 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.
Data from patients screened; patients screened but not 
randomized (and reason not randomized); patients who are 
randomized; patients randomized but not treated; patients 
re-randomized; patients in the ITT, mITT, safety, and PP 
analysis sets; patients who complete the treatment period; 
patients who complete the EOS visit; 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.
Text deleted; these analyses will 
not be done


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
134
Protocol text with changes shown
New wording
Reason/justification for change
9.5.1. Primary Estimand
The primary estimand assesses the effectiveness in the 
reduction of choreiform movements in patients with DCP 
with predominant choreiform movement disorder, evaluated 
by the central reviewers, focusing on the causal effects 
attributable to the IMP.
The primary estimand assesses the effectiveness in the 
reduction of choreiform movements in patients with DCP 
with predominant choreiform movement disorder, evaluated 
by the central reviewers, focusing on the causal effects 
attributable to the IMP.
Text added to account for new 
key secondary endpoints
9.5.2. Primary Endpoint
See new wording column
9.5.2.3. Minimal Clinically Important Difference and 
Minimal Clinically Important Change
New section added to account for 
new analyses
9.5.2.3. Minimal Clinically Important Difference and Minimal Clinically Important Change
See new wording column
To support the evaluation of the clinical impact of the 
change in dyskinesia as assessed by the primary endpoint, 
the minimal clinically important difference (MCID) and the 
minimal clinically important change (MCIC) will be 
calculated. The MCID and MCIC analyses will be 
performed based on 3 global impression of improvement 
anchors: caregiver (CaGI-I), investigator (CGI-I), and 
patient (PGI-I). 
The MCID and MCIC analysis will be performed separately 
for each anchor (CaGI-I, CGI-I, and PGI-I) yielding a set of 
thresholds, each reflecting the perspective of the caregiver, 
the clinician, or the patient, depending on the anchor used.
The MCID and MCIC analyses will be based on the 
methods described by Hauser et al 2014 and Hauser et al 
2022. Details will be provided in the statistical analysis 
plan.
New analyses


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
135
Protocol text with changes shown
New wording
Reason/justification for change
9.5.3 Secondary Estimands
The secondary estimands are the differences in means 
between TEV-50717 and placebo in the target patient 
population for (1) change from baseline to week 15 in 
centrally read MD-CRS part I total score; (2) CaGI-I at 
week 15; (3) CGI-I at week 15; (4) change from baseline to 
week 15 in centrally read UHDRS-TMC; (5) change from 
baseline to week 15 in centrally read UHDRS-TMD, 
regardless of whether or not dose reduction, suspension, or 
discontinuation occurred, and regardless of treatment-related 
adverse events.
The secondary estimands assess the effectiveness on 
patients’ ability to perform daily functions, the improvement 
in dyskinesia evaluated by the caregiver and the 
investigator, and the reduction in chorea and dystonia 
evaluated by the central reviewers, all with a focus on the 
causal effects attributable to the IMP.  
The secondary estimands are the differences in means 
between TEV-50717 and placebo in the target patient 
population for (1) change from baseline to week 15 in 
centrally read MD-CRS part I total score, (2) CaGI-I at 
week 15, (3) CGI-I at week 15, (4) change from baseline to 
week 15 in centrally read UHDRS-TMC, (5) change from 
baseline to week 15 in centrally read UHDRS-TMD, 
regardless of whether or not dose reduction, suspension, or 
discontinuation occurred, and regardless of treatment-
related adverse events.
The secondary estimands assess the effectiveness on 
patients’ ability to perform daily functions, the 
improvement in dyskinesia evaluated by the caregiver and 
the investigator, and the reduction in chorea and dystonia 
evaluated by the central reviewers, all with a focus on the 
causal effects attributable to the IMP.  
Text updated to account for new 
key secondary endpoints
9.5.4. Key Secondary Endpoints
See new wording column
4. Change from baseline to week 15 in centrally read 
UHDRS-TMC (TEV-50717 versus placebo)
5. Change from baseline to week 15 in centrally read 
UHDRS-TMD (TEV-50717 versus placebo)
New key secondary endpoints


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
136
Protocol text with changes shown
New wording
Reason/justification for change
9.5.4.1. Secondary Efficacy Analysis
See new wording column
4. UHDRS-TMC (centrally read) change from baseline to 
week 15 will be analyzed using an MMRM model in the 
same fashion as the primary analysis, with the exception 
that the baseline value of UHDRS-TMC (centrally read) 
will be included as the covariate instead of MD-CRS 
part II total score.
5. UHDRS-TMD (centrally read) change from baseline to 
week 15 will be analyzed using an MMRM model in the 
same fashion as the primary analysis, with the exception 
that the baseline value of UHDRS-TMD (centrally read) 
will be included as the covariate instead of MD-CRS 
part II total score.
New key secondary analyses for 
the new endpoints
9.6. Multiple Comparisons and Multiplicity
If the primary endpoint is statistically significant (p-value 
≤0.025), the 5 key secondary hypotheses will be tested using 
a hierarchical approach at the 1-sided significance level of 
α=0.025, in the following order: (1) MD-CRS part I total 
score, (2) CaGI-I, and (3) CGI-I, (4) UHDRS-TMC 
(centrally read), and (5) UHDRS-TMD (centrally read).
If the primary endpoint is statistically significant (p-value 
≤0.025), the 5 key secondary hypotheses will be tested 
using a hierarchical approach at the 1-sided significance 
level of α=0.025, in the following order: (1) MD-CRS part I 
total score, (2) CaGI-I, (3) CGI-I, (4) UHDRS-TMC 
(centrally read), and (5) UHDRS-TMD (centrally read).
New key secondary analyses for 
the new endpoints
9.7. Planned Interim Analysis
This is the first study to evaluate the efficacy of TEV-50717 
to reduce the severity of dyskinetic involuntary movements 
associated with CP in pediatric patients with DCP. 
Moreover, limited data are available on the effect of active 
treatment on MD-CRS part II total score in DCP that can 
support sample size calculations. Therefore, an IAs for 
futility and sample size re estimation are is planned.
Based on current initial assumptions, 185 patients is the 
sample size required to obtain a statistically significant 
result in the primary analysis with a power of approximately 
90% (see Section 9.1).
This is the first study to evaluate the efficacy of TEV-50717 
to reduce the severity of dyskinetic involuntary movements 
associated with CP in pediatric patients with DCP. 
Moreover, limited data are available on the effect of active 
treatment on MD-CRS part II total score in DCP that can 
support sample size calculations. Therefore, an IA for 
futility is planned.
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
137
Protocol text with changes shown
New wording
Reason/justification for change
The following text was deleted:
When approximately 90 patients have completed the study 
(including follow up), an iDMC will perform an unblinded 
IA for futility and sample size re estimation based on 
centrally read MD CRS part II total score. 
The sample size re estimation will be performed using the 
promising zone approach (Mehta and Pocock 2011). At the 
IA, the conditional power for the initially planned sample 
size of approximately 185 patients will be estimated given 
the observed data, and the sample size may be increased up 
to a total maximum of approximately 230 patients.
The Type I error rate will be controlled using the Chen, 
DeMets, and Lan method (Chen et al 2004); hence, α=0.025 
will be used for the primary analysis.
Text deleted to account for the 
change in sample size and the 
removal of the second interim 
analysis
The rules for futility recommendation in the first IA, and the 
futility and sample size re estimation in the second IA (eg, 
definition of the promising zone) will be included in the 
iDMC charter and the SAP. 
The rules for futility recommendation (eg, definition of the 
promising zone) will be included in the iDMC charter and 
the SAP. 
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis
9.8. Safety Endpoints and Analysis
The frequency and severity of suicidal ideation or behavior 
according to the children’s C-SSRS questionnaire will be 
presented for all patients aged ≥12 years by visit and by 
treatment group.
The frequency and severity of suicidal ideation or behavior 
according to the children’s C-SSRS questionnaire will be 
presented by visit and by treatment group.
Clarification
9.10. Pharmacokinetic/Pharmacodynamic Analysis
 
 
 
 
 
 
 
 
 
 
 
  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
138
Protocol text with changes shown
New wording
Reason/justification for change
15. REFERENCES
The following was deleted:
Bethoux F, Fatemi A, Fowler E, Marciniak C, Mayadev A, 
Waksman J, et al. Safety, tolerability, and sensorimotor 
effects of extended release dalfampridine in adults with 
cerebral palsy: a pilot study. Clin Ther 2017;39(2):337 46.
Chen YH, DeMets DL, Lan KK. Increasing the sample size 
when the unblinded interim result is promising. Stat Med 
2004;23(7):1023 38.
ClinicalTrials.gov. National Library of Medicine (US). 
Identifier NCT01898520, A Safety, Efficacy and 
Tolerability Study of Sativex for the Treatment of Spasticity 
in Children Aged 8 to 18 Years; 2013 Jul 12 [cited 2017 
May 17]; Available at: 
https://clinicaltrials.gov/ct2/show/NCT01898520
Mehta CR, Pocock SJ. Adaptive increase in sample size 
when interim results are promising: a practical guide with 
examples. Stat Med 2011;30(28):3267 84.
References deleted to account for 
the change in sample size and the 
removal of the second interim 
analysis as well changes in the 
introduction
See new wording column
Hauser RA, Barkay H, Wilhelm A, Wieman M, Savola J-M, 
Gordon MF. Minimal clinically important change in 
abnormal involuntary movement scale score in tardive 
dyskinesia as assessed in pivotal trials of 
deutetrabenazine. Parkinsonism Related Disorders. In 
Press.
Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, 
Schapira AH, et al. Minimal clinically important 
difference in Parkinson’s disease as assessed in pivotal 
trials of pramipexole extended release. Parkinsons Dis. 
2014;2014:467131.
New key secondary analyses for 
the new endpoints
AUSTEDO® (deutetrabenazine) tablets (US prescribing 
information). Teva Pharmaceuticals USA, Inc; 20192021. 
Available at: https://austedo.com/hd/pi.
AUSTEDO® (deutetrabenazine) tablets (US prescribing 
information). Teva Pharmaceuticals USA, Inc; 2021. 
Available at: https://austedo.com/hd/pi.
New USPI since last amendment


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
139
Protocol text with changes shown
New wording
Reason/justification for change
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Row: Sponsor’s Authorized Representative
Column:
Teva Branded Pharmaceutical Industries,
 
 
roducts R&D, Inc
Cell: 
Row: Sponsor’s Authorized Representative
Column: 
Teva Branded Pharmaceutical Products R&D, Inc
Cell: 
Administrative change
Row: Sponsor’s Representative of Global Patient Safety and 
Pharmacovigilance
Column:  
Teva Pharmaceutical Industries, 
 
Tel: 
Cell: 
Row: Sponsor’s Representative of Global Patient Safety and 
Pharmacovigilance
Column:  
Teva Pharmaceutical Industries, 
 
Tel: 
 
Cell: 
Administrative change
Row:  Randomization and Trial Supply Management 
(RTSM) vendor
Column:  
PAREXEL International Corp. Calyx
195 West Street4 Canal Street
Waltham, MA 02451 Nottingham, United Kingdom, NG1 
7EH
Tel:
Row:  Randomization and Trial Supply Management 
(RTSM) vendor
Column:  
Calyx
4 Canal Street
Nottingham, United Kingdom, NG1 7EH
Tel: 
Administrative change


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
140
Protocol text with changes shown
New wording
Reason/justification for change
APPENDIX B. INDEPENDENT DATA MONITORING COMMITTEE
The following was deleted:
When approximately 90 patients have completed the study 
(including follow up), an iDMC will perform an unblinded 
IA for futility and sample size re estimation based on 
centrally read MD CRS part II. Based on the results of the 
IA, the study may be stopped or the sample size may be kept 
as planned (approximately 185 total patients) or increased 
(up to approximately 230 total patients).
Text deleted to account for the 
change in sample size and the 
removal of the second interim 
analysis
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
3. Procedures During Administration of Investigational Medicinal Product (Double-Blind Treatment Period Inclusive of Titration Period)
a. Week 1 (day 7+1 day), week 2 (day 14±3 days total from baseline), week 4 (day 28±3 days total from baseline), week 5 (day 35±3 days total from 
baseline), and week 6 (day 42±3 days total from baseline)
The following was deleted:
•
contact RTSM
Study procedures and assessments 
have been updated for consistency 
with changes made to the protocol 
body and Table 3.
This justification applies to all 
changes indicated within 
Appendix C.
4. Procedures During Administration of Investigational Medicinal Product (Maintenance Period)
a. Week 9 (day 63±3 days total from baseline) and week 12 (day 84±3 days total from baseline)
See new wording column
•
urine pregnancy test (week 12 only)
5. Follow-Up (Weeks 16 and 17)
a. Week 16/End of Study follow-up visit (day 112 
1 week±2 days total from the week 15 visitbaseline)
a. Week 16/End of Study follow-up visit (1 week±2 days 
total from the week 15/ET visit)
b. Week 17 follow-up visit (day 1192 weeks±2 days total 
from week 15 visitbaseline, or 2 weeks after ET visit)
b. Week 17 follow-up visit (2 weeks±2 days total from 
week 15 visit, or 2 weeks after ET visit)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
141
Protocol text with changes shown
New wording
Reason/justification for change
6. Unscheduled Visits
Procedures performed during unscheduled visits may
include any of the following:
Procedures performed during unscheduled visits may 
include any of the following:
See new wording column
•
MD-CRS part I video recording and investigator 
assessment
•
MD-CRS part II video recording and investigator 
assessment
•
CaGI-I (global, caregiver rated)
•
CGI-I and CGI-S (global, physician rated)
•
PEDI-CAT (ADL, caregiver completed, 
content-balanced version)
•
PedsQL (QoL, patient/caregiver)
•
PGI-I (global, patient/caregiver)
•
UHDRS-TMS
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS
Table 10: Allowed Medications
Row:  Benzodiazepines, trihexyphenidyl, …
Column:  Condition
The following text was deleted:
Primary use  must not be for dyskinesia chorea…
Clarification
APPENDIX M. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19
The changes specified in this appendix will be effective for 
the duration of the COVID-19 pandemic when. Once the 
situation at specific sites/countries will allow returning to 
regular study activities, this appendix will become void for 
those country/sites, except in the case of COVID-19 
resurgence or emergence of another crisis affecting normal 
per-protocol conduct of the study.  
The changes specified in this appendix will be effective for 
the duration of the COVID-19 pandemic. Once the situation 
at specific sites/countries will allow returning to regular 
study activities, this appendix will become void for those 
country/sites, except in the case of COVID-19 resurgence or 
emergence of another crisis affecting normal per-protocol 
conduct of the study.  
Text revised due to the ongoing, 
changing nature of the COVID-19 
pandemic


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
142
16.2.
Administrative Letter 07 Dated 05 May 2021


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
143


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
144


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
145
16.3.
Amendment 04 Dated 09 March 2021
The reasons for this amendment are to clarify some of the inclusion/exclusion criteria, the 
addition of an IA for futility, to clarify the collection of additional blood samples due to 
discontinuation due to adverse events, and to clarify the manner in which patients will be 
enrolled into the open-label extension Study TV50717-CNS-30081. 
All major changes to the protocol body are listed below in the table and are reflected in the 
synopsis, as applicable. Minor editorial changes (typos, punctuation, etc) have been made to the 
protocol (and protocol synopsis, as appropriate).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
146
Protocol text with changes shown
New wording
Reason/justification for change
1.1. Introduction
Prematurity is the most common cause of CP, but other 
causes include stroke, hypoxic ischemic injury, infection, 
and brain malformation, and genetic abnormalities (CDC 
Causes and Risk Factors of Cerebral Palsy 2018; NINDS 
Cerebral Palsy: Hope Through Research 2019).
Prematurity is the most common cause of CP, but other 
causes include stroke, hypoxic ischemic injury, infection, 
brain malformation, and genetic abnormalities (CDC Causes 
and Risk Factors of Cerebral Palsy 2018; NINDS Cerebral 
Palsy: Hope Through Research 2019).
Added one of the causes of CP 
and added the NINDS reference to 
support this addition.
Dyskinesia in cerebral palsy (DCP) is a hyperkinetic 
movement disorder form of CP characterized by abnormal 
involuntary movements of the dystonic and choreiform 
types in approximately 6% to 15% of patients with CP. 
Dyskinesia in cerebral palsy (DCP) is a form of CP 
characterized by abnormal involuntary movements of the 
dystonic and choreiform types in approximately 6% to 15% 
of patients with CP. 
Clarified the form of DCP
1.2.2. Clinical Studies
The clinical development plan for TEV-50717 to date 
includes the following:
• NineThirteen completed Phase 1 studies in healthy adult 
volunteers
• Two ongoingcompleted pivotal studies in patients with 
TS with clinical conduct and analysis concluded and 
clinical study report (CSR) finalization pending
• One terminated Phase 3 long-term safety study in 
patients with TS with analysis of results ongoing
The clinical development plan for TEV-50717 to date 
includes the following:
•
Thirteen completed Phase 1 studies in healthy adult 
volunteers
•
Two completed pivotal studies in patients with TS with 
clinical conduct and analysis concluded and clinical 
study report (CSR) finalization pending
•
One terminated Phase 3 long-term safety study in 
patients with TS with analysis of results ongoing
Updated the status of the 
TEV-50717 studies that have been 
conducted/completed since the 
last amendment.
1.2.2.1. Clinical Pharmacology Studies
NineThirteen Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers.
Thirteen Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers.
Updated the status of the 
TEV-50717 studies that have been 
conducted/completed since the 
last amendment.
1.2.2.2. Clinical Safety and Efficacy Studies
See new wording column
Studies TV50717-CNS-30046 and TV50717-CNS-30060 
evaluated children and adolescent patients with tics 
associated with TS. Neither study met the primary efficacy 
endpoint. In both studies, TEV-50717 was generally safe 
and well tolerated. No deaths occurred in either study. One 
patient had 2 serious adverse events. There were no trends 
in changes from baseline in serum laboratory, vital signs, 
Text added for safety results of 
recently completed TS studies


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
147
Protocol text with changes shown
New wording
Reason/justification for change
ECG, and physical and neurological parameters. There was 
no evidence of a new safety signal in pediatric patients with
TS treated with TEV-50717 in comparison to the known 
safety profile of this drug in adult patients with HD or TD.
2.1. Primary and Secondary Study Objectives and Endpoints (Other sections affected by anyone of these changes: 9.5.5)
See new wording column
The following were added as other efficacy measures and 
endpoints:
•
MD-CRS part I total score (general assessment, 
physician rated)
•
MD-CRS part II total score (general assessment, 
physician rated)
Updated endpoints are in the 
Statistical Analysis Plan; added to 
the protocol for consistency.
•
UHDRS-TMS (physician rated)
•
UHDRS-TMC (physician rated)
•
UHDRS-TMD (physician rated)
•
UHDRS-TMS (physician rated)
•
UHDRS-TMC (physician rated)
•
UHDRS-TMD (physician rated)
Clarified these scales are to be 
rated by the physician
3.1. General Study Design and Study Schematic Diagram
For patients who are minors, the caregiver is typically a 
parent or legal guardian a legally accepted representative. In 
some countries, an adult (such as grandparent or nurse) can 
be appointed by the parent or legal guardian legally accepted 
representative (as per local regulations and laws) and would 
take over this responsibility as a caregiver. The parent or 
legal guardian legally accepted representative only has to 
sign the parent/ legal guardian legally accepted 
representative informed consent form (ICF) and not the 
caregiver ICF.
For adult patients, a caregiver must be appointed by the 
patient; this can be the parent, a legal guardian legally 
accepted representative, or other adult, as appropriate and 
according to local laws and regulations.
For patients who are minors, certain responsibilities in the 
protocol can only be completed by the parent/legal guardian 
legally accepted representative, ie, informed consent, 
withdrawal of consent, requests for discontinuation of the 
IMP, or withdrawal from the study for any reason. To 
For patients who are minors, the caregiver is typically a 
parent or a legally accepted representative. In some 
countries, an adult (such as grandparent or nurse) can be 
appointed by the parent or legally accepted representative 
(as per local regulations and laws) and would take over this 
responsibility as a caregiver. The parent or legally accepted 
representative only has to sign the parent/legally accepted 
representative informed consent form (ICF) and not the 
caregiver ICF.
For adult patients, a caregiver must be appointed by the 
patient; this can be the parent, a legally accepted 
representative, or other adult, as appropriate and according 
to local laws and regulations.
For patients who are minors, certain responsibilities in the 
protocol can only be completed by the parent/legally 
accepted representative, ie, informed consent, withdrawal of 
consent, requests for discontinuation of the IMP, or
withdrawal from the study for any reason. To further clarify, 
the caregiver is not allowed to make decisions on the child’s 
Clarified one of the terms for 
caregiver for patients who are 
minors


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
148
Protocol text with changes shown
New wording
Reason/justification for change
further clarify, the caregiver is not allowed to make 
decisions on the child’s health or where “parent/ legal 
guardian legally accepted representative” is specifically 
indicated in the protocol.
health or where “parent/legally accepted representative” is 
specifically indicated in the protocol.
IMP will be titrated during the double-blind treatment period 
starting with 6 mg of TEV-50717 or matching placebo IMP 
in the morning of days 2 and 3. Patients with a in the highest
body weight group (≥40 kg/88 lbs) will further dose in the
start an evening administration from starting on day 3 and 
for the remainder of the first week.
IMP will be titrated during the double-blind treatment 
period starting with 6 mg of TEV-50717 or matching 
placebo IMP in the morning of day 2. Patients in the highest 
body weight group (≥40 kg/88 lbs) will start an evening 
administration from day 3 and for the remainder of the first 
week.
Clarified when the dose may be 
increased for patients in the 
highest body weight group
After week 1,Dose increases may not occur more frequently 
than every 5 days, except for patients ≥40 kg/88 lbs. For 
patients ≥40 kg/88 lbs, the first dose increase may be 
performed in an interval less than 5 days, only once, on 
day 3.
Dose increases may not occur more frequently than every 
5 days, except for patients ≥40 kg/88 lbs. For patients 
≥40 kg/88 lbs, the first dose increase may be performed in 
an interval less than 5 days, only once, on day 3.
Clarified when the dose may be 
increased for patients in the 
highest body weight group
Washout period and follow-up: …
At the week 16 visit, patients may choose to enter 
Study TV50717-CNS-30081 (on that day) or up to 1 week 
later (2 weeks from the week 15 visit). Patients who 
complete treatment, but choose not to participate in the 
open-label safety extension Study TV50717-CNS-30081 
any time before week 17 of Study TV50717-CNS-30080 
will be contacted for a safety evaluation call occurring 
2 weeks after their last dose of IMP. Additional details for 
patients to enter Study TV50717-CNS-30081 are provided 
in the TV50717-CNS-30081 protocol.
Washout period and follow-up: …
At the week 16 visit, patients may choose to enter 
Study TV50717-CNS-30081 (on that day) or up to 1 week 
later (2 weeks from the week 15 visit). Patients who 
complete treatment but choose not to participate in the 
open-label safety extension Study TV50717-CNS-30081 
any time before week 17 of Study TV50717-CNS-30080 
will be contacted for a safety evaluation call occurring 
2 weeks after their last dose of IMP. Additional details for 
patients to enter Study TV50717-CNS-30081 are provided 
in the TV50717-CNS-30081 protocol.
Clarified the timing of when a 
patient can enter Study TV50717-
CNS-30081
See new wording column
When approximately 50 patients have completed the study 
(including follow-up), an independent Data Monitoring 
Committee (iDMC) will perform an unblinded non-binding 
interim analysis (IA) for futility based on centrally read 
MD-CRS part II total score. 
Text added for the addition of the 
second interim analysis
When approximately 90 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
IA for futility and sample size re-estimation based on 
centrally read MD-CRS part II total score.
When approximately 90 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
IA for futility and sample size re-estimation based on 
centrally read MD-CRS part II total score.
Text updated to account for the 
second interim analysis


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
149
Protocol text with changes shown
New wording
Reason/justification for change
An iDMC charter will be developed for the IAs, and the 
procedures to ensure the integrity of the study will be 
provided in the charter.
An iDMC charter will be developed for the IAs, and the 
procedures to ensure the integrity of the study will be 
provided in the charter.
Text updated to account for the 
second interim analysis
At the time of informed consent, the parent/legal guardian 
legally accepted representative will be…
At the time of informed consent, the parent/legally accepted 
representative will be…
Clarified one of the terms for 
caregiver for patients who are 
minors
See new wording column
Patients who screen fail or terminate early from the study 
due to emergency circumstances (such as coronavirus 
disease 2019 [COVID-19]) may be allowed to re-screen/re-
enter (respectively) the study at a later date, depending on 
the circumstances. Each case should be referred to the 
medical monitor and approved in advance.
Text added to allow patients to 
re-enter study.
3.4. Stopping Rules for the Study and Section 5.10.3 Independent Data Monitoring Committee
See new wording column
When approximately 50 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
non-binding IA for futility based on the primary endpoint, 
the centrally read MD-CRS part II total score. Based on the 
results of the IA, the study may be stopped for futility.
Text added for the addition of the 
second interim analysis
Table 3: Study Procedures and Assessments
See new wording column
Table 3 has been revised as described below:
•
The visit window for day 7 (week 1) was changed from 
±1 day to +1 day and a new visit window for day 14 
(week 2) was added
•
The visit window for the Titration and Maintenance 
Periods was revised to include ≥5 days from last dose 
change
•
 
 
•
For β-HCG test, the assessment at week 9 (day 63) was 
removed
•
An assessment for Contact RTSM was added 
•
The footnotes were revised to make consistent with the 
Revised to clarify and align the 
schedule of events and its 
corresponding footnotes against 
the updates included throughout 
the study design and body of the 
protocol


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
150
Protocol text with changes shown
New wording
Reason/justification for change
changes to the table and the body of the protocol
4.1. Patient Inclusion Criteria
12. For a patient who is a minor, the parent(s)/ legal 
guardian legally accepted representative(s) provide 
written informed consent, and the patient provides assent 
(in accordance with local regulations). Adult patients 
provide their own written informed consent (in 
accordance with local regulations) and the legally 
acceptable representative will sign, if needed.
In this study, eligible patients are patients with 
dyskinetic CP who may have some degree of mental, 
motor, and/or communication (eg, speech, writing, etc) 
limitations or disabilities. The patient may not be able to 
read the assent/consent form. Some patients may only be 
able to provide a limited assent/consent (for instance, by 
verbalizations or gestures). The investigator will 
determine the suitability of enrolling such patients in this 
study and will follow the local regulation to obtain the 
relevant assent/consent. 
12. For a patient who is a minor, the parent(s)/legally 
accepted representative(s) provide written informed 
consent, and the patient provides assent (in accordance 
with local regulations). Adult patients provide their own 
written informed consent (in accordance with local 
regulations) and the legally acceptable representative 
will sign, if needed.
In this study, eligible patients are patients with 
dyskinetic CP who may have some degree of mental, 
motor, and/or communication (eg, speech, writing, etc) 
limitations or disabilities. The patient may not be able to 
read the assent/consent form. Some patients may only 
be able to provide a limited assent/consent (for instance, 
by verbalizations or gestures). The investigator will 
determine the suitability of enrolling such patients in 
this study and will follow the local regulation to obtain 
the relevant assent/consent. 
Text added to provide additional 
guidance in consideration of 
exclusion crtierion “i”
13. Caregivers provide written informed consent after being 
assigned the role by an adult patient, or if this role is 
delegated by the parent/legal guardian legally accepted 
representative(s) of a patient who is a minor.
13. Caregivers provide written informed consent after being 
assigned the role by an adult patient, or if this role is 
delegated by the parent/legally accepted representative 
of a patient who is a minor.
Clarified one of the terms for 
caregiver for patients who are 
minors
4.2. Patient Exclusion Criteria
2. 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 and anticipated to remain stable 
(dose and frequency) within the study duration.
2. 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 and anticipated to remain stable 
(dose and frequency) within the study duration.
Clarified any antidepressant 
therapy received by the patient 
must remain stable throughout the 
study
3. Patient has a history of suicidal intent or related 
behaviors based on medical or psychiatric history or the 
C-SSRS within 2 years of screening:
3. Patient has a history of suicidal intent or related 
behaviors based on medical or psychiatric history or the 
C-SSRS within 2 years of screening:
Clarified how to assess the 
exclusion criterion


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
151
Protocol text with changes shown
New wording
Reason/justification for change
4. Patient has a history of a previous actual, interrupted, or 
aborted suicide attempt based on medical or psychiatric 
history or the C-SSRS.
4. Patient has a history of a previous actual, interrupted, or 
aborted suicide attempt based on medical or psychiatric 
history or the C-SSRS.
Clarified how to assess the 
exclusion criterion
Exclusion criteria #6 was deleted.
Upon further consideration of 
exclusion criterion #6, it was 
decided to remove the criteria 
surrounding BoNT and provide 
clarification in Appendix H.
76. Patient has received any of the following concomitant 
medications for dystonia or chorea within the specified 
exclusionary windows of screening:
Within 3 months: depot neuroleptics
–
Within 30 days: tetrabenazine, deutetrabenazine, or 
valbenazine
–
Within 21 days: reserpine
–
Within 14 days: neuroleptics (oral), typical and 
atypical antipsychotics (see Appendix H),
metoclopramide, levodopa, dopamine agonists, and 
MAOIs
Note: Use of benzodiazepines, muscle relaxants, 
trihexyphenidyl, baclofen (oral and intrathecal), 
gabapentin, and levetiracetam is allowed if the 
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.
6. Patient has received any of the following concomitant 
medications within the specified exclusionary windows 
of screening:
–
Within 30 days: tetrabenazine, deutetrabenazine, or 
valbenazine
–
Within 21 days: reserpine
–
Within 14 days: levodopa, dopamine agonists, and 
MAOIs
Clarified the concomitant 
medication types and criteria for 
patient exclusion
1817. Patient has a history of or acknowledges alcohol or 
other substance abuse in the 12 months before 
screening, as defined in the Diagnostic and 
Statistical Manual of Mental Disorders (version 5).
17. Patient has a history of or acknowledges alcohol or 
other substance abuse in the 12 months before 
screening.
Clarified how to assess the 
exclusion criterion
1918. Patient has a positive urine drug screen test result 
(with exception of medications listed in Table 9 
Table 10 of Appendix H) or is unable to refrain from 
18. Patient has a positive urine drug screen test result (with 
exception of medications listed in Table 10 of 
Appendix H). Any request to include a patient with a 
Clarified how patients with a 
positive urine result may be 
enrolled


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
152
Protocol text with changes shown
New wording
Reason/justification for change
substance abuse throughout the study. Any request to
include a patient with a positive urine drug screen 
test result should be discussed with, and approved 
by, the medical monitor. Refer to Section 7.5.2.2 
(urine drug screen) for more details.
positive urine drug screen test result should be discussed 
with, and approved by, the medical monitor. Refer to 
Section 7.5.2.2 (urine drug screen) for more details.
4.3. Withdrawal Criteria and Procedures for the Patient
See new wording column
5.
Patient engages in alcohol or other substance abuse.
New reason for patients to be 
withdrawn
12. If a post-baseline QTcF value >500 msec or change from 
baselinescreening >60 msec is found, the investigator 
should repeat the ECG assessment twice more and 
compare the average of these 3 post-baseline screening 
QTcF values to theand compare to the average of the 2 
pre-treatment QTcF values (baseline and at screening) to 
the average of the 3 post baseline QTcF values. The IMP 
must be stopped for any confirmed post-baseline QTcF 
average value >500 msec or average increase from 
baselinescreening >60 msec. In addition, a patient may 
be withdrawn from the study as described in Sections 
3.4, 3.5, and 5.10 and Appendix C.
12. If a post-baseline QTcF value >500 msec or change 
from screening >60 msec is found, the investigator 
should repeat the ECG assessment twice more and 
compare the average of these 3 post-screening QTcF 
values to the pre-treatment QTcF values at screening. 
The IMP must be stopped for any confirmed post-
baseline QTcF average value >500 msec or average 
increase from screening >60 msec. In addition, a patient 
may be withdrawn from the study as described in 
Sections 3.4, 3.5, and 5.10 and Appendix C.
Clarified when and how a change 
in QTcF would require study 
discontinuation
4.5. Rescreening
See new wording column
For COVID-19 updates, refer to Appendix M.
Updated to cross-reference the 
addition to Appendix M
5.1.1.1. Starting Dose and Dose Levels
Test IMP will be supplied in 20 count tablets per dose 
strength per bottle assembling 6, 12, 18, 24, 30, 36, 42, and 
48 mg dose kit combinations.
Test IMP will be supplied in 20-count tablets per dose 
strength per bottle assembling 6, 12, 18, 24, 30, 36, 42, and 
48 mg dose kit combinations.
Clarified the tablets in the dose kit


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
153
Protocol text with changes shown
New wording
Reason/justification for change
5.1.1.2. Dose Modification and Dose Stratification
•
IMP cannot should be swallowed whole. If the IMP is
crushed or split but should be swallowed whole, it 
should not be ingested; it should be replaced with a new 
tablet. The tablets will be taken with food (eg, a snack) 
and should not be taken on an empty stomach. Patients 
may be offered the optional use of a Medi+Straw®, 
which is a commercially available straw that can assist 
patients to overcome swallowing difficulties.
•
IMP should be swallowed whole. If the IMP is crushed 
or split, it should not be ingested; it should be replaced 
with a new tablet. The tablets will be taken with food 
(eg, a snack) and should not be taken on an empty 
stomach. Patients may be offered the optional use of a 
Medi+Straw®, which is a commercially available straw 
that can assist patients to overcome their swallowing 
difficulties.
Clarified how study drug should 
be taken
•
If there is only a single dose of IMP per day, the dose 
should be taken in the morning. However, if a patients
experiencing somnolence while taking the 6-mg dose in 
the morning, he/she may switch to taking it as an 
evening dose for the rest of the days up to day 14.
•
If there is only a single dose of IMP per day, the dose 
should be taken in the morning. However, patients 
experiencing somnolence while taking the 6-mg dose in 
the morning may switch to taking it as an evening dose 
for the rest of the days up to day 14.
Clarified wording
•
The starting dose isof 6 mg in all for patients. This dose
will be administered in the morning on days 2 and for 
the remainder of the first week. Patients in the highest 
body weight group (≥40 kg/88 lbs) will start an evening 
administration from day 3 and, followed by evening 
administration starting on day 3 for the remainder of the 
first week (if body weight is ≥40 kg/88 lbs). TEV-50717 
daily doses of 12 mg and higher will be administered as 
2 divided equal 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 the next dose, the missed dose should be 
skipped. If a patient is on the 6 mg once daily dose (12 
kg to <17 kg; 26 lbs to <37 lbs) and experiences 
somnolence while taking the 6 mg dose in the morning, 
he/she may switch to taking it as an evening dose for the 
rest of the days up to day 14.
•
After week 1, dose increases may not occur more 
frequently than every 5 days.
•
The starting dose of 6 mg will be administered in the 
morning on day 2 and for the remainder of the first 
week. Patients in the highest body weight group 
(≥40 kg/88 lbs) will start an evening administration from 
day 3 and for the remainder of the first week. TEV-
50717 daily doses of 12 mg and higher will be 
administered as 2 divided equal 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 the next dose, the 
missed dose should be skipped. 
Clarified when the dose may be 
increased for patients in the 
highest body weight group


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
154
Protocol text with changes shown
New wording
Reason/justification for change
See new wording column
•
Dose increases may not occur more frequently than 
every 5 days, except for patients ≥40 kg/88 lbs. For 
patients ≥40 kg/88 lbs, the first dose increase may be 
performed in an interval less than 5 days, only once, on 
day 3.
•
During the week 3 visit, the investigator or designee will 
make sure the patient receives the last treatment kit back 
so the patient can take the evening dose to complete the 
week 3 dosing for that day. Refer to the pharmacy 
manual for further details.
•
For any dose adjustment, the investigator or designee 
should confirm that patients have the bottle that contains 
the appropriate tablet strength and quantity to complete 
the recommended daily regimen.
Clarified how study drug should 
be taken
• During the titration period, the dose of IMP should be 
adjusted weekly according to Table 4….
•
During the titration period, the dose of IMP should be 
adjusted according to Table 4….
Clarified how study drug should 
be taken
Table 4: Maximum Daily Dose of IMP During the Titration Period by Day and Weight Category at Baseline
See new wording column
The following footnote was added: 
a
Dose increases may not occur more frequently than 
every 5 days, except for patients ≥40 kg/88 lbs. For 
patients ≥40 kg/88 lbs, the first dose increase may be 
performed in an interval less than 5 days, only once, on 
day 3.
Footnote added to align against 
the updates in the body of the 
protocol
c.
Patients in this weight category will receive the 6-mg 
once-daily dose in the morning on days 2 and 3, 
followed by evening twice-daily administration of 6 mg 
starting on day 3.
c.
Patients in this weight category will receive the 6-mg 
once-daily dose in the morning on day 2, followed by 
twice-daily administration of 6 mg starting on day 3.
Footnote updated to align against 
the updates in the body of the 
protocol
Table 6: Investigational Medicinal Products Used in the Study
See new wording column
Row:  Manufacturer
Column: TEV-50717 Test IMP
Anesta LLC
4745 Wiley Post Way 
Salt Lake City, UT 84116
Added new IMP manufacturer


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
155
Protocol text with changes shown
New wording
Reason/justification for change
See new wording column
Row: Manufacturer
Column: Placebo IMP
Anesta LLC
4745 Wiley Post Way 
Salt Lake City, UT 84116
Added new IMP manufacturer
Row:  Storage conditions
Column:  TEV-50717 Test IMP
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F), protected from light and moisture
Row: Storage conditions
Column: TEV-50717 Test IMP
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F)
Clarified IMP storage stipulations
Row:  Storage conditions
Column:  Placebo Test IMP
Stored at controlled room temperature, 20°C-25°C (68°F-
77°F), protected from light and moisture
Row: Storage conditions
Column: Placebo Test IMP
Stored at controlled room temperature, 20°C-25°C (68°F-
77°F)
Clarified IMP storage stipulations
5.2.1. Storage and Security
The IMPs (TEV-50717 and placebo IMP) must be stored 
protected from light, at a controlled room temperature, 20ºC 
to 25ºC (68ºF to 77ºF), in a dry, securely locked, 
substantially constructed cabinet or enclosure with access 
limited to authorized staff. 
Diversion is considered to have occurred when the legal 
supply chain of prescription analgesic medicinal products is 
broken, and medicinal products are transferred from a licit to 
an illicit channel of distribution or use.
The IMPs (TEV-50717 and placebo IMP) must be stored at 
a controlled room temperature, 20ºC to 25ºC (68ºF to 77ºF), 
in a securely locked, substantially constructed cabinet or 
enclosure with access limited to authorized staff.
Clarified IMP storage stipulations
5.2.3. Accountability
Each IMP shipment will include a packing slip listing the 
contents of the shipment, return instructions, and any 
applicable forms.
Each IMP shipment will include a packing slip listing the 
contents of the shipment and any applicable forms.
Clarified the content of IMP 
packing slip
A record of IMP accountability (ie, IMP and other study 
materials received, used, retained, returned, or destroyed) 
must be prepared and signed by the principal investigator or 
designee, with an account given for any discrepancies. 
Empty, partially used, Any used (partially used or empty) 
bottles and unused bottles of IMP will be kits/bottles that are 
A record of IMP accountability (ie, IMP and other study 
materials received, used, retained, returned, or destroyed) 
must be prepared and signed by the principal investigator or 
designee, with an account given for any discrepancies. Any 
used (partially used or empty) bottles and unused 
kits/bottles that are not destroyed at the site are returned to 
Clarified the instructions for IMP 
disposal


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
156
Protocol text with changes shown
New wording
Reason/justification for change
not destroyed at the site are returned to the sponsor or 
designee, as agreed with the sponsor (including expired and 
damaged kits).
the sponsor or designee, as agreed with the sponsor 
(including expired and damaged kits).
5.4. Treatment after the End of the Study
At the week 16 visit, patients may choose to enter Study 
TV50717-CNS-30081 (on that day) or up to 1 week later 
(2 weeks from the week 15 visit) they will have an 
additional week to make a decision. Patients who complete 
treatment but choose not to participate in the open-label 
safety extension Study TV50717-CNS-30081 before week 
17 of Study TV50717-CNS-30080 will be contacted for a 
safety evaluation call occurring 2 weeks after their last dose 
of IMP. Additional details for patients to enter Study 
TV50717-CNS-30081 are provided in the TV50717-CNS-
30081 protocol.
At the week 16 visit, patients may choose to enter 
Study TV50717-CNS-30081 (on that day) or up to 1 week 
later (2 weeks from the week 15 visit). Patients who 
complete treatment but choose not to participate in the 
open-label safety extension Study TV50717-CNS-30081 
before week 17 of Study TV50717-CNS-30080 will be 
contacted for a safety evaluation call occurring 2 weeks 
after their last dose of IMP. Additional details for patients to 
enter Study TV50717-CNS-30081 are provided in the 
TV50717-CNS-30081 protocol.
Clarified the timing of when a 
patient can enter 
Study TV50717-CNS-30081
See new wording column
Note: Patients can also roll over to the extension study 
within 2 to 4 weeks after the week 15 visit but will be 
required to complete additional scales and tests as part of 
Study TV50717-CNS-30081. Patients will further be 
allowed to roll over to Study TV50717-CNS-30081 between 
4 weeks and up to 6 months from the week 15 visit and will 
be subject to the full screening process. More details are 
presented in the TV50717-CNS-30081 protocol.
Clarified the timing of when a 
patient can enter 
Study TV50717-CNS-30081
5.6. Prior and Concomitant Medication
Caregivers and patients will be instructed during the course 
of the study to notify the investigator if any new medication 
is prescribed/administered (other than TEV-50717) or if 
there is any change in current medications, including over-
the-counter medications. Any prescribed new and/or any 
change in current medication should be reviewed with the 
investigator. Indication, dosage, and start and end dates 
should be entered on the CRF.
Caregivers and patients will be instructed during the course 
of the study to notify the investigator if any new medication 
is prescribed/administered (other than TEV-50717) or if 
there is any change in current medications, including over-
the-counter medications. Any prescribed new and/or any 
change in current medication should be reviewed with the 
investigator. Indication, dosage, and start and end dates 
should be entered on the CRF.
Clarified the investigator should 
be notified of any changes to 
current 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 QT corrected for heart 
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 QT prolongation 
Clarified QT prolongation rather 
than QTc


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
157
Protocol text with changes shown
New wording
Reason/justification for change
rate (QTc) prolongation or that is a known strong CYP 
inhibitor.
or that is a known strong CYP inhibitor.
Prohibited medications that are associated with QTc 
prolongation are listed in Appendix H, Table 10 Table 11. 
Prohibited antipsychotic drugs are listed in Appendix H, 
Table 11.
Prohibited medications that are associated with QT 
prolongation are listed in Appendix H, Table 11. 
Prohibited antipsychotic drugs 
table has been deleted.
5.7.Procedures for Monitoring Patient Compliance
A check of compliance with IMP intake will be performed 
during each in-clinic visit after the used IMP has been 
dispensedreturned, and IMP accountability records will be 
completed. At week 3, IMP administration compliance can 
be calculated only for weeks 1 and 2, as the last kit at 
week 3 is returned to the patient so that the patient can 
complete the week 3 dosing for that evening.
A check of compliance with IMP intake will be performed 
during each in-clinic visit after the used IMP has been 
returned, and IMP accountability records will be completed. 
At week 3, IMP administration compliance can be 
calculated only for weeks 1 and 2, as the last kit at week 3 is 
returned to the patient so that the patient can complete the 
week 3 dosing for that evening.
Clarified calculation of IMP 
compliance
5.8 Temporary Discontinuation of Investigational Medicinal Product
If a dose reduction occurs before a scheduled clinic visit, the 
clinic visit will be postponed so that efficacy evaluations can 
be performed at least 57 days after the change. 
If a dose suspension occurs before a scheduled clinic visit, 
an unscheduled visit should be scheduled as soon as possible 
so that efficacy evaluations can be performed at least 57
days after the change.
If a dose reduction occurs before a scheduled clinic visit, the 
clinic visit will be postponed so that efficacy evaluations 
can be performed at least 7 days after the change. 
If a dose suspension occurs before a scheduled clinic visit, 
an unscheduled visit should be scheduled as soon as 
possible so that efficacy evaluations can be performed at 
least 7 days after the change.
Clarified evaluations can occur 
7 days after a dose reduction or 
suspension
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP must should be 
suspended.
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP should be suspended.
Clarification
5.9. Randomization and Blinding
The iDMC will perform anone unblinded non-binding IA for 
futility, another unblinded IA for futility and sample size 
reassessment and safety monitoring throughout the study. 
An iDMC charter will be developed for the interim analyses, 
and the procedures to ensure the integrity of the study will 
be provided in the charter (see Section 5.10.3 for more 
details).
The iDMC will perform one unblinded non-binding IA for 
futility, another unblinded IA for futility and sample size 
reassessment and safety monitoring throughout the study. 
An iDMC charter will be developed for the interim 
analyses, and the procedures to ensure the integrity of the 
study will be provided in the charter (see Section 5.10.3 for 
more details).
Text updated to account for the 
second interim analysis


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
158
Protocol text with changes shown
New wording
Reason/justification for change
See new wording column
Patients re-entering the study will be manually assigned to 
their initial treatment group by the RTSM unblinded vendor. 
Blinding will be maintained for the patient, investigator, and 
sponsor as described above; the only information that will 
be available is that the patient was assigned to the same 
treatment group previously.
Guidance provided on how to 
handle blinding for patients who 
re-enter the study
5.10.3. Independent Data Monitoring Committee
See new wording column
When approximately 50 patients have completed the study 
(including follow-up), the iDMC will perform an unblinded 
non-binding IA for futility based on centrally read MD-CRS 
part II total score. 
Text added for the addition of the 
second interim analysis
The iDMC charter will be developed for the IAs, and the 
procedures to ensure the integrity of the study will be 
provided in the charter.
The iDMC charter will be developed for the IAs, and the 
procedures to ensure the integrity of the study will be 
provided in the charter.
Text updated to account for the 
second interim analysis
6. ASSESSMENT OF EFFICACY
See new wording column
Efficacy in this study will be evaluated using MD-CRS part 
I total score, MD-CRS part II total score, CaGI-I, CGI-I, 
CGI-S, PEDI-CAT, UHDRS-TMS, UHDRS-TMC, 
UHDRS-TMD, and PGI-I. It is recommended that the same 
order of administration/completion of the scales be kept per 
patient throughout the study, as best as possible (refer to the 
Study TV50717-CNS-30080 RECLAIM-DCP: Order of
scales administration/completion document). At all relevant 
visits where collected, PGI-I and CaGI-I are to be 
completed before all other investigator-rated scales.
The investigator should review all scales and questionnaires 
in a timely manner for any potential reporting of adverse 
events and document this review accordingly. At each study 
visit, as applicable, the investigator should compare the 
current scores to the baseline scores.
Stated the efficacy assessments 
and clarified the timing of those 
assessments
6.1. Primary Efficacy Measure
The MD-CRS part II will be administered by the 
investigational center physician, or other appropriately 
trained study team member, and video recorded at screening, 
The MD-CRS part II will be administered by the 
investigational center physician, or other appropriately 
trained study team member, and video recorded at 
Clarified who can administered 
the MD-CRS


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
159
Protocol text with changes shown
New wording
Reason/justification for change
baseline, week 9, week 12, week 15/ET, and week 16/EOS 
visits.
screening, baseline, week 9, week 12, week 15/ET, and 
week 16/EOS visits.
See new wording column
The MD-CRS has been updated to version 2 with changes 
to the scoring language. This version should be used when 
available. However, a patient will complete all study visits 
using the same version.
Clarified the version of the 
MD-CRS
•
Central reading (baseline, week 9, week 12, week 15/ET, 
and week 16/EOS): Video review of MD CRS part II will 
be assessed periodically in a blinded manner (ie, visit, 
investigator site rating, and other study related 
information) by a central review board.
•
Central reading (baseline, week 9, week 12, week 15/ET, 
and week 16/EOS): Video review of MD CRS part II 
will be assessed periodically in a blinded manner (ie, 
visit, investigator site rating, and other study related 
information) by a central review board.
Clarification
6.2.1. Movement Disorder-Childhood Rating Scale Part I Total Score
See new wording column
The protocol refers to MD-CRS as a physician-rated scale, 
but in certain instances, based on the experience of the rater, 
certain non-physicians may be approved to rate the MD-
CRS.
Clarified who can administered 
the MD-CRS
6.2.2. Caregiver Global Impression of Improvement Scale
The CaGI-I is to be completed assessed before all other 
investigator-rated scales during visits where CaGI-I is 
collected (Table 3).
The CaGI-I is to be completed before all other investigator-
rated scales during visits where CaGI-I is collected 
(Table 3).
Clarification
6.3.2. Unified Huntington’s Disease Rating Scale-Total Motor Score
The UHDRS-TMS is administered at baseline, week 9, week 
12, and week 15/ET visits and will be rated by the 
investigator.
The UHDRS-TMS is administered at baseline, week 9, 
week 12, and week 15/ET visits and will be rated by the 
investigator.
Clarified who can rate the 
UHDRS-TMS
6.3.4. Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
See new wording column
When rating dystonia (question #11) buccal-oral-lingual and 
facial dystonia (blepharospasm, jaw opening and closing) 
should be included in the assessment of the truncal region.
Clarified what should be part of 
the assessment for dystonia
6.3.7. Patient Global Impression of Improvement Scale
The PGI-I is to be completedassessed before all other 
investigator-rated scales during visits where PGI-I is 
collected (Table 3).
The PGI-I is to be completed before all other investigator-
rated scales during visits where PGI-I is collected (Table 3).
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
160
Protocol text with changes shown
New wording
Reason/justification for change
7. ASSESSMENT OF SAFETY
See new wording column
The investigator should review all scales and questionnaires 
in a timely manner for any potential reporting of adverse 
events and document this review accordingly.
Guidance provided on timing of 
the assessments of all scales and 
questionnaires
7.1.2. Recording and Reporting of Adverse Events
The follow-up period of recording of adverse events is 
defined as 2 weeks after the last dose of IMP for patients 
who will not roll over into or up to baseline/day 1 in the 
open-label safety extension study Study TV50717-CNS-
30081 (whichever comes first) or 2 weeks after the ET visit 
for patients who terminate early from the study, or the date 
of enrollment in the open label extension (OLE) study 
TV50717 CNS 30081 for patients rolling over to the OLE 
study.
The follow-up period of recording of adverse events is 
defined as 2 weeks after the last dose of IMP or up to 
baseline/day 1 in the open-label extension 
Study TV50717-CNS-30081 (whichever comes first) or 
2 weeks after the ET visit for patients who terminate early 
from the study.
Clarified the timing of when a 
patient can enter Study TV50717-
CNS-30081
See new wording column
To enable the assessment of the potential relationship of an 
adverse event and plasma concentration of IMP and 
metabolites, blood samples will be collected based on the 
scenarios described in Table 9.  
Additional guidance provided on 
how to handle blood samples for 
plasma concentration of IMP and 
metabolites
7.2. Safety Rating Scales
See new wording column
The investigator should review all scales and questionnaires 
in a timely manner for any potential reporting of adverse 
events and document this review accordingly. At each study 
visit, as applicable, the investigator should compare the 
current scores to the baseline scores.
Guidance provided on timing of 
the assessments of all scales and 
questionnaires
7.2.1. Children’s Columbia-Suicide Severity Rating Scale
For children over 13 years of age, parent/legal guardian
legally accepted representative involvement is strongly 
encouraged. Questions should be directed to the child, but 
the caregiver parent/ legal guardian legally accepted 
representative should be encouraged to add relevant 
information.
For children over 13 years of age, parent/legally accepted 
representative involvement is strongly encouraged. 
Questions should be directed to the child, but the caregiver 
parent/legally accepted representative should be encouraged 
to add relevant information.
Clarified one of the terms for 
caregiver for patients who are 
minors


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
161
Protocol text with changes shown
New wording
Reason/justification for change
7.3. Pregnancy
See new wording column
Note: Female partners’ pregnancies of male participants are 
not required to be proactively monitored.
Clarification
7.5.1. Serum Chemistry, Hematology, and Urinalysis
See new wording column
Laboratory tests performed at screening may be repeated to 
determine patient eligibility.
Text added to allow for repeat 
testing for study entry
7.5.2.1. Beta-Human Chorionic Gonadotropin Tests
β-HCG tests in urine will be performed for all female 
patients aged 12 years or older of childbearing potential at 
baseline and other in-clinic visits as detailed in Table 3.
β-HCG tests in urine will be performed for all female 
patients aged 12 years or older of childbearing potential at 
baseline and other in-clinic visits as detailed in Table 3.
Clarified when pregnancy tests 
should be performed
7.5.2.2. Urine Drug Screen
See new wording column
A urine drug screen performed at screening may be repeated 
to determine patient eligibility.
Text added to allow for repeat 
testing for study entry
If a given parameter cannot be tested using urine, or if the 
investigator considers additional testing is needed, an 
alternative matrix (eg, serum) may be considered acceptable. 
Such tests may be performed locally.
If a given parameter cannot be tested using urine, or if the 
investigator considers additional testing is needed, an 
alternative matrix (eg, serum) may be considered 
acceptable. Such tests may be performed locally.
Clarification on the possible 
additional testing that may be 
considered upon conducting the 
urine drug screen
See new wording column
Some of the drugs listed in this urine drug screen may be 
permitted in certain cases when the particular medication is 
being used under a physician’s or clinician’s guidance and 
in compliance with the physician’s or clinician’s 
recommendation for a specific condition (for example, 
phenobarbital [barbiturates] for seizures, stimulant 
medications [including amphetamine, methylphenidate, and 
lisdexamfetamine] for attention deficit hyperactivity 
disorder, and opiates or oxycodone for pain) and 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. Such cases should be discussed with 
the medical monitor. Patients who either are using these 
medications or have a positive drug screen for these 
substances or derivatives should be submitted to the medical 
monitor for consideration of participation in this study. 
Clarification on the possible 
exceptions that may be considered 
upon conducting the urine drug 
screen


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
162
Protocol text with changes shown
New wording
Reason/justification for change
Patients with a substance use disorder are excluded from 
this clinical trial. However, if per the investigator’s 
judgment, a patient does not meet the criteria for substance 
use disorder, a positive drug screen result for these 
medications or derivatives, without medical explanation, 
should be discussed on a case-by-case basis with the 
medical monitor to determine the patient’s eligibility, based 
on the information available.
7.7. Vital Signs
(The same position and arm or leg should be used each time 
vital signs are measured for a given patient.)
(The same position and arm or leg should be used each time 
vital signs are measured for a given patient.)
Specified the leg could be used 
for vital sign measurement
See new wording column
For patients who find standing difficult or do not allow for a 
reliable blood pressure and pulse measurement, alternative 
methods to collect orthostatic blood pressure and pulse 
should be discussed with the medical monitor.
Clarified that alternative methods 
for assessing vital signs can be 
discussed with the medical 
monitor
7.8. Electrocardiography
See new wording column
The investigator should review the ECG at screening to 
determine patient eligibility for the study and subsequent 
ECGs for the patient’s continuation in the study. All ECGs 
should be reviewed by the investigator for any clinically 
significant findings during the visit and before the patient 
leaves the clinic.
Clarified screening ECGs should 
be reviewed for eligibility
If a post-baseline QTcF value >500 msec or change from 
baselinescreening >60 msec is found, the investigator should 
repeat the ECG assessment twice and compare the average 
of the 2 these 3 post-screening QTcF values to the 
pre-treatment QTcF values (baseline and screening) to the 
average of the 3 post baseline QTcF values at screening. 
The IMP must be stopped for any confirmed post-baseline 
QTcF average value >500 msec or average increase from 
baseline screening >60 msec. 
If a post-baseline QTcF value >500 msec or change from 
screening >60 msec is found, the investigator should repeat 
the ECG assessment twice and compare the average of these 
3 post-screening QTcF values to the pre-treatment QTcF 
values at screening. The IMP must be stopped for any 
confirmed post-baseline QTcF average value >500 msec or 
average increase from screening >60 msec. 
Clarification when and how 
change in QTcF would require 
study discontinuation
See new wording column
Note: Abnormal ECG results at week 3 and week 7 may 
result in patient withdrawal from the study as detailed in 
Section 4.3.
Cross-reference added for 
possibility of patient withdrawal 
due to abnormal ECG results


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
163
Protocol text with changes shown
New wording
Reason/justification for change
7.12. Concomitant Medication or Treatment
Parents/patients will be instructed during the course of the 
study to notify the investigator if any new medication is 
prescribed/administered (other than TEV 50717) or if there 
is any change in current medications, including over-the-
counter medications. Any new prescribed/administered 
medication and/or any change in current 
prescribed/administered medication should be reviewed with 
the investigator.
Parents/patients will be instructed during the course of the 
study to notify the investigator if any new medication is 
prescribed/administered (other than TEV 50717) or if there 
is any change in current medications, including over-the-
counter medications. Any new prescribed/administered 
medication and/or any change in current 
prescribed/administered medication should be reviewed 
with the investigator.
Revisions to concomitant 
medication stipulations
Text added to provide additional 
clarity around patient 
considerations pertaining to 
concomitant medications and the 
responsibilities of the medical 
monitor
Patients may be included in this study if they are using 
cannabis or formulations or derivatives of cannabis in 
relatively stable amounts, for medical purposes (where 
applicable according to local regulation), under the 
guidance, supervision, or prescription of a clinician and 
anticipated to remain stable (dose and frequency) within the 
study duration.
Patients may be included in this study if they are using 
cannabis or formulations or derivatives of cannabis in 
relatively stable amounts, for medical purposes (where 
applicable according to local regulation), under the 
guidance, supervision, or prescription of a clinician and 
anticipated to remain stable (dose and frequency) within the 
study duration.
Patients with a substance use disorder (by Diagnostic and 
Statistical Manual of Mental Disorders, 5th edition, criteria) 
are excluded from this clinical trial.
Patients with a substance use disorder are excluded from 
this clinical trial.
See new wording column
Certain considerations mentioned in the table require the 
review of the medical monitor. Changes to the allowed 
medications may be permitted in the context of this study 
and should be discussed with the medical monitor. If the 
wellbeing of the patient and the urgency of the clinical 
decision do not allow discussion with the medical monitor 
prior to the medication change, the investigator should 
notify the medical monitor in a timely manner following 
this decision.
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 CYP2D6 inhibitor. Prohibited 
medications that are associated with QTc prolongation are 
listed in Appendix H, Table 10 Table 11, while prohibited 
antipsychotic drugs are listed in Appendix H, Table11.
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 QT prolongation 
or that is a known strong CYP2D6 inhibitor. Prohibited 
medications that are associated with QT prolongation are 
listed in Appendix H, Table 11.
Prohibited antipsychotic drugs 
table has been deleted


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
164
Protocol text with changes shown
New wording
Reason/justification for change
8.1. Pharmacokinetic Assessment
See new wording column
 
 
 
 
 
 
See new wording column
Table 9 (Blood Sampling Scenarios) has been added
9.1. Sample Size and Power Considerations
Simulations for the study, including the IA for futility and 
sample size re-estimation, and the corresponding statistical 
methods to control the Type I error rate were performed. 
The overall power ofwas approximately 9083% under the 
initial assumptions, and the overall Type I error rate of less 
than 0.025 for the primary analysis werewas confirmed. 
Further simulations were performed to evaluate the power 
and additional operating characteristics of the study under 
different assumptions of the effect size.
Simulations for the study, including the IA for futility and 
sample size re-estimation, and the corresponding statistical 
methods to control the Type I error rate were performed. 
The overall power was approximately 83% under the initial 
assumptions, and the overall Type I error rate of less than 
0.025 for the primary analysis was confirmed. Further 
simulations were performed to evaluate the power and 
additional operating characteristics of the study under 
different assumptions of the effect size.
Text updated to account for the 
second interim analysis
9.2.1. Intent-to-Treat Analysis Set
See new wording column
For patients who discontinue the study and re-enter it 
(repeating the study from baseline), only the data from the 
repeated participation will be included in the ITT analysis 
set.
Clarification for patients who 
re-enter the study
9.2.3. Safety Analysis Set
See new wording column
Rules for handling safety data for patients who discontinue 
the study and re-enter it will be provided in the SAP.
Clarification for patients who 
re-enter the study


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
165
Protocol text with changes shown
New wording
Reason/justification for change
9.3.1. Handling Withdrawals and Missing Data
The following cases will be considered as MNAR: 
• early terminations related to tolerability
• treatment-related adverse events
• early terminations related to lack of efficacy 
The following cases will be considered as MAR:
• intermittent missing data
• early termination for patients who are lost to follow-up 
• early terminations due to COVID-19
The following cases will be considered as MNAR: 
• early terminations related to tolerability
• treatment-related adverse events
• early terminations related to lack of efficacy 
The following cases will be considered as MAR:
• intermittent missing data
• early termination for patients who are lost to follow-up 
• early terminations due to COVID-19
Text added to provide additional 
clarity around the cases for 
missing data
For all other cases, and for cases classified as above,
classification as MAR/MNAR will be done/revisited in a 
blinded manner on a case-by-case basis prior to the IA for 
futility, the IA for futility and sample size reassessment and 
prior to database lock for final analysis.
For all other cases, and for cases classified as above, 
classification as MAR/MNAR will be done/revisited in a 
blinded manner on a case-by-case basis prior to the IA for 
futility, the IA for futility and sample size reassessment and 
prior to database lock for final analysis.
Text added to provide additional 
clarity around the cases for 
missing data
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 
not treated); patients re-randomized; patients in the ITT, 
mITT, safety, and PP analysis sets; patients who complete 
the treatment period; patients who complete the EOS visit; 
patients who intend to enroll into the open-label extension 
study; patients who do not intend to be enrolled into the 
open-label extension study (and reason for not enrolling); 
and patients who withdraw from the study will be 
summarized using descriptive statistics. 
Data from patients screened; patients screened but not 
randomized (and reason not randomized); patients who are 
randomized; patients randomized but not treated; patients 
re-randomized; patients in the ITT, mITT, safety, and PP 
analysis sets; patients who complete the treatment period; 
patients who complete the EOS visit; patients who intend to 
enroll into the open-label extension study; patients who do 
not intend to be enrolled into the open-label extension 
study; and patients who withdraw from the study will be 
summarized using descriptive statistics. 
Clarified that the reasons patient 
were not treated or not enrolled 
would not be collected and added 
re-randomized patients
9.5.5. Other Efficacy Endpoints
Other efficacy endpoints (change from baseline to week 
15/proportion at week 15; TEV-50717 versus placebo) are 
the following:
•
MD-CRS part I total score (general assessment, 
physician rated)
•
MD-CRS part II total score (general assessment, 
Other efficacy endpoints (change from baseline to 
week 15/proportion at week 15; TEV-50717 versus placebo) 
are the following:
•
MD-CRS part I total score (general assessment, 
physician rated)
•
MD-CRS part II total score (general assessment, 
Text added to provide additional 
clarity around the MD-CRS


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
166
Protocol text with changes shown
New wording
Reason/justification for change
physician rated)
•
MD-CRS Global Index (calculated from MD-CRS 
parts I and II total scores)
•
UHDRS-TMS (physician rated)
•
UHDRS-TMC (physician rated)
•
UHDRS-TMD (physician rated)
physician rated)
•
MD-CRS Global Index (calculated from MD-CRS 
parts I and II total scores)
•
UHDRS-TMS (physician rated)
•
UHDRS-TMC (physician rated)
•
UHDRS-TMD (physician rated)
9.7. Planned Interim Analysis
Therefore, an IAs for futility and sample size re-estimation 
is are planned.
Therefore, IAs for futility and sample size re-estimation are 
planned.
Change made to account for the 
multiple IA
See new wording column
When approximately 50 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
non-binding IA for futility based on centrally read MD-CRS 
part II total score.  
Text updated to account for the 
second interim analysis
The rules for futility recommendation in the first IA, and the 
futility and sample size re-estimation in the second IA (eg, 
definition of the promising zone) will be included in the 
iDMC charter and the SAP. The iDMC charter will also 
provide the wording that will be used to communicate the 
iDMC recommendation. The SAP will be finalized before 
the IAs will be performed.
The rules for futility recommendation in the 1st IA, and the 
futility and sample size re-estimation in the 2nd IA (eg, 
definition of the promising zone) will be included in the 
iDMC charter and the SAP. The iDMC charter will also 
provide the wording that will be used to communicate the 
iDMC recommendation. The SAP will be finalized before 
the IAs will be performed.
Text updated to account for the 
second interim analysis
9.8. Safety Endpoints and Analysis
Changes in laboratory, ECG, and vital signs measurements 
data will be summarized descriptively. AllECG and vital 
signs values will be compared with predefined criteria to 
identify potentially clinically significant values or changes, 
and such values will be listed.
Changes in laboratory, ECG, and vital signs measurements 
data will be summarized descriptively. ECG and vital signs 
values will be compared with predefined criteria to identify 
potentially clinically significant values or changes, and such 
values will be listed.
Change made to clarify which 
data should be compared with 
predefined criteria
REFERENCES
See new wording column
National Institute of Neurological Disorders and Stroke 
(NINDS). Cerebral Palsy: Hope Through Research. 
Available at: https://www ninds nih.gov/Disorders/Patient-
Caregiver-Education/Hope-Through-Research/Cerebral-
Palsy-Hope-Through-Research. Accessed 27 February 
2020.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
167
Protocol text with changes shown
New wording
Reason/justification for change
Posner K, Brown G, Stanley B, Brent, D, Yershova K, 
Oquendo M, et al. The Columbia–Suicide Severity Rating 
Scale: Initial Validity and Internal Consistency Findings 
From Three Multisite Studies With Adolescents and Adults. 
American Journal ofinitial validity and internal consistency 
findings from three multisite studies with adolescents and 
adults. Am J Psychiatry 2011;168(12):1266-77.
Posner K, Brown G, Stanley B, Brent, D, Yershova K, 
Oquendo M, et al. The Columbia–Suicide Severity Rating 
Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J 
Psychiatry 2011;168(12):1266-77.
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Row:  Scales and Central Rater for MD-CRS
Column:
Bracket Global LLC
575 East Swedesford Road
Suite 200
WayneSignant Health
785 Arbor Way
Blue Bell, PA
19087
19422
Tel: 
Row:  Scales and Central Rater for MD-CRS
Column:
Signant Health
785 Arbor Way
Blue Bell, PA 19422
Tel: 
Administrative change
APPENDIX B. INDEPENDENT DATA MONITORING COMMITTEE
When approximately 9050 patients have completed the 
study (including follow-up), an independent Data 
Monitoring Committee (iDMC) will perform an unblinded 
non-binding interim analysis (IA) for futility and sample 
size re estimation based on centrally read Movement 
Disorder-Childhood Rating Scale part II. (MD-CRS part II) 
total score. Based on the results of the interim analysisIA, 
the study may be stopped.
When approximately 50 patients have completed the study 
(including follow-up), an independent Data Monitoring 
Committee (iDMC) will perform an unblinded non-binding 
interim analysis (IA) for futility based on centrally read 
Movement Disorder-Childhood Rating Scale part II (MD-
CRS part II) total score. Based on the results of the IA, the 
study may be stopped.
When approximately 90 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
IA for futility and sample size re-estimation based on 
centrally read MD CRS part II. Based on the results of the 
IA, the study may be stopped or the sample size may be kept 
as planned (approximately 185 total patients) or increased 
(up to approximately 230 total patients).
When approximately 90 patients have completed the study 
(including follow-up), an iDMC will perform an unblinded 
IA for futility and sample size re-estimation based on 
centrally read MD CRS part II. Based on the results of the 
IA, the study may be stopped or the sample size may be 
kept as planned (approximately 185 total patients) or 
increased (up to approximately 230 total patients).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
168
Protocol text with changes shown
New wording
Reason/justification for change
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for Screening (Day -31)
•
patients, parent(s)/legal guardianlegally accepted 
representative(s), and caregivers must provide their 
respective written informed consent and/or assent (as 
appropriate) before any study related procedures are 
performed.
•
patients, parent(s)/legally accepted representative(s), and 
caregivers must provide their respective written 
informed consent and/or assent (as appropriate) before 
any study related procedures are performed.
Study procedures and assessments 
have been updated for consistency 
with changes made to the protocol 
body and Table 3.
This justification applies to all 
changes indicated within 
Appendix C.
–
use of patient’s study videos for future analysis of 
gait digital markers and release of patient’s study 
videos for use in publications or educational 
presentations
–
use of patient’s study videos for future analysis of 
gait digital markers and release of patient’s study 
videos for use in publications or educational 
presentations
•
clinical laboratory tests (chemistry, hematology, and 
urinalysis); these tests may be repeated to determine 
patient eligibility
•
urine drug screen; these tests may be repeated to 
determine patient eligibility
•
clinical laboratory tests (chemistry, hematology, and 
urinalysis); these tests may be repeated to determine 
patient eligibility
•
urine drug screen; these tests may be repeated to 
determine patient eligibility
See new wording column
•
contact RTMS
2. Procedures Before Administration of Investigational Medicinal Product (Baseline [Day 1±0 days])
See new wording column
The investigator should review all available data to 
determine patient eligibility before randomizing to the 
study.  
•
assignment of randomization/treatment numbers after 
patient eligibility is confirmed based on all available 
visit assessments, and entry into case report form (CRF)
•
assignment of randomization/treatment numbers after 
patient eligibility is confirmed based on all available 
visit assessments, and entry into case report form (CRF)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
169
Protocol text with changes shown
New wording
Reason/justification for change
3. Procedures During Administration of Investigational Medicinal Product (Double-Blind Treatment Period Inclusive of Titration Period).
a. Week 1 (day 7+1 day), week 2 (day 14±3 days total from baseline), week 4 (day 28±3 days total from baseline), week 5 (day 35±3 days total from 
baseline), and week 6 (day 42±3 days total from baseline)
See new wording column
•
contact RTMS
b. Week 3 (day 21±3 days total from baseline) and week 7 (day 49±3 days total from baseline)
The following procedures and assessments will be 
performed at weeks 3 and 7:
•
Caregiver Global Impression of Improvement (CaGI-
I) (global, caregiver rated). The CaGI-I is to be 
completed assessed before all other investigator-rated 
scales during visits where CaGI-I is collected.
•
Patient Global Impression of Improvement Scale 
(PGI-I) (global, patient/caregiver). The PGI-I is to be 
completed assessed before all other investigator-
rated scales during visits where PGI-I is collected.
The following procedures and assessments will be 
performed at weeks 3 and 7:
•
Caregiver Global Impression of Improvement 
(CaGI-I) (global, caregiver rated). The CaGI-I is to 
be completed before all other investigator-rated 
scales during visits where CaGI-I is collected.
•
Patient Global Impression of Improvement Scale 
(PGI-I) (global, patient/caregiver). The PGI-I is to be 
completed before all other investigator-rated scales 
during visits where PGI-I is collected.
•
dispense/collect IMP
During the week 3 visit, the last dose bottle is to be 
returned to the patient in order to take 1 last tablet in the 
evening to complete the week 3 dosing for that day. 
Refer to the pharmacy manual for further details.
•
dispense/collect IMP
During the week 3 visit, the last dose bottle is to be 
returned to the patient in order to take 1 last tablet in the 
evening to complete the week 3 dosing for that day. 
Refer to the pharmacy manual for further details.
See new wording column
•
contact RTMS
4. Procedures During Administration of Investigational Medicinal Product (Maintenance Period)
a. Week 9 (day 63±3 days total from baseline) and week 12 (day 84±3 days total from baseline)
The following was deleted:
•
urine pregnancy test
See new wording column
•
contact RTMS
b. Week 15 (day 105±3 days total from baseline) or early termination (ET)
See new wording column
•
contact RTMS


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
170
Protocol text with changes shown
New wording
Reason/justification for change
6.
Unscheduled Visits
See new wording column
APPENDIX D. QUALITY CONTROL AND QUALITY ASSURANCE
Audit and Inspection
See new wording column
For COVID-19 updates, refer to Appendix M.
Updated to cross-reference the 
addition to Appendix M
APPENDIX E. ETHICS
See new wording column
Patients who started the study as minors and reached the age 
of majority during the study should sign the adult ICF.
Added text for clarification
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS
Prohibited medications that are associated with QTc 
prolongation are listed in Table 10Table 11, whereas 
prohibited antipsychotic drugs are listed in Table 11.
Prohibited medications that are associated with QTc
prolongation are listed in Table 11.
Prohibited antipsychotic drugs 
table has been deleted.
Table 910: Allowed Medications
See new wording column
Table 10 has been revised as described below:
– added text to include dose was “and anticipated to 
remain stable (dose and frequency) within the study 
duration”
– included additional allowed medications
– provided clarification around permissible use/receipt of 
botulinum neurotoxin (BoNT) with approval from the 
medical monitor
Added a table note that changes to any dose required pre-
approval from medical monitor
Table 10 has been revised to 
clarify the updated expectations 
surrounding allowed medications 
in alignment with recent updates 
to the protocol body and 
inclusion/exclusion criteria 
Table 1011: Prohibited QTc Prolonging Drugs
See new wording column
Hydroxychloroquine was added as a new prohibited drug. 
The following description was also added:
Hydroxychloroquine is contraindicated in this trial due to 
the risk of QT prolongation and should be considered as not 
Hydroxychloroquine was added as 
a new prohibited drug.  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
171
Protocol text with changes shown
New wording
Reason/justification for change
allowed. If there is a medical decision to initiate 
chloroquine, hydroxychloroquine, mefloquine, or other 
drugs related to chloroquine, the IMP should be suspended 
or discontinued and an ECG should be obtained. Please 
consult with the medical monitor for further advice.
Table 11: Prohibited Antipsychotic Drugs
Table deleted
Prohibited antipsychotic drugs 
table has been deleted.
APPENDIX I. TOTAL BLOOD VOLUME
Table 12:
Total Blood Volumes
Table 12:
Total Blood Volumes
Table number updated
See new wording column
 
  
 
 
 
 
 
APPENDIX K. DATA MANAGEMENT AND RECORD KEEPING
Data Collection
If data are processed from other sources (eg, central 
laboratory, bioanalytical laboratory, central image center, 
electronic diary data, and electronic patient-reported 
outcome tablet or phone), these data will be sent to the 
investigational center…
If data are processed from other sources (eg, central 
laboratory, bioanalytical laboratory, central image center, 
electronic diary data, and electronic patient-reported 
outcome tablet or phone), these data will be sent to the 
investigational center…
Added another device for possible 
other sources
APPENDIX M. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19
Section 3.5. Schedule of Study Procedures and Assessments
It will further allow a visual confirmation of a patient’s 
condition using FaceTime® non-recording live video and 
assessment of any new adverse events, as possible, 
depending on patient cooperation and the communication 
platform being in good working order.
It will further allow a visual confirmation of a patient’s 
condition using non-recording live video and assessment of 
any new adverse events, as possible, depending on patient 
cooperation and the communication platform being in good 
working order.
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
172
Protocol text with changes shown
New wording
Reason/justification for change
The remote visit will not allow for measuring vital signs or 
obtaining an electrocardiogram (ECG) or urine beta 
chorionic gonadotropin (β-HCG) test, unless a home nursing 
vendor is at the patient’s home to provide that service where 
available.
The remote visit will not allow for measuring vital signs or 
obtaining an electrocardiogram (ECG) or urine beta 
chorionic gonadotropin (β-HCG) test, unless a home 
nursing vendor is at the patient’s home to provide that 
service where available.
Clarification
All shipping arrangements will be the site’s responsibility 
and will occur between site and patient or as a direct-to-
patient shipment from the site to patient coordinated by the 
sponsor’s third party shipping vendor, where available, and 
according to local practices and regulations.
All shipping arrangements will be the site’s responsibility 
and will occur between site and patient or as a direct-to-
patient shipment from the site to patient coordinated by the 
sponsor’s third party shipping vendor, where available, and 
according to local practices and regulations.
Clarification
See new wording column
Section 4.5. Rescreening
Patients who screen fail or terminate early from the study 
due to emergency circumstances (such as coronavirus 
disease 2019 [COVID-19] restrictions) may be allowed to 
re-screen/re-enter (respectively) the study at a later date, 
depending on the circumstances. Each case should be 
referred to the medical monitor and approved in advance. 
Patients re-entering the study will be manually assigned to 
their initial treatment group. Patients will have to redo the 
entire study from the start, aside from the blinded CYP2D6 
genotyping; these results will carried over from the first 
participation.
Clarification for possible re-entry 
into the study in an emergency 
situation
See new wording column
Section 5.9. Randomization and Blinding
Patients re-entering the study will be manually assigned to 
their initial treatment group by the RTSM unblinded vendor. 
Blinding will be maintained for the patient, investigator, and 
sponsor as described above; the only information that will 
be available is that the patient was assigned to the same 
treatment group as previously.
Clarification for possible re-entry 
into the study in an emergency 
situation
Section 7. Assessment of Safety
In the event of an emergency situation (eg, the COVID-19 
pandemic), in case a patient cannot return to the clinic for 
the scheduled visits (eg, due to quarantine, isolation, 
patient’s concern, or closure of the site clinic), patients will 
be allowed to obtain vital signs and ECGs using local clinics 
In the event of an emergency situation (eg, the COVID-19 
pandemic), in case a patient cannot return to the clinic for 
the scheduled visits (eg, due to quarantine, isolation, 
patient’s concern, or closure of the site clinic), patients will 
be allowed to obtain vital signs and ECGs using local 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
173
Protocol text with changes shown
New wording
Reason/justification for change
(primary health care provider) or home nursing service, 
where available.
clinics (primary health care provider) or home nursing 
service, where available
Appendix D. Quality Control and Quality Assurance
Study Monitoring
In case of an emergency situation (eg, the COVID-19 
pandemic), where study monitors may not be able to access 
the investigational centers for on-site visits in a timely 
manner. A remote monitoring risk mitigation plan, sites will 
be utilized for sites where on site monitoring visits are not 
permitted. Details monitored remotely where allowed and in 
accordance with the local regulations. Additional details are 
provided in the monitoring plan.
Study Monitoring
In case of an emergency situation (eg, the COVID-19 
pandemic), where study monitors may not be able to access 
the investigational centers for on-site visits, sites will be 
monitored remotely where allowed and in accordance with 
the local regulations. Additional details are provided in the 
monitoring plan.
Minor clarification for remote 
monitoring considerations in an 
emergency situation
See new wording column
Audit and Inspection
In case of an emergency situation (eg, the COVID-19 
pandemic), where auditors may not be able to access the 
investigational centers for on-site visits, investigational 
centers will be audited remotely where allowed and in 
accordance with local regulations.
Minor clarification for remote 
auditing considerations in an 
emergency situation


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
174
16.4.
Amendment 03 Dated 08 June 2020
The primary reason for this amendment is to provide the management of coronavirus disease 
2019 (COVID-19) pandemic-related operational updates as detailed in a new appendix 
(Appendix M). Administrative changes have been applied, including updating the Table of 
Contents.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
175
Original text with changes shown
New wording
Reason/Justification for change
3.1. General Study Design and Study Schematic Diagram
See New Wording Column
For coronavirus disease 2019 (COVID-19) 
updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
3.5. Schedule of Study Procedures and Assessments
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
4.3. Withdrawal Criteria and Procedures for the Patient
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
6. ASSESSMENT OF EFFICACY
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
7. ASSESSMENT OF SAFETY
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
7.5.2.1. Beta-Human Chorionic Gonadotropin Tests
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
7.5.2.2. Urine Drug Screen
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
9. Statistics
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
10. Quality Control and Quality Assurance
See New Wording Column
For COVID-19 updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
Appendix D. Quality Control and Quality Assurance
See New Wording Column
For coronavirus disease 2019 (COVID-19) 
updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
Appendix E. Ethics
See New Wording Column
For coronavirus disease 2019 (COVID-19) 
updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
176
Original text with changes shown
New wording
Reason/Justification for change
Appendix H. List Of Allowed And Prohibited Medications
See New Wording Column
For coronavirus disease 2019 (COVID-19) 
updates, refer to Appendix M.
Updated sections to cross-reference the addition of Appendix M
Appendix M. Management of Study Activities During COVID-19
New appendix and text
Additional text too numerous to include in this 
table; refer to Appendix M of this protocol.
Updated to manage study conduct during the COVID-19 
pandemic.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
177
16.5.
Amendment 02 Dated 17 October 2019
The primary reason for this amendment is to add new secondary endpoints, provide additional 
withdrawal criteria, and to clarify the inclusion/exclusion criteria.  
This amendment is considered to be substantial by the sponsor’s authorized representative. These 
substantive changes included revised inclusion criteria and new criteria for early withdrawal of 
study treatment.  
Other minor or editorial 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–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
178
Original text with changes shown
New wording
Reason/Justification for change
Synopsis and throughout the protocol 
Parent/caregiver
caregiver
Clarification 
Caregiver/adult
caregiver
Synopsis [Regions Planned]
North America, Asia, and the European Union
North America, Asia, and Europe
Clarification 
Synopsis [General Study Design] (Other sections affected by anyone of these changes: 3.1)
This is a Phase 3, 21-week, multicenter, randomized, 
double-blind, placebo-controlled, parallel group study to 
evaluate the efficacy and safety of TEV-50717 
administered as oral tablets at a starting dose of 6 mg 
once daily in patients (age 6 through 18 years) with 
DCP with predominant choreiform movement disorder, 
who have had CP symptoms, of a non-progressive 
nature, since infancy (≤2 years of age). “Predominant” 
in this instance indicates that the choreiform movement 
disorder is the main cause of impairment or distress. 
This is a Phase 3, 21-week, multicenter, randomized, 
double-blind, placebo-controlled, parallel group study to 
evaluate the efficacy and safety of TEV-50717 
administered as oral tablets at a starting dose of 6 mg 
once daily in patients (age 6 through 18 years) with 
DCP with predominant choreiform movement disorder, 
who have had CP symptoms, of a non-progressive 
nature, since infancy (≤2 years of age). “Predominant” 
in this instance indicates that the choreiform movement 
disorder is the main cause of impairment or distress.
Clarification 
Synopsis [General Study Design] (Other sections affected by anyone of these changes: 3.1)
For the purposes of this protocol, a caregiver is defined 
as an adult, who is familiar with the patient and 
responsible for daily care, enabling that person to 
effectively complete the protocol requirements. The 
caregiver accompanies the patient to the visits and 
provides input to the relevant scales as required by the 
protocol.  
For patients who are minors, the caregiver is typically a 
parent or legal guardian. In some countries an adult 
(such as grandparent or nurse) can be appointed by the 
parent or legal guardian (as per local regulations and 
laws) and would take over this responsibility as 
acaregiver. The parent or legal guardian only has to sign 
the parent/legal guardian informed consent form (ICF) 
and not the caregiver ICF.
For adult patients, a caregiver must be appointed by the 
For the purposes of this protocol, a caregiver is defined 
as an adult who is familiar with the patient and 
responsible for daily care, enabling that person to 
effectively complete the protocol requirements. The 
caregiver accompanies the patient to the visits and 
provides input to the relevant scales as required by the 
protocol.  
For patients who are minors, the caregiver is typically a 
parent or legal guardian. In some countries, an adult 
(such as grandparent or nurse) can be appointed by the 
parent or legal guardian (as per local regulations and 
laws) and would take over this responsibility as a 
caregiver. The parent or legal guardian only has to sign 
the parent/legal guardian informed consent form (ICF) 
and not the caregiver ICF.
For adult patients, a caregiver must be appointed by the 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
179
Original text with changes shown
New wording
Reason/Justification for change
patient; this can be the parent, a legal guardian, or other 
adult, as appropriate and according to local laws and 
regulations.
For patients who are minors, certain responsibilities in 
the protocol can only be completed by the parent/legal 
guardian, ie, informed consent, withdrawal of consent, 
requests for discontinuation of IMP, or withdrawal from 
the study for any reason. To further clarify, the 
caregiver is not allowed to make decisions on child’s 
health, or where “parent/legal guardian” is specifically 
indicated in the protocol.
patient; this can be the parent, a legal guardian, or other 
adult, as appropriate and according to local laws and 
regulations.
For patients who are minors, certain responsibilities in 
the protocol can only be completed by the parent/legal 
guardian, ie, informed consent, withdrawal of consent, 
requests for discontinuation of the IMP, or withdrawal 
from the study for any reason. To further clarify, the 
caregiver is not allowed to make decisions on child’s 
health or where “parent/legal guardian” is specifically 
indicated in the protocol.
IMP will be titrated during the double-blind treatment 
period starting with 6 mg of TEV-50717 or matching 
placebo IMP in the morning of days 2 and 3., followed 
by Patients with a body weight ≥40 kg/88 lbs will 
further dose in the evening administration starting on 
day 3 and for the remainder of the first week (if body 
weight is ≥40 kg/88 lbs). 
IMP will be titrated during the double-blind treatment 
period starting with 6 mg of TEV-50717 or matching 
placebo IMP in the morning of days 2 and 3. Patients 
with a body weight ≥40 kg/88 lbs will further dose in 
the evening starting on day 3 and for the remainder of 
the first week. 
Clarification 
Synopsis [Screening Period]
After written informed consent/(and written assent 
and/or co consent for patients 14 years of age and older, 
as appropriate,) is obtained, ... 
After written informed consent/assent, as appropriate, is 
obtained, ...
Clarification 
...The EAB will also confirm, based on video 
recordings, that choreiform is clinically the predominant 
movement disorder of the patient’s DCP. EAB 
assessment results will be available to the investigator 
prior to baseline and randomization. At all other visits, 
Tthe MD-CRS part II will be administered by the 
investigational center physician and video review, for 
central-blinded reading. In this study, the MD-CRS 
part II will be scored only based on chorea.
...The EAB will also confirm, based on video 
recordings, that choreiform is clinically the predominant 
movement disorder of the patient’s DCP. EAB 
assessment results will be available to the investigator 
prior to baseline and randomization. The MD-CRS 
part II will be administered by the investigational center 
physician and video review, for central-blinded reading. 
In this study, the MD-CRS part II will be scored only 
based on chorea.
Clarification 
Synopsis [Titration Period]
Patients will be classified as CYP2D6 impaired if they 
are receiving a strong CYP2D6 inhibitor or are a 
CYP2D6 poor metabolizer. At the baseline visit, a 
Patients will be classified as CYP2D6 impaired if they 
are receiving a strong CYP2D6 inhibitor or are a 
CYP2D6 poor metabolizer. At the baseline visit, a 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
180
Original text with changes shown
New wording
Reason/Justification for change
telephone for non-recording live video will be provided 
to the patient and caregiver. Patients and their 
caregiver/adult will interact weekly with the 
investigator/staff, either by telephone contact (with non-
recording live video) ...
telephone for non-recording live video will be provided 
to the patient and caregiver. Patients and their caregiver 
will interact weekly with the investigator/staff, either by 
telephone contact (with non-recording live video) 
Synopsis [Washout Period] (Other sections affected by anyone of these changes: Synopsis [Plan for Treatment or Care], 3.1, and 5.4)
Patients who complete treatment, but choose not to 
participate not participating in the open-label safety 
extension Study TV50717-CNS-30081 will be 
contacted have a follow up telephone contact for a
safety evaluation call occurring1 week after the end of 
the washout period (2 weeks after their last dose of IMP
[week 17]).
Patients who complete treatment, but choose not to 
participate in the open-label safety extension Study 
TV50717-CNS-30081 will be contacted for a safety 
evaluation call occurring 2 weeks after their last dose of 
IMP.
Clarification 
Synopsis [Washout Period] (Other sections affected by anyone of these changes: 3.1)
All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after 
their last dose of IMPET; evaluations will be as 
described for week 17. 
All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after 
ET; evaluations will be as described for week 17. 
Change originally included in Letter of 
Clarification #5 (Section 16.2).
Synopsis [Inclusion Criteria] (Other sections affected by anyone of these changes: 4.1)
5.
Patient has an MD-CRS part II total score of ≥10 at 
the baseline visit, based on investigator scoring of 
chorea.
7.
Choreiform is the predominant (ie, the main cause 
of impairment or distress) movement disorder as 
assessed at screening.
12. Patient and caregiver/adult provided written 
informed consent according to local regulations 
(eg, for patients/adolescents, the patient has 
provided written assent and/or co consent for 
patients 14 years of age and older, as appropriate).
For a patient who is a minor, the parent(s)/legal 
guardian(s) provide written informed consent, and 
the patient provides assent (in accordance with local 
regulations). Adult patients provide their own 
written informed consent (in accordance with local 
5.
Patient has an MD-CRS part II total score of ≥10 at 
the baseline visit, based on investigator scoring of 
chorea.
7.
Choreiform is the predominant (ie, the main cause 
of impairment or distress) movement disorder as 
assessed at screening.
12. For a patient who is a minor, the parent(s)/legal 
guardian(s) provide written informed consent, and 
the patient provides assent (in accordance with local 
regulations). Adult patients provide their own 
written informed consent (in accordance with local 
regulations).
13. Caregivers provide written informed consent after 
being assigned the role by an adult patient, or if this 
role is delegated by the parent/legal guardian of a 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
181
Original text with changes shown
New wording
Reason/Justification for change
regulations).
13. Caregivers provide written informed consent after 
being assigned the role by an adult patient, or if this 
role is delegated by the parent/legal guardian of a 
patient who is a minor.
patient who is a minor.
Synopsis [Exclusion Criteria]
6. Patient who is currently receiving or who, in the last 
4 months before screening, has received botulinum 
neurotoxin (BoNT) in an investigational clinical 
trial.
–
Note: Patients may be included in the study if 
they have at least 2 treatments of Food and 
Drug Administration-approved BoNT at a 
regular interval (eg, every 3 to 4 months), 
in reasonably stable dosages and locations 
(subject to investigator’s judgment) to 
treat lower limb spasticity or dystonia, and 
if they are expected to continue this stable 
regimen of BoNT injections for the 
duration of this study. The patient is 
expected to continue on this stable 
regimen of BoNT injections on a regularly 
scheduled interval every 3 months for the 
duration of this study. The injection for 
spasticity or dystonia must be in a 
muscular region that is separate from the 
main areas affected by choreiform 
movement disorder.
“Food and Drug Administration-approved 
BoNT” is to be defined as an FDA-
approved compound, not necessarily an 
FDA-approved treatment for children. 
BoNT treatments other than FDA-
approved drugs can be submitted to the 
medical monitor for consideration.
–
Note: Patients who received BoNT injections 
6. Patient who is currently receiving or who, in the last 
4 months before screening, has received botulinum 
neurotoxin (BoNT) in an investigational clinical 
trial.
–
Note: Patients may be included in the study if 
they have at least 2 treatments of Food and 
Drug Administration-approved BoNT at a 
regular interval (eg, every 3 to 4 months), 
in reasonably stable dosages and locations 
(subject to investigator’s judgment) to 
treat lower limb spasticity or dystonia, and 
if they are expected to continue this stable 
regimen of BoNT injections for the 
duration of this study. The patient is 
expected to continue on this stable 
regimen of BoNT injections on a regularly 
scheduled interval every 3 months for the 
duration of this study. The injection for 
spasticity or dystonia must be in a 
muscular region that is separate from the 
main areas affected by choreiform 
movement disorder.
“Food and Drug Administration-approved 
BoNT” is to be defined as an FDA-
approved compound, not necessarily an 
FDA-approved treatment for children. 
BoNT treatments other than FDA-
approved drugs can be submitted to the 
medical monitor for consideration.
–
Note: Patients who received BoNT injections 
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
182
Original text with changes shown
New wording
Reason/Justification for change
more than 4 months before screening and 
who do not plan to continue these 
injections may be considered for this 
study.
more than 4 months before screening and 
who do not plan to continue these 
injections may be considered for this 
study.
13. Patient has evidence of diminished hepatic 
impairmentfunction, as indicated by the following:
13. Patient has evidence of diminished hepatic function, 
as indicated by the following:
Clarification 
19. Patient has a positive urine drug screen test result 
(with exception of medications listed in Table 9 of 
Appendix H) or is unable to refrain from substance 
abuse throughout the study.
19. Patient has a positive urine drug screen test result 
(with exception of medications listed in Table 9 of 
Appendix H) or is unable to refrain from substance 
abuse throughout the study.
Clarification 
1.2.2. Clinical Studies
The clinical development plan for TEV-50717 to date 
includes the following:
1.
SixNine completed Phase 1 studies in healthy adult 
volunteers
The clinical development plan for TEV-50717 to date 
includes the following:
2.
Nine completed Phase 1 studies in healthy adult 
volunteers
Update
1.2.2. Clinical Pharmacology Studies
Six Nine Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers. 
Nine Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers. 
3.1. General Study Design
...and assessment of sedation according to the Epworth 
Sleepiness Scale (for children and adolescents) (ESS) 
questionnaire of using a telephone with non recording 
live video will be made possible, and the adoption of 
live video to support patient/caregiver interview will 
then be maintained throughout the study for the 
evaluation of safety/tolerability and dyskinesia severity. 
...and assessment of sedation according to the Epworth 
Sleepiness Scale (for children and adolescents) (ESS) 
questionnaire. 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
183
Original text with changes shown
New wording
Reason/Justification for change
Figure 1:Overall Study Schematic Diagram
Clarification 
3.2 Planned Number of Patients and Regions
This study is planned to be conducted in approximately 
70 investigational centers in North America, Asia, and 
the European Union (EU). 
This study is planned to be conducted in approximately 
70 investigational centers in North America, Asia, and 
Europe. 
Clarification 
Table 3: Study Procedures and Assessments 
First Column
Row: Informed consent/assent and/or co consent for 
patients (as applicable)j
First Column
Row: Informed consent/assentj
Clarification 
d
For patients who withdraw prematurely, an ET 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 IMPET; 
evaluations will be as described for week 17.
j
 
r
For females who are postmenarchal or aged ≥12 
years of childbearing potential. Serum test will be 
administered at baselinescreening and week 15, 
whereas a urine test will be administered at 
screeningbaseline and all other in-clinic visits.
z
Parents/Caregivers and 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.
d
For patients who withdraw prematurely, an ET 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 ET; evaluations will be as 
described for week 17
j
 
r
For females who are postmenarchal or aged ≥12 
years of childbearing potential. Serum test will be 
administered at screening and week 15, whereas a 
urine test will be administered at baseline and all 
other in-clinic visits.
z
Caregivers and 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.
Clarification 
4.2. Exclusion Criteria
6. Patient who is currently receiving or who, in the last 
4 months before screening, has received botulinum 
6. Patient who is currently receiving or who, in the last 
4 months before screening, has received botulinum 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
184
Original text with changes shown
New wording
Reason/Justification for change
neurotoxin (BoNT) in an investigational clinical 
trial.
–
Note: Patients may be included in the study if they 
have at least 2 treatments of Food and Drug 
Administration-approved BoNT at a regular 
interval (eg, every 3 to 4 months), in reasonably 
stable dosages and locations (subject to 
investigator’s judgement) to treat lower limb 
spasticity or dystonia, and if they are expected 
to continue this stable regimen of BoNT 
injections for the duration of this study. The 
patient is expected to continue on this stable 
regimen of BoNT injections on a regularly 
scheduled interval every 3 months for the 
duration of this study. The injection for 
spasticity or dystonia must be in a muscular 
region that is separate from the main areas 
affected by choreiform movement disorder.
“Food and Drug Administration-approved 
BoNT” is to be defined as an FDA-approved 
compound, not necessarily an FDA-approved 
treatment for children. BoNT treatments other 
than FDA-approved drugs can be submitted to 
the medical monitor for consideration.
–
Note: Patients who received BoNT injections more 
than 4 months before screening and who do not 
plan to continue these injections may be 
considered for this study.
neurotoxin (BoNT) in an investigational clinical 
trial.
–
Note: Patients may be included in the study if they 
have at least 2 treatments of Food and Drug 
Administration-approved BoNT at a regular 
interval (eg, every 3 to 4 months), in reasonably 
stable dosages and locations (subject to 
investigator’s judgement) to treat lower limb 
spasticity or dystonia, and if they are expected 
to continue this stable regimen of BoNT 
injections for the duration of this study. The 
patient is expected to continue on this stable 
regimen of BoNT injections on a regularly 
scheduled interval every 3 months for the 
duration of this study. The injection for 
spasticity or dystonia must be in a muscular 
region that is separate from the main areas 
affected by choreiform movement disorder.
“Food and Drug Administration-approved 
BoNT” is to be defined as an FDA-approved 
compound, not necessarily an FDA-approved 
treatment for children. BoNT treatments other 
than FDA-approved drugs can be submitted to 
the medical monitor for consideration.
–
Note: Patients who received BoNT injections more 
than 4 months before screening and who do not 
plan to continue these injections may be 
considered for this study.
13. Patient has evidence of diminished hepatic 
impairmentfunction, as indicated by the following:
13. Patient has evidence of diminished hepatic function, 
as indicated by the following:
19. Patient has a positive urine drug screen test result 
(with exception of medications listed in Table 9 of 
Appendix H) or is unable to refrain from substance 
abuse throughout the study.
19. Patient has a positive urine drug screen test result 
(with exception of medications listed in Table 9 of 
Appendix H) or is unable to refrain from substance 
abuse throughout the study.
4.3. Withdrawal Criteria and Procedures for the Patient


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
185
Original text with changes shown
New wording
Reason/Justification for change
9. Patient has evidence of diminished hepatic function 
based on the following liver function laboratory test 
results:
a. AST or ALT >2.5 × ULN
b. ALP or total bilirubin >2 × ULN
10.Patient develops Neuroleptic Malignant Syndrome 
(NMS)
9. Patient has evidence of diminished hepatic function 
based on the following liver function laboratory test 
results:
a. AST or ALT >2.5 × ULN
b. ALP or total bilirubin >2 × ULN
10.Patient develops Neuroleptic Malignant Syndrome 
(NMS)
Clarification 
5.5. Restrictions
If the removal of a strong CYP2D6 inhibitor is required 
from a clinical perspective, the medical monitor should 
be contacted so that an appropriate change in IMP 
dosing can be made. The addition of a strong CYP2D6
inhibitor is prohibited during the study.
If the removal of a strong CYP2D6 inhibitor is required 
from a clinical perspective, the medical monitor should 
be contacted so that an appropriate change in IMP 
dosing can be made. The addition of a strong CYP2D6 
inhibitor is prohibited during the study.
Clarification 
As with other VMAT2 inhibitors (tetrabenazine and 
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. 
As with other VMAT2 inhibitors (tetrabenazine and 
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. 
Use of illicitnon-approved drugs (per protocol) is 
prohibited from the time of signing of the ICF and 
throughout study participation.
Use of non-approved drugs (per protocol) is prohibited 
from the time of signing of the ICF and throughout 
study participation.
5.6. Prior and Concomitant Medication
At each clinic visit after the screening visit, the 
investigator will ask patients and/or parent(s)/caregiver 
whether they or the patient, respectively, have has taken 
any medications (other than IMP), including over-the-
counter medications, vitamins, or herbal or nutritional 
supplements, since the previous visit. ParentsCaregivers 
and 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 
At each clinic visit after the screening visit, the 
investigator will ask patients and/or caregiver whether 
the patient has taken any medications (other than IMP), 
including over-the-counter medications, vitamins, or 
herbal or nutritional supplements, since the previous 
visit. Caregivers and 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, 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
186
Original text with changes shown
New wording
Reason/Justification for change
investigator. Indication, dosage, and start and end dates 
should be entered on the CRF. 
and start and end dates should be entered on the CRF. 
5.8. Temporary Discontinuation of Investigational Medicinal Product
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP must be 
suspended. Since TEV-50717 does not have any known 
effect on potassium and magnesium levels, the reference 
to potassium and magnesium is in the context of other 
factors related to any current underlying condition, such 
as severe diarrhea or intake of drugs that lower serum 
potassium and magnesium. The investigator will be 
responsible to manage the patient’s condition per the 
site’s standard of care and assess continuation of 
treatment. The medical monitor must should be 
contacted to discuss the suspension and possible 
resumption of the IMPdetermine the appropriate 
investigation and treatment. IMP treatment may only be 
restarted once serum potassium and/or magnesium 
levels have normalized.
The pPatients who restart IMP treatment will follow the 
visit schedule as outlined in Table 3. 
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP must be 
suspended. Since TEV-50717 does not have any known 
effect on potassium and magnesium levels, the 
reference to potassium and magnesium is in the context 
of other factors related to any current underlying 
condition, such as severe diarrhea or intake of drugs that 
lower serum potassium and magnesium. The 
investigator will be responsible to manage the patient’s 
condition per the site’s standard of care and assess 
continuation of treatment. The medical monitor should 
be contacted to discuss the suspension and possible 
resumption of the IMP. IMP treatment may only be 
restarted once serum potassium and/or magnesium 
levels have normalized.
Patients who restart IMP treatment will follow the visit 
schedule as outlined in Table 3. 
Clarification 
6.1. Primary Efficacy Measure
Assessment of MD-CRS part II items will be based 
solely on chorea in this study and performed as follows: 
•
Local assessment (all time points): the 
investigational center physician will administer the 
MD-CRS part II and complete the assessment of item 
scores. Note: the physicians will receive training on 
MD-CRS scoring prior to the study.
•
EAB review (screening): EAB will review the MD-
CRS part II at the screening visit to confirm that 
dyskinesia severity is aligned with the protocol 
criteria for inclusion into the study. The review will 
include determination of the predominant dyskinesia 
type and scoring of MD-CRS part II items. The EAB 
Assessment of MD-CRS part II items will be based 
solely on chorea in this study and performed as follows: 
•
Local assessment (all time points): the 
investigational center physician will administer the 
MD-CRS part II and complete the assessment of item 
scores. Note: the physicians will receive training on 
MD-CRS scoring prior to the study.
•
EAB review (screening): EAB will review the MD-
CRS part II at the screening visit to confirm that 
dyskinesia severity is aligned with the protocol 
criteria for inclusion into the study. The review will 
include determination of the predominant dyskinesia 
type and scoring of MD-CRS part II items. The EAB 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
187
Original text with changes shown
New wording
Reason/Justification for change
will inform the site prior to the baseline visit if there 
are any discrepancies between the local and central 
assessments, and offer to discuss with the 
investigator. Ultimately, it is the investigator who 
determines the patient’s eligibility. EAB assessment 
of screening MD-CRS part II total score will not be 
included in the statistical analysis.
will inform the site prior to the baseline visit if there 
are any discrepancies between the local and central 
assessments, and offer to discuss with the 
investigator. Ultimately, it is the investigator who 
determines the patient’s eligibility. EAB assessment 
of screening MD-CRS part II total score will not be 
included in the statistical analysis.
6.3.2. Unified Huntington’s Disease Rating Scale-Total Motor Score
The Total Motor Score assessment of the UHDRS 
(UHDRS TMS) comprises 15 items and assesses eye 
movements, speech, alternating hand movements, 
dystonia, chorea, and gait. The UHDRS-TMS is 
calculated as the sum of the 31 motor assessments; each 
of which ranges between 0 to 4. The minimum score is 
0 (absent) and the maximum score is 124108 (worst) 
(Huntington Study Group 1996).
The Total Motor Score assessment of the UHDRS 
(UHDRS TMS) comprises 15 items and assesses eye 
movements, speech, alternating hand movements, 
dystonia, chorea, and gait. The UHDRS-TMS is 
calculated as the sum of the 31 motor assessments; each 
of which ranges between 0 to 4. The minimum score is 
0 (absent) and the maximum score is 124 (worst) 
(Huntington Study Group 1996).
6.3.6. Pediatric Quality of Life Inventory, Cerebral Palsy Module
The scales comprise parallel child self-report and parent 
proxy-report formats. Child self report includes For 
children ages 5 to6 and 7 years, and 8 to 12 years, and 
13 to 18 years. A a child self-report and a parent proxy 
report are completed. is included in reports for ages 2 to 
4 years (toddler), 5 to 7 years (young child), 8 to 12 
years (child), and 13 to 18 years (adolescent), and The 
parent proxy report assesses parents’ perceptions of 
their child’s health-related quality of life (QoL). For 
children ages 13 to 18 years, no parent proxy report is 
required. The instructions ask how much of a problem 
each item has been during the past 1 month. A 5-point 
response scale is utilized across child self-report and 
parent proxy report as follows:
The scales comprise parallel child self-report and parent 
proxy-report formats. For children ages 6 and 7 years 
and 8 to 12 years, a child self-report and a parent proxy 
report are completed. The parent proxy report assesses 
parents’ perceptions of their child’s health-related 
quality of life (QoL). For children ages 13 to 18 years, 
no parent proxy report is required. The instructions ask 
how much of a problem each item has been during the 
past 1 month. A 5-point response scale is utilized across 
child self-report and parent proxy report as follows:
Clarification 
7.1.2. Recording and Reporting of Adverse Events
The follow-up period of recording of adverse events is 
defined as 2 weeks after the last dose of IMP for 
patients who will not roll over into the open-label safety 
The follow-up period of recording of adverse events is 
defined as 2 weeks after the last dose of IMP for 
patients who will not roll over into the open-label safety 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
188
Original text with changes shown
New wording
Reason/Justification for change
extension study or 2 weeks after the ET visit for patients 
who terminate early from the study, or the date of 
enrollment in the open label extension (OLE) study 
TV50717-CNS-30081 for patients rolling over to the 
OLE study.
extension study or 2 weeks after the ET visit for patients 
who terminate early from the study, or the date of 
enrollment in the open label extension (OLE) study 
TV50717-CNS-30081 for patients rolling over to the 
OLE study.
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. Adverse events of patients rolling 
over to the OLE study TV50717-CNS-30081 will 
continue to be monitored as part of the OLE study.
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. Adverse events of patients rolling 
over to the OLE study TV50717-CNS-30081 will 
continue to be monitored as part of the OLE study. 
Clarification 
7.2.2. Child Behavior Checklist (for Ages 6-18)
The Syndrome Scale comprises 1138 questions related 
to problem behaviors. This study will use a recall period 
of “now or within the last week,” representing a 
modification from the original scale, which was “now or 
within the last 6 months”. For each item, the 
parent/caregiver will circle 0 if the item is not true of 
their child, 1 if the item is somewhat or sometimes true, 
and 2 if the item is very true or often true.
The Syndrome Scale comprises 113 questions related to 
problem behaviors. This study will use a recall period of 
“now or within the last week,” representing a 
modification from the original scale, which was “now or 
within the last 6 months”. For each item, the caregiver 
will circle 0 if the item is not true of their child, 1 if the 
item is somewhat or sometimes true, and 2 if the item is 
very true or often true.
Clarification 
7.4. Medication Error and Special Situations Related to the Investigational Medicinal Products
Any administration of IMP that is not in accordance 
with the study protocol should be reported inon the CRF 
and in the patients source documents either as a 
violationdeviation if it the event meets the 
violationdeviation criteria specified in the protocol 
(Appendix D), or as a deviation, in the patients source 
documents, regardless of whether or not an adverse 
event occurs as a result.
Any administration of IMP that is not in accordance 
with the study protocol should be reported in the CRF 
and in the patient’s source documents as a deviation if 
the event meets the violation criteria specified in the 
protocol (Appendix D), regardless of whether or not an 
adverse event occurs as a result.
Clarification 
7.12. Concomitant Medication or Treatment
Concomitant therapy or medication usage will be 
monitored throughout the study according to time points 
detailed in Table 3. Parents/patients will be instructed 
Concomitant therapy or medication usage will be 
monitored throughout the study according to time points 
detailed in Table 3. Parents/patients will be instructed 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
189
Original text with changes shown
New wording
Reason/Justification for change
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. Of note, any 
formulation/derivative of cannabis is prohibited during 
the study.
Patients may be included in this study if they are using 
cannabis or formulations or derivatives of cannabis in 
relatively stable amounts, for medical purposes (where 
applicable according to local regulation), under the 
guidance, supervision, or prescription of a clinician. 
Patients who are either using cannabis or its derivatives 
or formulations or patients who have a positive drug 
screen for cannabis or its derivatives or formulations 
can be submitted to the medical monitor for 
consideration of participation in this study. Patients with 
a substance use disorder (by Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition, criteria) are 
excluded from this clinical trial. If per the investigator’s 
judgment, however, a patient does not meet the criteria 
for substance use disorder, a positive drug screen for 
cannabis or its metabolites, without medical 
explanation, will be discussed on a case-by-case basis 
between the research site, the Medical Monitor, and the 
sponsor to determine the patient’s eligibility, based on 
the information available. Patients should be advised 
that the recreational use of cannabis or its derivatives or 
formulations should be avoided during this study. 
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 CYP2D6
inhibitor. Prohibited medications that are associated 
with QTc prolongation are listed in Appendix H, Table 
10, while prohibited antipsychotic drugs are listed in 
Appendix H, Table 11.
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. 
Patients may be included in this study if they are using 
cannabis or formulations or derivatives of cannabis in 
relatively stable amounts, for medical purposes (where 
applicable according to local regulation), under the 
guidance, supervision, or prescription of a clinician. 
Patients who are either using cannabis or its derivatives 
or formulations or patients who have a positive drug 
screen for cannabis or its derivatives or formulations 
can be submitted to the medical monitor for 
consideration of participation in this study. Patients with 
a substance use disorder (by Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition, criteria) are 
excluded from this clinical trial. If per the investigator’s 
judgment, however, a patient does not meet the criteria 
for substance use disorder, a positive drug screen for 
cannabis or its metabolites, without medical
explanation, will be discussed on a case-by-case basis 
between the research site, the Medical Monitor, and the 
sponsor to determine the patient’s eligibility, based on 
the information available. Patients should be advised 
that the recreational use of cannabis or its derivatives or 
formulations should be avoided during this study. 
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 CYP2D6 
inhibitor. Prohibited medications that are associated 
with QTc prolongation are listed in Appendix H, Table 
10, while prohibited antipsychotic drugs are listed in 
Appendix H, Table 11.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
190
Original text with changes shown
New wording
Reason/Justification for change
8.1. Pharmacokinetic Assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bolded text added for emphasis
9.10. Pharmacokinetic/Pharmacodynamic Analysis
 
 
 
 
 
 
 
 
 
 
 
 
Clarification
10. QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix D for information regarding quality 
control and quality assurance. This includes information 
about protocol amendments, deviations and violations, 
responsibilities of the investigator to study personnel, 
study monitoring, and audit and inspection.
Refer to Appendix D for information regarding quality 
control and quality assurance. This includes information 
about protocol amendments, deviations, responsibilities 
of the investigator to study personnel, study monitoring, 
and audit and inspection.
Clarification 
15.
REFERENCES 
AUSTEDO® (deutetrabenazine) tablets (US prescribing 
information). Teva Pharmaceuticals USA, Inc; 20179. 
Available at: https://austedo.com/hd/pi.
AUSTEDO® (deutetrabenazine) tablets (US prescribing 
information). Teva Pharmaceuticals USA, Inc; 2019. 
Available at: https://austedo.com/hd/pi.
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
191
Original text with changes shown
New wording
Reason/Justification for change
Xenazine: Highlights of Prescribing Information. 
20185. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/20
15/021894s010lbl.pdfhttps://dailymed.nlm.nih.gov/dail
ymed/drugInfo.cfm?setid=ac768bab-8afa-4446-bc7f-
caeeffec0cda. Accessed 27 Oct 201505 Aug 2019.
Xenazine: Highlights of Prescribing Information. 2018. 
Available at: 
https://dailymed nlm.nih.gov/dailymed/drugInfo.cfm?se
tid=ac768bab-8afa-4446-bc7f-caeeffec0cda. Accessed 
05 Aug 2019.
Appendix A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative:
Teva Pharmaceutical Industries, 
 
Cell: 
Sponsor’s Authorized Representative:
Teva Pharmaceutical Industries, 
 
 
Cell: 
Clarification 
Pharmacokinetic Samples
Watson Pharma Pvt. Ltd. 
Seawoods Grand Central, Tower 2
Level-11, Wing-E, Plot No. R-1
Sector 40, Nerul, Navi Mumbai 400706 
Tel: 
Contact: 
Pharmacokinetic Samples
Watson Pharma Pvt. Ltd. 
Seawoods Grand Central, Tower 2
Level-11, Wing-E, Plot No. R-1
Sector 40, Nerul, Navi Mumbai 400706 
Tel: 
Contact: 
Addition
Scales and Central Rater for MD-CRS
Bracket Global LLC
575 East Swedesford Road
Suite 200
Wayne, PA
Scales and Central Rater for MD-CRS
Bracket Global LLC
575 East Swedesford Road
Suite 200
Wayne, PA
Addition


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
192
Original text with changes shown
New wording
Reason/Justification for change
19087
Tel: 
19087
Tel: 
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
patients, or parent(s)/legally acceptable 
representative must provide legal guardian(s), and 
caregivers must provide their respective written 
informed consent, and/or assent (as appropriate) the 
patients must give assent (as applicable) before any 
study related procedures are performed. 
Assent/consent may also be provided to 2 optional 
ICFs:
–
 
 
–
use of patient’s study videos for future analysis 
of gait digital markers and release of patient’s 
study videos for use in publications or 
educational presentations 
patients, parent(s)/legal guardian(s), and caregivers 
must provide their respective written informed 
consent and/or assent (as appropriate) before any 
study-related procedures are performed. 
Assent/consent may also be provided to 2 optional 
ICFs:
–
 
–
use of patient’s study videos for future analysis 
of gait digital markers and release of patient’s 
study videos for use in publications or 
educational presentations 
Clarification 
5.
Follow-Up (Weeks 16 and 17)
a. Week 16/End of Study follow-up visit (day 
112±2 days total from baseline), or 1 week 
after ET)
5.
Follow-Up (Weeks 16 and 17)
a. Week 16/End of Study follow-up visit (day 
112±2 days total from baseline)
Change originally included in Letter of 
Clarification #5 (Section 16.3).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
193
Original text with changes shown
New wording
Reason/Justification for change
6.
Unscheduled Visits
An unscheduled visit may be performed at any time 
during the study at the patient’s or parent’s/legally 
acceptable representative’scaregiver’s request and as 
deemed necessary by the investigator. The date and 
reason for the unscheduled visit will be recorded on the 
CRF as well as any other data obtained from procedures 
and assessments.
6.
Unscheduled Visits
An unscheduled visit may be performed at any time 
during the study at the patient’s or parent’s/caregiver’s 
request and as deemed necessary by the investigator. 
The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained 
from procedures and assessments.
Clarification 
APPENDIX D. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations and 
Violations
Important Protocol DeviationsViolations
Any deviation from the protocol that affects, to a 
significant degree, (a) the safety, physical, or mental 
integrity of the patients in the study and/or (b) the 
scientific value of the study will be considered an
important protocol deviationviolation. PImportant 
protocol deviationsviolations 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 Good 
Clinical Practice (GCP) guidelines; noncompliance to 
IMP administration; and use of prohibited medications. 
Protocol violations will be identified and recorded by 
investigational center personnel in the case report form 
(CRF). All important protocol deviationsviolations will 
be reported to the responsible IEC/IRB, as required.
When an important protocol deviationviolation is 
reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the 
patient to continue in the study, with documented 
approval from the medical expert. The decision will be 
based on ensuring the safety of the patient and 
preserving the integrity of the study.
Changes in the inclusion and exclusion criteria of the 
protocol are not prospectively granted by the sponsor. If 
Protocol Amendments and Protocol Deviations
Important Protocol Deviations
Any deviation from the protocol that affects, to a 
significant degree, (a) the safety, physical, or mental 
integrity of the patients in the study and/or (b) the 
scientific value of the study will be considered an 
important protocol deviation. Important protocol 
deviations may include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-
specific inclusion and exclusion criteria, primary 
objective variable criteria, or Good Clinical Practice 
(GCP) guidelines; noncompliance to IMP 
administration; and use of prohibited medications. All 
important protocol deviations will be reported to the 
responsible IEC/IRB, as required.
When an important protocol deviation is reported, the 
sponsor will determine whether to withdraw the patient 
from the study or permit the patient to continue in the 
study, with documented approval from the medical 
expert. The decision will be based on ensuring the 
safety of the patient and preserving the integrity of the 
study.
Changes in the inclusion and exclusion criteria of the 
protocol are not prospectively granted by the sponsor. If 
investigational center personnel learn that a patient who 
did not meet protocol inclusion and exclusion criteria 
was entered in a study, they must immediately inform 
Clarification 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
194
Original text with changes shown
New wording
Reason/Justification for change
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 important protocol deviationviolation. 
If such patient has already completed the study or has 
withdrawn early, no action will be taken, but the 
deviationviolation will be recorded.
the sponsor of the important protocol deviation. If such 
patient has already completed the study or has 
withdrawn early, no action will be taken, but the 
deviation will be recorded.
APPENDIX F. BIRTH CONTROL METHODS AND PREGNANCY TESTING
Females (aged 12 years or older) of childbearing 
potential are defined as the following:
Females of childbearing potential are defined as the 
following:
Clarification
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS
Medications that are allowed, provided that conditions 
outlined in the table are met, are shown in Table 9. 
Investigators are encouraged to contact the medical 
monitor for any questions regarding the medications 
listed below.  
Medications that are allowed, provided that conditions 
outlined in the table are met, are shown in Table 9. 
Investigators are encouraged to contact the medical 
monitor for any questions regarding the medications 
listed below.  
Table 9: Allowed Medications
Row: Allowed strong CYP2D6 inhibitorsa
Row: Allowed strong CYP2D6 inhibitorsa
Clarification
Column: Generic/Drug class
Row: Cannabis or formulations or derivatives of 
cannabis
Column: Generic/Drug class
Row: Cannabis or formulations or derivatives of 
cannabis 
Column: Condition
Row: Patients may be included in this study if they are 
using cannabis or formulations or derivatives of 
cannabis in relatively stable amounts, for medical 
purposes, under the guidance, supervision, or 
prescription of a clinician.
Column: Condition
Row: Patients may be included in this study if they are 
using cannabis or formulations or derivatives of 
cannabis in relatively stable amounts, for medical 
purposes, under the guidance, supervision, or 
prescription of a clinician. 
Table 12: Total Blood Volumes
Row 1
Column 4: Week 16/EOS
Row 1
Column 4: Week 16/EOS
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
195
16.6.
Letter of Clarification 06 Dated 05 August 2019


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
196
16.7.
Letter of Clarification 05 Dated 16 January 2019


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
197


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
198
16.8.
Amendment 01 Dated 20 December 2018
The primary reason for this amendment is to address comments and recommendations from the 
Food and Drug Administration in relation to study design and the scales used to perform 
assessments. This amendment is considered to be substantial (ie, requires approval by competent 
authorities, 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.
Table 3 (Study Procedures and Assessments) has been revised to reflect changes described 
below.
Other minor or editorial 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–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
199
Original text with changes shown
New wording
Reason/Justification for change
TITLE PAGE affected by this change:
Confidentiality Statement
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.
Confidentiality Statement
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.
Confidentiality language updated per 
template. Letter of Clarification 04
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1 Primary and Secondary Study Objectives and Endpoints “Intext table” (Other sections affected by anyone of these changes: Sections 2.1, 2.1.2, 3.1, 
3.4, 3.5, 4.1, 5.2.3, 5.10.3, 6.2.1, 6.3.5, 7, 7.2, 9.2.2, 9.5.1, 9.5.2, 9.5.2.1, 9.5.2.2, 9.5.3, 9.5.4, 9.5.4.1, 9.5.5, 9.6, 9.7, Table 3, and Appendix C)
The primary efficacy endpoint is the change from 
baseline to week 15 in the MD-CRS part II total score
(movement disorder severity, centrally read) (TEV-
50717 versus placebo).
The primary efficacy endpoint is the change from 
baseline to week 15 in the MD-CRS part II total score 
(movement disorder severity, centrally read) (TEV-
50717 versus placebo).
Updating the verbiage associated with 
MD-CRS II and how the scale is to be 
measured for clarity.
The key secondary efficacy endpoints (TEV-50717 
versus placebo) are the following:
•
MD-CRS part I total score (general assessment, 
centrally read) change from baseline to week 15
Other efficacy measures and endpoints (TEV-50717 
versus placebo) include the following:
•
MD-CRS Global Index (calculated from MD CRS 
parts I and II total scores)
•
PEDI-CAT (ADL, parent/caregiver completed, 
counter content-balanced version)
The safety variables include adverse events (and the 
number of patients who withdraw from the study due to 
adverse events), vital signs, laboratory tests 
(hematology, chemistry, and urinalysis), ECG 
measurements, CBCL, ESRS, ESS, and the children’s 
C-SSRS.
The key secondary efficacy endpoints (TEV-50717 
versus placebo) are the following:
•
MD-CRS part I total score (general assessment, 
centrally read) change from baseline to week 15
Other efficacy measures and endpoints (TEV-50717 
versus placebo) include the following:
•
MD-CRS Global Index (calculated from MD CRS 
parts I and II total scores)
•
PEDI-CAT (ADL, parent/caregiver completed, 
content-balanced version)
The safety variables include adverse events (and the 
number of patients who withdraw from the study due to 
adverse events), vital signs, laboratory tests 
(hematology, chemistry, and urinalysis), ECG 
measurements, CBCL, ESRS, ESS, and the children’s 
C-SSRS.
Updating the verbiage associated with 
MD-CRS I and how the scale is to be 
measured for clarity.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
200
Original text with changes shown
New wording
Reason/Justification for change
2.1.1.
Justification of Primary Endpoint 
The MD-CRS has 2 parts: part I for general assessment 
of the functioning and impact of CP on the activities of 
the patient, and part II for a specific motor assessment 
of the severity of the movement disorder. The raw score 
of part II (0 to 28) is normalized in a scale of 0 to 1 as 
Index II (MD CRS II). Similar normalization is done for 
the part I raw score as Index I (0 to 1) and for the sum 
of the raw scores of parts I and II as the Global Index (0 
to 1).
The MD-CRS has 2 parts: part I for general assessment 
of the functioning and impact of CP on the activities of 
the patient, and part II for a specific motor assessment 
of the severity of the movement disorder.
Changes following FDA request..
3.
STUDY DESIGN
3.1. General Study Design and Study Schematic Diagram (Other sections affected by this change: Appendix C)
Screening period (up to 31 days): 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,; 12-lead 
ECG,; along with MD-CRS part II rating scale 
(physician rated, with video recordedrecording, 
centrally read with video review, centrally read by the 
Enrollment Adjudication Board [EAB]) to assess 
severity of dyskinesia; Clinical Global Impression of 
Severity (CGI-S) to assess global clinical impression of 
DCP severity, comorbid CP symptoms, and behavioral 
status. The option; children’s Columbia-Suicide 
Severity Rating Scale (C-SSRS); assessment of drug-
induced parkinsonism according to the Extrapyramidal 
Symptom Rating Scale (subscales I and II; ESRS); 
assessment of change in behavior according to the Child 
Behavior Checklist (for ages 6-18) (CBCL) 
questionnaire; and assessment of sedation according to 
the Epworth Sleepiness Scale (for children and 
adolescents) (ESS) questionnaire of using a telephone 
with non-recording live video will be made possible, 
Screening period (up to 31 days): 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; 12-lead 
ECG; along with MD-CRS part II (physician rated, with 
video recording, centrally read with video review, 
centrally read by the Enrollment Adjudication Board 
[EAB]) to assess severity of dyskinesia; Clinical Global 
Impression of Severity (CGI-S) to assess global clinical 
impression of DCP severity, comorbid CP symptoms, 
and behavioral status; children’s Columbia-Suicide 
Severity Rating Scale (C-SSRS); assessment of drug-
induced parkinsonism according to the Extrapyramidal 
Symptom Rating Scale (subscales I and II; ESRS); 
assessment of change in behavior according to the Child 
Behavior Checklist (for ages 6-18) (CBCL) 
questionnaire; and assessment of sedation according to 
the Epworth Sleepiness Scale (for children and 
adolescents) (ESS) questionnaire of using a telephone 
with non-recording live video will be made possible,
and the adoption of live video to support 
Clarification has been provided for 
assessments to be completed during the 
screening period, and new assessments 
have been included.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
201
Original text with changes shown
New wording
Reason/Justification for change
and the adoption of live video to support 
patient/caregiver interview will then be maintained 
throughout the study for the evaluation of 
safety/tolerability and dyskinesia severity. Screening 
may be conducted over 2 separate visits at the discretion 
of the investigator. The diagnosis of CP and DCP will 
be established based on clinical features as described in 
the inclusion/exclusion criteria. The EAB will also 
confirm, based on video recordings, that choreiform is 
clinically the predominant movement disorder of the 
patient’s DCP. EAB assessment results will be available 
to the investigator prior to baseline and randomization. 
At all other visits, the MD-CRS part II rating scale will 
be administered by the investigational center physician 
and video recorded review for central-blinded reading.
patient/caregiver interview will then be maintained 
throughout the study for the evaluation of 
safety/tolerability and dyskinesia severity. Screening 
may be conducted over 2 separate visits at the discretion 
of the investigator. The diagnosis of CP and DCP will 
be established based on clinical features as described in 
the inclusion/exclusion criteria. The EAB will also 
confirm, based on video recordings, that choreiform is 
clinically the predominant movement disorder of the 
patient’s DCP. EAB assessment results will be available 
to the investigator prior to baseline and randomization. 
At all other visits, the MD-CRS part II will be 
administered by the investigational center physician and 
video review for central blinded reading.
Titration period (7 weeks): Patients who remain eligible 
for participation in the study will be randomized at the 
baseline visit (day 1) and instructed to take the first dose 
of blinded IMP the following morning, without regard 
to food. with food (eg, a snack) and should not be taken 
on an empty stomach.
Safety/tolerability in-clinic 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.identifying subjects at risk for suicide 
according to the C-SSRS questionnaire, assessment of 
drug-induced parkinsonism according to the ESRS 
(subscales I and II), assessment of change in behavior 
according to the CBCL questionnaire, and assessment 
of sedation according to the ESS questionnaire.
Titration period (7 weeks): Patients who remain eligible 
for participation in the study will be randomized at the 
baseline visit (day 1) and instructed to take the first dose 
of blinded IMP the following morning, with food (eg, a 
snack) and should not be taken on an empty stomach.
Safety/tolerability in-clinic evaluations during titration 
include assessment of vital signs, monitoring for 
adverse events and concomitant medications, 12-lead 
ECGs, identifying subjects at risk for suicide according 
to the C-SSRS questionnaire, assessment of drug-
induced parkinsonism according to the ESRS (subscales 
I and II), assessment of change in behavior according to 
the CBCL questionnaire, and assessment of sedation 
according to the ESS questionnaire.
Clarification has been provided that the 
IMP should be administered with food.
Assessments to be completed during the 
titration period have been updated and 
added.
3.5. Schedule of Study Procedures and Assessments (Other sections affected by any one of these changes: Section 6.1, 6.2.1, 6.2.2, 6.2.3, 6.3.7, 6.3.8, 
Appendix C, and Appendix I)
Row: Study week
Column: Follow-up
16/EOS (Day 112)
Row: Study week
Column: Follow-up
16/EOS (Day 112)
The Schedule of Assessments has been 
updated to reflect all changes made to the 
study design. Assessments and time points 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
202
Original text with changes shown
New wording
Reason/Justification for change
Row: Vital signs and weight
Column: Screening, -31 days
X
Row: Vital signs and weight
Column: Screening, -31 days
X
for assessments have been added and/or 
removed as indicated (left). Three new 
safety scales have been included. 
Footnotes have also been updated for 
clarity and to align with updates made to 
the study design.
Row: Physical examination
Column: BL, Day 1
X
Row: Physical examination
Column: BL, Day 1
X
Row: Neurological examination
Column: BL, Day 1
X
Row: Neurological examination
Column: BL, Day 1
X
Row: Urine drug screen
Column: Titration, Week 3 (Day 21) 
X
Row: Urine drug screen
Column: Titration, Week 3 (Day 21) 
X
Row: Urine drug screen
Column: Maintenance, Week 9 (Day 63)
X
Row: Urine drug screen
Column: Maintenance, Week 9 (Day 63)
X
Row: Urine drug screen
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: Urine drug screen
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: β-HCG test
Column: Titration, Week 3 (Day 21) 
X
Row: β-HCG test
Column: Titration, Week 3 (Day 21) 
X
Row: β-HCG test
Column: Titration, Week 7 (Day 49)
X
Row: β-HCG test
Column: Titration, Week 7 (Day 49)
X
Row: β-HCG test
Column: Maintenance, Week 9 (Day 63)
X
Row: β-HCG test
Column: Maintenance, Week 9 (Day 63)
X
Row: β-HCG test
Row: β-HCG test


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
203
Original text with changes shown
New wording
Reason/Justification for change
Column: Maintenance, Week 12 (Day 84)
X
Column: Maintenance, Week 12 (Day 84)
X
Row: β-HCG test
Column: Follow-up, Week 16/EOS (Day 112)  
X 
Row: β-HCG test
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: MD-CRS part I (physician rated, with video 
recording)
Column: Study week
MD-CRS part I (physician rated, with video recording)
Row: MD-CRS part I (physician rated, with video 
recording)
Column: Screening, -31 days
X
Row: MD-CRS part I (physician rated, with video 
recording)
Column: Screening, -31 days
Row: MD-CRS part I (physician rated, with video 
recording)
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: MD-CRS part I (physician rated, with video 
recording)
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: MD-CRS part I (centrally read, with video review)
Column: Study week
Row: MD-CRS part I (centrally read, with video review)
Column: Study week
Row: MD-CRS part I (centrally read, with video review)
Column: BL, Day 1
X
Row: MD-CRS part I (centrally read, with video review)
Column: BL, Day 1
X
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 9 (Day 63)
X
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 9 (Day 63)
X
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 12 (Day 84)
X
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 12 (Day 84)
X
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 15/ET (Day 105)
Row: MD-CRS part I (centrally read, with video review)
Column: Maintenance, Week 15/ET (Day 105)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
204
Original text with changes shown
New wording
Reason/Justification for change
X
X
Row: MD-CRS part I (centrally read, with video review)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: MD-CRS part I (centrally read, with video review)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: MD-CRS part II (physician rated, with video 
recording)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: MD-CRS part II (physician rated, with video 
recording)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: MD-CRS part II (centrally read, with video 
recordingreview)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: MD-CRS part II (centrally read, with video 
review)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: CaGI-I
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: CaGI-I
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: CGI-I (global, physician rated)
Column: Follow-up Week 16/EOS (Day 112)
X
Row: CGI-I (global, physician rated)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: CGI-S (global, physician rated)
Column: Screening, -31 days
X
Row: CGI-S (global, physician rated)
Column: Screening, -31 days
X
Row: CGI-S (global, physician rated)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: CGI-S (global, physician rated)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: PGI-I (global, patient/caregiver)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: PGI-I (global, patient/caregiver)
Column: Follow-up, Week 16/EOS (Day 112)
X
Row: ESRS subscales I and II
Column: Study week
Row: ESRS subscales I and II
Column: Study week


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
205
Original text with changes shown
New wording
Reason/Justification for change
Row: ESRS subscales I and II
Column: Screening, -31 days
X
Row: ESRS subscales I and II
Column: Screening, -31 days
X
Row: ESRS subscales I and II
Column: BL, Day 1
X
Row: ESRS subscales I and II
Column: BL, Day 1
X
Row: ESRS subscales I and II
Column: Titration, Week 3 (Day 21)
X
Row: ESRS subscales I and II
Column: Titration, Week 3 (Day 21)
X
Row: ESRS subscales I and II
Column: Titration, Week 7 (Day 49)
X
Row: ESRS subscales I and II
Column: Titration, Week 7 (Day 49)
X
Row: ESRS subscales I and II
Column: Maintenance, Week 9 (Day 63)
X
Row: ESRS subscales I and II
Column: Maintenance, Week 9 (Day 63)
X
Row: ESRS subscales I and II
Column: Maintenance, Week 12 (Day 84)  
X
Row: ESRS subscales I and II
Column: Maintenance, Week 12 (Day 84)  
X
Row: ESRS subscales I and II
Column: Maintenance, Week 15/ET (Day 105)  
X
Row: ESRS subscales I and II
Column: Maintenance, Week 15/ET (Day 105)  
X
Row: ESRS subscales I and II
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: ESRS subscales I and II
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: ESRS subscales I and II
Column: Unscheduled  
X
Row: ESRS subscales I and II
Column: Unscheduled  
X
Row: CBCL
Row: CBCL


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
206
Original text with changes shown
New wording
Reason/Justification for change
Column: Study week
Column: Study week
Row CBCL
Column: Screening, -31 days
X
Row: CBCL
Column: Screening, -31 days
X
Row: CBCL
Column: BL, Day 1
X
Row: CBCL
Column: BL, Day 1
X
Row: CBCL
Column: Titration, Week 3 (Day 21)
X
Row: CBCL
Column: Titration, Week 3 (Day 21)
X
Row: ESRS subscales I and II
Column: Titration, Week 7 (Day 49)
X
Row: ESRS subscales I and II
Column: Titration, Week 7 (Day 49)
X
Row: CBCL
Column: Maintenance, Week 9 (Day 63)
X
Row: CBCL
Column: Maintenance, Week 9 (Day 63)
X
Row: CBCL
Column: Maintenance, Week 12 (Day 84)  
X
Row: CBCL
Column: Maintenance, Week 12 (Day 84)  
X
Row: CBCL
Column: Maintenance, Week 15/ET (Day 105)  
X
Row: CBCL
Column: Maintenance, Week 15/ET (Day 105)  
X
Row: CBCL
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: CBCL
Column: Follow-up, Week 16/EOS (Day 112)  
X
Row: CBCL
Column: Unscheduled  
X
Row: CBCL
Column: Unscheduled  
X


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
207
Original text with changes shown
New wording
Reason/Justification for change
Row: Assess adverse events
Column: Screening, -31 days
X
Row: Assess adverse events
Column: Screening, -31 days
4.2 Patient Exclusion Criteria 
Not applicable.
12. Patients with a history of torsade de pointes, 
congenital long QT syndrome, bradyarrhythmias, other 
cardiac arrhythmias, or uncompensated heart failure.
Included an additional exclusion criteria 
pertaining to cardiac history.
Letter of Clarification 03
1314.
Patient has evidence of clinically significant 
renal impairment, indicated by a serum creatinine >1.5 
× ULN at screening.
14. Patient has evidence of clinically significant renal 
impairment, indicated by a serum creatinine >1.5 × 
ULN at screening.
Added the serum creatinine range that will 
indicate clinically significant renal 
impairment for clarity.
Letter of Clarification 03
5.1. Investigational Medicinal Products Used in the Study
5.1.1.
Test Investigational Medicinal Product (Other sections affected by this change: Section 3.1, 5.1.1.1, and 5.1.1.2)
Test IMP (TEV-50717 [deutetrabenazine, previously 
SD-809]) will be administered as oral tablets. The IMP 
is a matrix formulation and is designed to be taken 
without regard to food. The effects of food on the 
bioavailability of TEV 50717 were studied in patients 
administered a single dose with and without food. Food 
had no effect on the area under the plasma drug 
concentration time curve of α HTBZ or β HTBZ, 
although the maximum serum concentration was 
increased by approximately 50% in the presence of food 
(AUSTEDO USPI 2017). with food (eg, a snack) and 
should not be taken on an empty stomach.
Test IMP (TEV-50717 [deutetrabenazine, previously 
SD-809]) will be administered as oral tablets with food 
(eg, a snack) and should not be taken on an empty 
stomach.
Updated guidance of administration of 
IMP.
5.8. Temporary Discontinuation of Investigational Medicinal Product
Dose adjustments should be made based on all available 
information, including the patient’s and 
parent’s/caregiver’s reports of adverse events and motor 
function improvement, 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 
Dose adjustments should be made based on all available 
information, including the patient’s and 
parent’s/caregiver’s reports of adverse events and motor 
function improvement, 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 
Updated guidance on dose adjustments for 
temporary discontinuation of IMP based 
on the number of dose reductions or 
duration of dose suspension.
Letter of Clarification 04


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
208
Original text with changes shown
New wording
Reason/Justification for change
should be notified. Suspension of IMP treatment for up 
to 1 week, if warranted, is allowed. If the patient restarts 
IMP within 7 days of suspension, the full dose of IMP 
may be resumed without titration at the same dose level 
or 1 dose lower (last tolerated dose). Suspension of IMP 
treatment for adverse events must be reviewed with the 
medical monitor before IMP treatment is restarted. 
Suspensions for more than 7 days must be reviewed by 
the medical monitor before therapy is restarted, and also 
to determine if there is adequate time for patients to be 
reinstated and complete study evaluations. The reason 
for a dose reduction or suspension must be clearly 
documented in the related adverse event form.
Dose reduction or suspension is allowed once during the 
titration period and once during the maintenance period. 
Patients who restart IMP treatment will remain at the 
current dose throughout that period with no further dose 
changes and will, otherwise, follow the visit schedule as 
outlined in the protocol. If a dose reduction 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.
If a dose suspension occurs before a scheduled clinic 
visit, an unscheduled visit should be scheduled as soon 
as possible so that efficacy evaluations can be 
performed at least 5 days after the change. 
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.
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP must be 
suspended. The medical monitor must be contacted to 
determine the appropriate investigation and treatment. 
IMP treatment may only be restarted once serum 
potassium and/or magnesium levels have normalized. 
The patients who restart IMP treatment will follow the 
should be notified. Suspension of IMP treatment for up 
to 1 week, if warranted, is allowed. If the patient restarts 
IMP within 7 days of suspension, the full dose of IMP 
may be resumed without titration at the same dose level 
or 1 dose lower (last tolerated dose). Suspension of IMP 
treatment for adverse events must be reviewed with the 
medical monitor before IMP treatment is restarted. 
Suspensions for more than 7 days must be reviewed by 
the medical monitor before therapy is restarted, and also 
to determine if there is adequate time for patients to be 
reinstated and complete study evaluations. The reason 
for a dose reduction or suspension must be clearly 
documented in the related adverse event form.
Dose reduction or suspension is allowed once during the 
titration period and once during the maintenance period. 
Patients who restart IMP treatment will remain at the 
current dose throughout that period with no further dose 
changes and will, otherwise, follow the visit schedule as 
outlined in the protocol. If a dose reduction 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. 
If a dose suspension occurs before a scheduled clinic 
visit, an unscheduled visit should be scheduled as soon 
as possible so that efficacy evaluations can be 
performed at least 5 days after the change. 
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.
If a patient’s serum potassium or magnesium level falls 
below the lower limit of normal, IMP must be 
suspended. The medical monitor must be contacted to 
determine the appropriate investigation and treatment. 
IMP treatment may only be restarted once serum 
potassium and/or magnesium levels have normalized. 
The patients who restart IMP treatment will follow the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
209
Original text with changes shown
New wording
Reason/Justification for change
visit schedule as outlined in Table 3. Patients who 
withdraw from the study will proceed as described in 
Section 4.3.
visit schedule as outlined in Table 3. Patients who 
withdraw from the study will proceed as described in 
Section 4.3.
5.11.
Total Blood Volume (Other sections affected by this change: Appendix I)
The total blood volume to be collected for each patient 
in this study is approximately 4140 mL (at maximum), 
as detailed in Appendix I.
The total blood volume to be collected for each patient 
in this study is approximately 40 mL (at maximum), as 
detailed in Appendix I.
Updated total blood draw volumes to align 
with updated volumes presented in table 
12.
6.1. Primary Efficacy Measure
The MD-CRS part II does not differentiate whether the 
dyskinesia is of the dystonic or choreiform phenotype, 
and the worst dyskinesia in any of the regions observed 
during the assessment session will be taken as the score 
for each affected body region. The minimum score is 0 
(absent) and the maximum score is 28 
(marked/prolonged).
For data analysis, the raw score of MD CRS part II 
items (0 to 28) is normalized to a 0 to 1 range as Index 
II (MD CRS II). Raw scores (0 to 28) reflecting severity 
of the movement disorder will be used to qualify a 
patient for inclusion in the study.
The MD-CRS part II does not differentiate whether the 
dyskinesia is of the dystonic or choreiform phenotype, 
and the worst dyskinesia in any of the regions observed 
during the assessment session will be taken as the score 
for each affected body region. The minimum score is 0 
(absent) and the maximum score is 28 
(marked/prolonged).
Streamlined the description of the 
MD-CRS part II to include only necessary 
protocol details. Further details to be 
provided in the SAP.
6.2. Key Secondary Efficacy Measures
6.2.1.
Movement Disorder-Childhood Rating Scale Part I Total Score
The MD-CRS part I evaluates impact of DCP on the 
activities of the patient and provides a general 
assessment of the movement disorder of motor function 
(7 items), oral/verbal function (3 items), self-care (3 
items), and attention/alertness (2 items) on a scale of 0 
(present) to 4 (absent) (Battini et al 2008, Battini et al 
2014). The rawminimum score of MD CRS part I (is 0 
toand the maximum score is 60) is normalized to a 0 to 
1 range as Index I (MD CRS I).
The MD-CRS part I evaluates impact of DCP on the 
activities of the patient and provides a general 
assessment of the movement disorder of motor function 
(7 items), oral/verbal function (3 items), self-care (3 
items), and attention/alertness (2 items) on a scale of 0 
(present) to 4 (absent) (Battini et al 2008, Battini et al 
2014). The minimum score of MD-CRS part I is 0 and 
the maximum score is 60).
Streamlined the description of the 
MD-CRS part I to include only necessary 
protocol details. Further details to be 
provided in the SAP.
6.3. Other Efficacy Measures
6.3.1.
Movement Disorder-Childhood Rating Scale Global Index


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
210
Original text with changes shown
New wording
Reason/Justification for change
The MD-CRS Global Index is a global measure of the 
MD-CRS that consolidates the information from 
Indexesparts I and II using the method of weighted 
means of the 2 normalized indexes obtained from each 
part (Battini et al 2008). The minimum score is 0 and 
the maximum score is 1.
The MD-CRS Global Index is a global measure of the 
MD-CRS that consolidates the information from parts I 
and II using the method of weighted means of the 2 
normalized indexes obtained from each part (Battini et 
al 2008). The minimum score is 0 and the maximum 
score is 1.
Streamlined the description of the 
calculation of the MD-CRS Global Index.
6.3.4.
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia
The UHDRS-Total Maximal Dystonia (TMD) is part of 
the UHDRS-TMS assessment and assesses the severity 
of dystonia in the trunk and the 4 extremities. The 
minimum score is 0 (absent) and the maximum score is 
20 (marked/prolonged) (Huntington Study Group 1996).
The UHDRS-Total Maximal Dystonia (TMD) is part of 
the UHDRS-TMS assessment and assesses the severity 
of dystonia in the trunk and the 4 extremities. The 
minimum score is 0 (absent) and the maximum score is 
20 (marked/prolonged) (Huntington Study Group 1996).
Streamlined the description of the method 
to measure the UHDRS-TMD.
7.1.6.
Protocol-Defined Adverse Events of Special Interest
No protocol defined adverse events of special interest 
for expedited reporting were identified for this study. 
Events of drug-induced parkinsonism, changes in 
behavior, and sleepiness will be monitored using 
standardized scores and presented as part of safety 
analysis (see Section 7.2).
No protocol defined adverse events of special interest 
for expedited reporting were identified for this study. 
Events of drug-induced parkinsonism, changes in 
behavior, and sleepiness will be monitored using 
standardized scores and presented as part of safety 
analysis (see Section 7.2).
Updated language based on 
communications with regulatory 
authorities and their feedback.
7.2.2.
Child Behavior Checklist (for Ages 6-18) (Other sections affected by this change: Section 3.5, Table 3)
Not applicable.
The CBCL assesses behavioral and emotional status in 
children ages 6 through 18 years of age as reported by 
the parent/caregiver (Achenbach and Ruffle 2000; 
Achenbach 2005). The full CBCL has two parts, a 
Competence Scale (Parts I to VII) and a Syndrome 
Scale (behavioral items).
The Competence Scale (Parts I to VII) assesses various 
activities (eg, sports, hobbies, games, organizations, 
clubs, teams, groups, jobs, and chores), interpersonal 
relationships, and academic performance. 
The Syndrome Scale comprises 118 questions related to 
problem behaviors. This study will use a recall period of 
“now or within the last week,” representing a 
modification from the original scale, which was “now or 
Added section to include a description of 
an additional safety scale to be assessed in 
the study (ie, CBCL).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
211
Original text with changes shown
New wording
Reason/Justification for change
within the last 6 months”. For each item, the 
parent/caregiver will circle 0 if the item is not true of 
their child, 1 if the item is somewhat or sometimes true, 
and 2 if the item is very true or often true. 
The CBCL is part of the Achenbach System of 
Empirically Based Assessment that identifies 
syndromes that are behavioral clusters that indicate 
certain types of behavioral, social, or emotional 
problems. The problem behaviors are scored on the 
following 8 empirically based syndromes: 
anxious/depressed, withdrawn/depressed, somatic 
complaints, social problems, thought problems, 
attention problems, rule-breaking behavior, and 
aggressive behavior. 
The Competence and Syndrome Scales are displayed on 
profiles in relation to gender and age-specific 
percentiles and T scores based on national normative 
samples.  
The full CBCL assessment (Competence and Syndrome 
Scales) will be completed at screening and at week 
15/ET. Only the CBCL Syndrome scale will be 
completed at baseline, weeks 3, 7, 9, 12, and 16/EOS.
7.2.3.
Extrapyramidal Symptom Rating Scale
Not applicable.
The ESRS was designed to assess 4 types of drug-
induced movement disorders: parkinsonism, akathisia, 
dystonia, and TD (Chouinard and Margolese 2005). In 
this study, parkinsonism and akathisia will be evaluated 
with subscales I (subjective questionnaire) and II 
(evaluation for parkinsonism/akathisia). The ESRS is 
administered at screening; baseline; and weeks 3, 7, 9, 
12, 15/ET, and 16/EOS.
The subscale I of the ESRS questionnaire rates 
subjective parkinsonism/akathisia at periods other than 
the day of examinations during the last 7 days. It is 
scored on a 4-point scale (0=Absent, 1=Mild, 
2=Moderate, or 3=Severe). The evaluation takes into 
Added section to include a description of 
an additional safety scale to be assessed in 
the study (ie, ESRS).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
212
Original text with changes shown
New wording
Reason/Justification for change
account the verbal report of the patient on: 1) the 
frequency and duration of the symptom during the day, 
2) the number of days the symptom was present during 
the last week, and 3) the subjective evaluation of the 
intensity of the symptom by the patient. 
The subscale II of the ESRS questionnaire for 
evaluation of parkinsonism and akathisia includes 17 
items with scores ranging from 0-102 to assess the 
following: tremor (0–48), gait and posture (0–6), 
postural stability (0 6), rigidity (0–24), expressive 
automatic movements (0–6), bradykinesia (0-6), and 
akathisia (0–6).
7.2.4.
Epworth Sleepiness Scale (for Children and Adolescents)
Not applicable.
The ESS is a self-administered questionnaire composed 
of 8 questions that provide a measure of a patient’s 
general level of daytime sleepiness (Johns 1991). Johns 
(2015) proposed the ESS as the official modified 
version of the ESS for children and adolescents. In 
2017, Janssen et al published results of their validation 
analysis and concluded that the ESS developed for 
children and adolescents is a reliable and internally 
valid measure of daytime sleepiness in adolescents 12 to 
18 years of age, but further studies are needed to 
establish the internal validity of the questionnaire for 
children under 12 years and the external validity and 
accuracy of cut-off points for children and adolescents. 
The ESS is administered at screening; baseline; and 
weeks 3, 7, 9, 12, 15/ET, and 16/EOS. The ESS asks 
respondents to rate, on a 4 point Likert scale (0–3), their 
usual chances of dozing off or falling asleep in different 
situations or activities that most people engage in as part 
of their daily lives. The total ESS score is the sum of 8 
item scores and can range between 0 and 24 with the 
higher the score indicating a higher level of daytime 
sleepiness. Most people can complete the ESS without 
assistance in 2 or 3 minutes.
Categories
Added section to include a description of 
an additional safety scale to be assessed in 
the study (ie, ESS).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
213
Original text with changes shown
New wording
Reason/Justification for change
•
0=would never fall asleep
•
1=slight chance of falling asleep
•
2=moderate chance of falling asleep
•
3=high chance of falling asleep
7.11.
Neurological Examinations
Any neurological examination finding that is judged by 
the investigator as a potentially clinically significant 
change (worsening) compared with the 
screeningbaseline value will be considered an adverse 
event, recorded on the CRF, and monitored as described 
in Section 7.1.2.
Any neurological examination finding that is judged by 
the investigator as a potentially clinically significant 
change (worsening) compared with the baseline value 
will be considered an adverse event, recorded on the 
CRF, and monitored as described in Section 7.1.2.
Updated to clarify that the baseline value 
will be used as a comparator for 
neurological examination findings.
7.12.
Concomitant Medication or Treatment
Concomitant therapy or medication usage will be 
monitored throughout the study according to time points 
detailed in Table 3. 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. Of note, any 
formulation/derivative of cannabis is prohibited during 
the study.
Concomitant therapy or medication usage will be 
monitored throughout the study according to time points 
detailed in Table 3. 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. Of note, any 
formulation/derivative of cannabis is prohibited during 
the study.
Updated language to include a statement 
on the prohibition of cannabis during the 
study.
8.3.1.
CYP2D6 Genotyping/Pharmacogenetics (Other sections affected by this change: Appendix I)
At the screening visit, a mandatory blood sample (43.0 
to 5.0 mL) will be obtained for analysis of CYP2D6 
genotype from all patients in the study at the time point 
detailed in Table 3. The CYP2D6 genotype results will 
be provided to the RTSM, which drives each patient’s 
dose regimen, and the patient’s genotype for CYP2D6 
will remain blinded during the conduct of the study. 
 
 
 
At the screening visit, a mandatory blood sample (3.0 to 
5.0 mL) will be obtained for analysis of CYP2D6 
genotype from all patients in the study at the time point 
detailed in Table 3. The CYP2D6 genotype results will 
be provided to the RTSM, which drives each patient’s 
dose regimen, and the patient’s genotype for CYP2D6 
will remain blinded during the conduct of the study. 
 
 
 
 
Updated to correct the blood volume to be 
taken at screening. 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
214
Original text with changes shown
New wording
Reason/Justification for change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.1. Sample Size and Power Considerations
The initial sample size estimation of approximately 185 
patients randomized to TEV-50717 versus placebo in a 
2:1 ratio (approximately 124 in the TEV-50717 group; 
approximately 61 in the placebo group) is the sample 
size required to obtain a statistically significant result in 
the primary analysis based on a 1-sided test for mean 
difference at a significance level of α=0.025 with a 
power of approximately 90%, assuming a mean 
difference of 0.0631.8 and a standard deviation (SD) of 
0.1263.5 in each treatment group. 
The initial assumptions regarding the mean difference 
and SD are based on the change from baseline to month 
6 in patients treated with trihexyphenidyl reported by 
Battini et al (2014), assuming an effect size of 55% for 
TEV-50717 versus placebo. The effect size of 55% was 
assumed based on the observed effect sizes of TEV-
50717 in the pivotal studies in HD and TD. In the 
current study, these assumptions correspond to a mean 
difference of 2.0.07 in MD-CRS part II total score and 
an SD of 0.1263.5 in each treatment group.
The rate of missing not at random (MNAR) data for the 
primary analysis is expected to be 10%. MNAR data 
will be imputed in a conservative manner as if they were 
obtained from patients in the placebo treatment group, 
The initial sample size estimation of approximately 185 
patients randomized to TEV-50717 versus placebo in a 
2:1 ratio (approximately 124 in the TEV-50717 group; 
approximately 61 in the placebo group) is the sample 
size required to obtain a statistically significant result in 
the primary analysis based on a 1-sided test for mean 
difference at a significance level of α=0.025 with a 
power of approximately 90%, assuming a mean 
difference of 1.8 and a standard deviation (SD) of 3.5 in 
each treatment group. 
The initial assumptions regarding the mean difference 
and SD are based on the change from baseline to month 
6 in patients treated with trihexyphenidyl reported by 
Battini et al (2014), assuming an effect size of 55% for 
TEV-50717 versus placebo. The effect size of 55% was 
assumed based on the observed effect sizes of TEV-
50717 in the pivotal studies in HD and TD. In the 
current study, these assumptions correspond to a mean 
difference of 2.0 in MD-CRS part II total score and an 
SD of 3.5 in each treatment group.
The rate of missing not at random (MNAR) data for the 
primary analysis is expected to be 10%. MNAR data 
will be imputed in a conservative manner as if they 
were obtained from patients in the placebo treatment 
Updated the mean difference and SD 
values used for this study to more 
accurately represent sample size and 
power considerations.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
215
Original text with changes shown
New wording
Reason/Justification for change
regardless of the actual treatment group. As a result, the 
mean difference is expected to be reduced from 2.0.07
to 0.0631.8 in the primary analysis. The impact of the 
missing data imputation on the SD is negligible.
group, regardless of the actual treatment group. As a 
result, the mean difference is expected to be reduced 
from 2.0 to 1.8 in the primary analysis. The impact of 
the missing data imputation on the SD is negligible.
9.2.2.
Modified Intent to Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a 
subset of the ITT analysis set including all randomized
patients with centrally read total raw scores of ≥10 on 
MD CRS part II items at baseline, and at least 1 post-
baseline centrally read MD-CRS part II assessment.
The modified intent-to-treat (mITT) analysis set is a 
subset of the ITT analysis set including all randomized 
patients with at least 1 post-baseline centrally read MD-
CRS part II assessment.
The mITT analysis set was clarified to 
state that all randomized patients who had 
at least 1 post-baseline centrally read MD-
CRS part II assessment were included.
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the 
mITT analysis set including only patients who meet the 
following criteria:
•
compliant with study medication (80% to 105%)
•
complete the study without any major protocol 
deviations that may impact efficacy 
•
centrally read baseline MD-CRS part II total score 
of ≥10
The per-protocol (PP) analysis set is a subset of the 
mITT analysis set including only patients who meet the 
following criteria:
•
compliant with study medication (80% to 105%)
•
complete the study without any major protocol 
deviations that may impact efficacy 
•
centrally read baseline MD-CRS part II total score 
of ≥10
An additional criteria based on the 
MD-CRS part II total score was included 
for the PP analysis set.
9.5.4.1. Secondary Efficacy Analysis
Not applicable.
In addition, sensitivity analyses for the key secondary 
endpoints will be performed in the same fashion as the 
primary endpoint.
Updated to clarify sensitivity analysis of 
key secondary endpoints.
9.8. Safety Endpoints and Analysis
Not applicable.
Assessment of drug-induced parkinsonism according to 
the ESRS (subscales I and II), assessment of change in 
behavior according to the CBCL questionnaire, and 
assessment of sedation according to the ESS 
questionnaire will be summarized descriptively.
Updated the safety analysis to include the 
3 new safety scales that will be assessed 
during the study.
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS
Benzodiazepines, muscle relaxants, (including 
tizanidine), trihexyphenidyl, baclofen (oral and 
Benzodiazepines, muscle relaxants, (including 
tizanidine), trihexyphenidyl, baclofen (oral and 
Letter of Clarification 01
Updated the list of allowed medications to 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
216
Original text with changes shown
New wording
Reason/Justification for change
intrathecal), gabapentin, and levetiracetam
intrathecal), gabapentin, and levetiracetam
include tizanidine.
APPENDIX I.
TOTAL BLOOD VOLUME
Table 12 from the original amendment has been 
reconstructed. 
Table 12 was revised to reflect the following changes:
1.
Maximum blood draw was revised to a maximum 
of 40 mL (from 41 mL)
2.
Blood volume per test per visit and the total for 
each visit was added.
3.
β-HCG and prothrombin/INR were added.
Blood draws at week 16/EOS and unscheduled visits 
were clarified as obtained at the investigator’s 
discretion.
Letter of Clarification 04
Blood draw volumes were updated, so 
table 12 was updated to align with blood 
draws dictated throughout the protocol.
Global
Updated amendment number, dates, section numbers, 
and tables of contents. Corrected typos; errors in 
punctuation, grammar, and formatting; and 
inconsistencies in style.
Not applicable.
Clarification


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
217
16.9.
Letter of Clarification 04 Dated 05 December 2018


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
218


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
219


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
220
16.10.
Letter of Clarification 03 Dated 22 November 2018


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
221


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
222
16.11.
Letter of Clarification 02 Dated 16 November 2018


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
223


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
224


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
225
16.12.
Letter of Clarification 01 Dated 17 October 2018


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
226


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
227
APPENDIX A.
CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Teva Branded Pharmaceutical Products R&D, Inc
Cell
Legal Representative of the Sponsor in the EU
Merckle GmbH, Graf-Arco-Str. 3, 89079 Ulm, 
Germany | Registry Court: Ulm HRB 5125
Tel: 
Sponsor’s Medical Expert/Contact Point designated 
by the Sponsor for Further Information on the Study
Teva Pharmaceutical Industries, 
 
Cell: 
Study Principal Investigator
Vanderbilt University Medical Center, Department of 
Neurology
1161 21st Avenue South
A-0118 MCN
Nashville, TN 37232-2551
Tel: 
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance
For serious adverse events:
Send by email to the local safety officer/contract research 
organization (LSO/CRO). 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.
Teva Pharmaceutical Industries, 
 
Tel: 
 
Cell
Contract Research Organization
ICON plc
South County Business Park
Leopardstown
Dublin 18, Ireland
Tel: 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
228
Central Clinical Laboratory
Q2 Solutions – Global Headquarters
5827 South Miami Blvd.
Morrisville, NC 27560
Tel: 
Pharmacokinetic Samples
Watson Pharma Pvt. Ltd. 
Seawoods Grand Central, Tower 2
Level-11, Wing-E, Plot No. R-1
Sector 40, Nerul, Navi Mumbai 400706 
Tel: 
Contact: 
Bioanalytical Operations
Central Electrocardiogram Evaluation
Spaulding Medical, LLC
525 S. Silverbrook Drive
West Bend, WI 53095
Tel: 
Randomization and Trial Supply Management 
(RTSM) vendor
Calyx
4 Canal Street
Nottingham, United Kingdom, NG1 7EH
Tel: 
Scales and Central Rater for MD-CRS
Signant Health
785 Arbor Way
Blue Bell, PA 19422
Tel: 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
229
APPENDIX B.
INDEPENDENT DATA MONITORING COMMITTEE
When approximately 50 patients have completed the study (including follow-up), an independent 
Data Monitoring Committee (iDMC) will perform an unblinded non-binding interim analysis 
(IA) for futility based on centrally read Movement Disorder-Childhood Rating Scale part II 
(MD-CRS part II) total score. Based on the results of the IA, the study may be stopped.
The iDMC sessions can be open or closed. During open sessions, representatives of the sponsor 
and the Steering Committee 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).
Details on how the iDMC chairperson will communicate with the sponsor in regard to issues 
resulting from the conduct and clinical aspects of the study can be seen in the iDMC charter. The 
sponsor 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 
investigational medicinal product assignments are outlined in the iDMC charter.
Further details are given in the Data Monitoring Plan and iDMC Statistical Analysis Plan. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
230
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for Screening (Day -31)
The screening visit will take place not more than 31 days before the baseline visit. Screening 
may be conducted over 2 separate visits at the discretion of the investigator. The following 
procedures/assessments will be performed at the screening visit:

patients, parent(s)/legally accepted representative(s), and caregivers must provide 
their respective written informed consent and/or assent (as appropriate) before any 
study-related procedures are performed. Assent/consent may also be provided to 2 
optional ICFs:

 

use of patient’s study videos for future analysis of gait digital markers and release 
of patient’s study videos for use in publications or educational presentations 

review of eligibility criteria

medical and psychiatric history

demographics

vital signs measurements (including orthostatic blood pressure) and weight

physical examination

neurological examination

height

12-lead electrocardiogram (ECG)

clinical laboratory tests (chemistry, hematology, and urinalysis); these tests may be 
repeated to determine patient eligibility

urine drug screen; these tests may be repeated to determine patient eligibility

cytochrome P450 2D6 (CYP2D6) genotype

beta-human chorionic gonadotropin (β-HCG) serum pregnancy test (for females aged 
12 years or older of childbearing potential)

MD-CRS part II video recording and investigator assessment

Clinical Global Impression of Severity (CGI-S) (global, physician rated)

Children’s Columbia-Suicide Severity Rating Scale (C-SSRS) (Baseline/Screening)

Child Behavior Checklist (for ages 6-18) (CBCL), full version (Competence and 
Syndrome)

Extrapyramidal Symptom Rating Scale (subscales I and II; ESRS)

Epworth Sleepiness Scale (for children and adolescents) (ESS)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
231

concomitant medications

contact RTSM
2. Procedures Before Administration of Investigational Medicinal Product (Baseline 
[Day 1±0 days])
Patients who meet the inclusion and exclusion criteria at the screening visit will continue to 
the baseline visit when baseline assessments will be conducted. The investigator should 
review all available data to determine patient eligibility before randomizing to the study. 
The following procedures/assessments will be performed at the baseline visit:

review of eligibility criteria

assignment of randomization/treatment numbers after patient eligibility is confirmed 
based on all available visit assessments, and entry into case report form (CRF)

vital signs measurements (including orthostatic blood pressure) and weight

physical examination

neurological examination

urine pregnancy test

MD-CRS part I video recording and investigator assessment

MD-CRS part II video recording and investigator assessment

Clinical Global Impression of Severity (CGI-S) (global, physician rated)

Pediatric Evaluation Disability Inventory-Computer Adapted Test (PEDI-CAT) 
(activities of daily living [ADL], caregiver completed, content-balanced version)

Cerebral Palsy module of Pediatric Quality of Life Inventory (PedsQL) (quality of 
life [QoL], patient/caregiver)

Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS) 
assessment

Children’s C-SSRS (Since Last Visit)

CBCL, Syndrome scale only (since last visit) 

ESRS (subscales I and II)

ESS 

adverse events assessment

concomitant medications

dispense investigational medicinal product (IMP)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
232
3. Procedures During Administration of Investigational Medicinal Product 
(Double-Blind Treatment Period Inclusive of Titration Period)
a. Week 1 (day 7+1 day), week 2 (day 14±3 days total from baseline), week 4 
(day 28±3 days total from baseline), week 5 (day 35±3 days total from baseline), 
and week 6 (day 42±3 days total from baseline)
The following procedures and assessments will be performed at weeks 1, 2, 4, 5, and 6:

telephone contact (with non-recording live video)

Clinical Global Impression of Improvement (CGI-I) (global, physician-rated)

assessment of IMP accountability/compliance/supply

adverse events assessment

concomitant medications

evaluation/adjustment of IMP dose
b. Week 3 (day 21±3 days total from baseline) and week 7 (day 49±3 days total 
from baseline)
The following procedures and assessments will be performed at weeks 3 and 7:

vital signs measurements and weight

12-lead ECG

urine drug screen (week 3 only)

urine pregnancy test

Caregiver Global Impression of Improvement (CaGI-I) (global, caregiver rated). The 
CaGI-I is to be completed before all other investigator-rated scales during visits 
where CaGI-I is collected.

Patient Global Impression of Improvement Scale (PGI-I) (global, patient/caregiver). 
The PGI-I is to be completed before all other investigator-rated scales during visits 
where PGI-I is collected.

Children’s C-SSRS (Since Last Visit)

CBCL, Syndrome scale only (since last visit)

ESRS (subscales I and II)

ESS 

CGI-I and CGI-S (global, physician rated) 

dispense/collect IMP
During the week 3 visit, the last dose bottle is to be returned to the patient in order to 
take 1 last tablet in the evening to complete the week 3 dosing for that day. Refer to 
the pharmacy manual for further details.

assessment of IMP accountability/compliance/supply


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
233

adverse events assessment

concomitant medications

evaluation/adjustment of IMP

contact RTSM
4. Procedures During Administration of Investigational Medicinal Product 
(Maintenance Period)
a. Week 9 (day 63±3 days total from baseline) and week 12 (day 84±3 days total 
from baseline)
The following procedures and assessments will be performed at weeks 9 and 12:

vital signs measurements and weight

urine drug screen (week 9 only)

urine pregnancy test (week 12 only)

MD-CRS part I video recording and investigator assessment

MD-CRS part II video recording and investigator assessment

CaGI-I (global, caregiver rated)

CGI-I and CGI-S (global, physician rated)

PGI-I (global, patient/caregiver)

UHDRS-TMS

Children’s C-SSRS (Since Last Visit)

CBCL, Syndrome scale only (since last visit)

ESRS (subscales I and II)

ESS 

dispense/collect IMP

assessment of IMP accountability/compliance/supply

adverse events assessment

concomitant medications

contact RTSM
b. Week 15 (day 105±3 days total from baseline) or early termination (ET)
The following procedures and assessments will be performed at week 15 or ET:

vital signs measurements (including orthostatic blood pressure) and weight

physical examination

neurological examination


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
234

height

12-lead ECG


clinical laboratory tests (chemistry, hematology, and urinalysis)

urine drug screen

β-HCG serum pregnancy test (for females aged 12 years or older of childbearing 
potential)

MD-CRS part I video recording and investigator assessment

MD-CRS part II video recording and investigator assessment

CaGI-I (global, caregiver rated)

CGI-I and CGI-S (global, physician rated)

PEDI-CAT (ADL, caregiver completed, content-balanced version)

PedsQL (QoL, patient/caregiver)

PGI-I (global, patient/caregiver)

UHDRS-TMS

Children’s C-SSRS (Since Last Visit) 

CBCL, full version (since last visit) (Competence and Syndrome)

ESRS (subscales I and II)

ESS

collect IMP

assessment of IMP accountability/compliance/supply

adverse events assessment

concomitant medications

obtain reason for early termination (if applicable)

contact RTSM
5. Follow-Up (Weeks 16 and 17)
a. Week 16/End of Study follow-up visit (1 week±2 days total from the week 
15/ET visit)
The following procedures and assessments will be performed at the week 16 follow-up visit:

vital signs measurements and weight

12-lead ECG (if there is an abnormality at the week 15/ET visit)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
235

clinical laboratory tests (chemistry, hematology, and urinalysis) (if there is an 
abnormality at the week 15/ET visit)

urine drug screen

urine pregnancy test

MD-CRS part I video recording and investigator assessment

MD-CRS part II video recording and investigator assessment

CaGI-I (global, caregiver rated)

CGI-I and CGI-S (global, physician rated)

PGI-I (global, patient/caregiver)

Children’s C-SSRS (Since Last Visit)

CBCL, Syndrome scale only (since last visit)

ESRS (subscales I and II)

ESS 

adverse events assessment

concomitant medications
b. Week 17 follow-up visit (2 weeks±2 days total from week 15 visit, or 2 weeks 
after ET visit)
The following procedures and assessments will be performed at the week 17 follow-up visit:

telephone contact 

adverse events assessment

concomitant medications
6. Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s or 
parent’s/caregiver’s request and as deemed necessary by the investigator. The date and 
reason for the unscheduled visit will be recorded on the CRF as well as any other data 
obtained from procedures and assessments.
Procedures performed during unscheduled visits may include any of the following:

telephone contact (at the investigator’s discretion)

evaluation/adjustment of IMP

vital signs measurements and weight

physical examination (at the investigator’s discretion)

neurological examination (at the investigator’s discretion)

12-lead ECG (at the investigator’s discretion)


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
236

clinical laboratory tests (chemistry, hematology, and urinalysis) (at the investigator’s 
discretion)

β-HCG serum pregnancy test (for females aged 12 years or older of childbearing 
potential) (at the investigator’s discretion)

MD-CRS part I video recording and investigator assessment

MD-CRS part II video recording and investigator assessment

CaGI-I (global, caregiver rated)

CGI-I and CGI-S (global, physician rated)

PEDI-CAT (ADL, caregiver completed, content-balanced version)

PedsQL (QoL, patient/caregiver)

PGI-I (global, patient/caregiver)

UHDRS-TMS

CBCL, Syndrome scale only (since last visit)

ESRS (subscales I and II)

ESS 

Children’s C-SSRS (Since Last Visit) (at the investigator’s discretion)

CBCL, Syndrome scale only (since last visit) (at the investigator’s discretion)

ESRS (subscales I and II) (at the investigator’s discretion)

ESS (at the investigator’s discretion)

dispense/collect IMP (at the investigator’s discretion)

assessment of IMP accountability/compliance/supply (at the investigator’s discretion)


adverse event assessment

concomitant medications


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
237
APPENDIX D. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics Committee 
(IEC)/institutional review board (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.
Important Protocol Deviations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include non-
adherence on the part of the patient, the investigator, or the sponsor to protocol-specific inclusion 
and exclusion criteria, primary objective variable criteria, or Good Clinical Practice (GCP) 
guidelines; noncompliance to IMP administration; and use of prohibited medications. All 
important protocol deviations will be reported to the responsible IEC/IRB, as required.
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation . If such patient has already completed the study or 
has withdrawn early, no action will be taken, but the deviation will be recorded.
For coronavirus disease 2019 (COVID-19) updates, refer to Appendix M.
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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
238
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 that the study is conducted 
according to applicable standard operating procedures, the protocol, and other written 
instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication.
For COVID-19 updates, refer to Appendix M.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, standard operating procedures, GCP guidelines, and applicable regulatory 
requirements. The sponsor’s Global Clinical Quality Assurance, independent of Global Specialty 
Development, is responsible for determining the need for (and timing of) an investigational 
center audit.
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines.
For COVID-19 updates, refer to Appendix M.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
239
APPENDIX E. ETHICS
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and parent(s)/legally acceptable representative (as applicable) of all pertinent aspects of 
the study, including the written information approved by the Independent Ethics Committee 
(IEC)/institutional review board (IRB). All written and oral information about the study will be 
provided in a language as nontechnical as practical to be understood by the patient and 
parent(s)/legally acceptable representative. The patient and parent(s)/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 (ICF) will be obtained from each 
parent(s)/legally acceptable representative, and a signed and dated assent form will be obtained 
from each patient (if the patient is able/as applicable) before any study-specific procedures or 
assessments are done and after the aims, methods, anticipated benefits, and potential hazards are 
explained, according to IEC/IRB requirements. The forms will also be signed and dated by the 
person who conducted the informed consent discussion. The investigator will keep the original 
informed consent and assent forms, and copies will be given to the patients (and each 
parent(s)/legally acceptable representative). It will also be explained to the patients (and each 
parent(s)/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. Patients 
who started the study as minors and reached the age of majority during the study should sign the 
adult ICF. 
For coronavirus disease 2019 (COVID-19) updates, refer to Appendix M.
Competent Authorities and IECs/IRBs
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In case report files and other 
documents or image material submitted to the sponsor, patients will be identified not by their 
names but by an identification number.
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the case report file. 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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
240
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
241
APPENDIX F.
BIRTH CONTROL METHODS AND PREGNANCY 
TESTING
Females of childbearing potential are defined as the following:

not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

postmenarchal or ≥12 years of age
Females who are not of childbearing potential are defined as the following:

premenarchal or being in the period of a female’s life before the first menstrual period 
occurs 
Highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly are considered. Such methods include the 
following:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, and 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
1 month (for IMPs potentially teratogenic/genotoxic) before the first dose of IMP

Progestogen-only hormonal contraception (oral, injectable, and implantable) 
associated with inhibition of ovulation; these should be 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 that 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, and post-ovulation 
methods), declaration of abstinence for the duration of a study, and withdrawal are 
not acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
242
APPENDIX G. LOST TO FOLLOW-UP
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center.
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit:

The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient and parent(s)/caregiver, as 
applicable, on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the patient wishes to and/or should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of “lost to follow-up.”


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
243
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS
Medications that are allowed, provided that conditions outlined in the table are met, are shown in 
Table 10. Investigators are encouraged to contact the medical monitor for any questions 
regarding the medications listed below.  
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 QT corrected for heart rate (QTc) 
prolongation or that is a known strong cytochrome P450 inhibitor. 
Prohibited medications that are associated with QTc prolongation are listed in Table 11.
For coronavirus disease 2019 (COVID-19) updates, refer to Appendix M.
Table 10:
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 and anticipated to remain stable (dose and frequency) 
within the study duration
Antidepressants
Must be receiving stable treatment (including dose) for at least 6 weeks 
before screening and anticipated to remain stable (dose and frequency) 
within the study duration
Benzodiazepines, trihexyphenidyl, 
baclofen (oral and intrathecal), 
tizanidine, muscle relaxants, gabapentin, 
levetiracetam, carbamazepine, 
topiramate, and other anticonvulsants, 
neuroleptics (oral), typical and atypical 
antipsychotics, and metoclopramide
Dosing must have been stable for at least 4 weeks before screening and 
anticipated to remain stable (dose and frequency) within the study 
duration.
Any exceptions to this period of stability for these classes of drugs should 
be reviewed with the medical monitor, and approval for entry into the 
study will be required.
Note: PRN (as needed) use is prohibited.
Botulinum toxin
May be included in the study if they have at least 2 treatments of 
botulinum neurotoxin (BoNT) at a regular interval (eg, every 3 to 
4 months), in reasonably stable dosages and locations (subject to 
investigator’s judgment) to treat lower limb spasticity or dystonia, and if 
they are expected to continue this stable regimen of BoNT injections for 
the duration of this study. The injection for spasticity or dystonia must be 
in a muscular region that is separate from the main areas affected by 
choreiform movement disorder. Pre-approval from the medical monitor is 
required for patients receiving BoNT outside of the regular interval.
Cannabis or formulations or derivatives 
of cannabis 
Patients may be included in this study if they are using cannabis or 
formulations or derivatives of cannabis in relatively stable amounts, for 
medical purposes, under the guidance, supervision, or prescription of a 
clinician. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
244
Table 10:
Allowed Medications (Continued)
Generic/Drug class
Condition
Additional medications allowed with pre-approval from medical monitor
Albuterol, levalbuterol
Asthma
Guaifenesin
Cold symptoms
Antihistamines
Allergies
Melatonin
Insomnia
Allowed strong CYP2D6 inhibitorsa
Bupropion
Antidepressant (aminoketone)
Stable medications allowed according to inclusion/exclusions criteria
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 study medication, as shown in Table 4.
Note: Changes to the allowed medications may be permitted in the context of this study if pre-approved by the 
medical monitor.
CYP=cytochrome P450; PRN=as needed.
Table 11:
Prohibited QTc-Prolonging Drugs
Generic
Class/Clinical use
Note
Azithromycin
Antibiotic/bacterial infection
Patients are allowed to 
take up to 500 mg/day of 
azithromycin
Chloroquine/Mefloquine
Anti-malarial/malaria infection
Clarithromycina
Antibiotic/bacterial infection
Domperidone
Anti-nausea/nausea
Not available in the USA
Droperidol
Sedative; anti-nausea/anesthesia adjunct, nausea
Erythromycina
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
Hydroxychloroquine
Hydroxychloroquine is contraindicated in this trial due to the 
risk of QT prolongation and should be considered as not 
allowed. If there is a medical decision to initiate 
chloroquine, hydroxychloroquine, mefloquine, or other 
drugs related to chloroquine, the IMP should be suspended 
or discontinued, and an ECG should be obtained. Please 
consult with the medical monitor for further advice.
a Systemic use only. Topical use is allowed.
QTc=QT corrected for heart rate; GI=gastrointestinal; USA=United States of America.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
245
APPENDIX I.
TOTAL BLOOD VOLUME
Total blood volume to be collected for each patient in this study is approximately 40 mL (at 
maximum). Blood draw volumes and ranges (in mL) are depicted in Table 12.
Table 12:
Total Blood Volumes
Test
Screening
Week 15/ET
Week 16/EOS
Unscheduled
)
Chemistry
1.25-3.5
1.25-3.5
(1.25-3.5)
(1.25-3.5)
Hematology
1.0-2.0
1.0-2.0
(1.0-2.0)
(1.0-2.0)
CYP2D6 genotyping
3.0-5.0
β-HCG
1.25-3.5
1.25-3.5
(3.5)
Prothrombin/INR
4.5
4.5
(4.5)
(4.5)
Total volume (mL) per 
patient per visit 
18.5
21.5
CYP2D6=cytochrome P450 2D6; EOS=end of study; β-HCG=Beta-human chorionic gonadotropin; 
INR=International Normalized Ratio.
Notes: Values in parentheses indicate possible blood draws. Blood draws at week 16/EOS and unscheduled visits are 
optional.
 
  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
246
APPENDIX J.
PRODUCT COMPLAINTS
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include, but are not limited to, the following:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside)

incorrect packaging or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible.
1. Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to the protocol Yes/No


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
247

description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s)
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP.
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or a serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2).
4. Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
248
APPENDIX K. DATA MANAGEMENT AND RECORD KEEPING
Direct Access to Source Data and Documents
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data, unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data), the results (with the exception of the cytochrome 
P450 2D6 [CYP2D6] test results) will be sent to the investigational center, where they will be 
retained but not transcribed to the CRF, unless otherwise noted in the protocol (eg, results of 
centrally read MD-CRS part II items will not be shared with the investigators). These data may 
also be sent electronically to the sponsor (or organization performing data management).
The medical experts, study monitors, auditors, Independent Ethics Committee (IEC)/institutional 
review board (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, and videos) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (United States) and documents of other 
concerned competent authorities. Before using the CDMS, it will be fully validated, and all users 
will receive training on the system and study-specific training. After they are trained, users will 
be provided with individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, and electronic patient-reported outcome tablet or phone), 
these data will be sent to the investigational center, where they will be retained but not 
transcribed to the CRF, unless otherwise noted in the protocol. These data may also be sent 
electronically to the sponsor (or organization performing data management). All patient data 
must have supportive original source documentation in the medical records, or equivalent, before 
they are transcribed to the CRF. Data may not be recorded directly on the CRF and considered as 
source data unless the sponsor provides written instructions specifying which data are permitted 
to be recorded directly to the CRF.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
249
For patients who enter a study but do not meet the eligibility criteria, at a minimum, data for 
screening failure reason, demography, and any serious adverse events from the time of informed 
consent will be entered in the CRF.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s standard operating procedures (SOPs) for clinical studies. Day-to-day data 
management tasks for this study are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities.
Data will be verified by the study monitor using the data source and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. 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, and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
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 acknowledgment that all data have 
been captured and confirmed as accurate. 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.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to, the following:

full case histories

signed informed consent forms

patient identification lists

case report forms for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, and electronic diary)

safety reports

financial disclosure reports/forms


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
250

reports of receipt, use, and disposition of the IMPs

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 the contract 
research organization 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 the sponsor at least 60 days 
before any planned disposition of study records. After receipt of such request, the sponsor may 
make arrangements for appropriate archival or disposition, including requiring that the 
investigator deliver such records to the sponsor. The investigator shall notify the sponsor of any 
accidental loss or destruction of study records.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
251
APPENDIX L. PUBLICATION POLICY
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 results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results: 
“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. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with the following International 
Committee of Medical Journal Editors authorship requirements:

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.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
252
APPENDIX M. MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19
This appendix is to address the modification in study conduct during the coronavirus disease 
2019 (COVID-19) pandemic. 
The changes specified in this appendix will be effective for the duration of the COVID-19 
pandemic. Once the situation at specific sites/countries will allow returning to regular study 
activities, this appendix will become void for those country/sites, except in the case of 
COVID-19 resurgence or emergence of another crisis affecting normal per-protocol conduct of 
the study.
The following sections are affected:  
Section 3.1. General Study Design and Study Schematic Diagram
A COVID-19 addendum informed consent will be created to inform patients of the planned 
changes. The site will be allowed to conduct remote assent and consent by phone. Site will 
obtain and document a verbal confirmation from patient and parent/legally acceptable 
representative that they received this information and understood it. The informed consent 
addendum will be signed by the patient and family as applicable at the first next in-clinic visit. 
Any updates prior to the updated consent form should be consented verbally and documented in 
the medical sources.  
Section 3.5. Schedule of Study Procedures and Assessments
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, or 
closure of the site clinic), home or remote visits are permitted for patients who are not able to go 
to the investigational site for their visit(s) or if the investigational site staff are not able to see 
patients at the investigational site.
Remote visits will allow collecting the following clinician-rated scales: 

Columbia-Suicide Severity Rating Scale (C-SSRS)

Clinical Global Impression of Improvement (CGI-I)

Clinical Global Impression of Severity (CGI-S)

Part I of the Extrapyramidal Symptom Rating Scale (subscales I and II) [ESRS]. 
It will further allow a visual confirmation of a patient’s condition using non-recording live video 
and assessment of any new adverse events, as possible, depending on patient cooperation and the 
communication platform being in good working order. The remote visit will not allow for fully 
completing performance outcome assessments that require physical examinations, including 
those required for the Movement Disorder-Childhood Rating Scale (MD-CRS), Unified 
Huntington’s Disease Rating Scale (UHDRS), or ESRS scales. The MD-CRS Part I & II are 
optional at the investigator’s discretion and may be incomplete considering patient’s imbalance 
when standing and walking and prioritizing patient safety. UHDRS-Total Motor Score (TMS) 
and ESRS should be completed as much as possible; some fields (ie, rigidity, stability) may be 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
253
left blank as they cannot be assessed remotely. The pull test should not be done due to safety 
considerations. The remote visit will not allow for measuring vital signs or obtaining an 
electrocardiogram (ECG) or urine beta chorionic gonadotropin (β-HCG) test, unless a home 
nursing vendor is at the patient’s home to provide that service where available.
The week 3 and week 7 visits can be completed as remote visits if safety assessments 
(specifically vital signs, ECG, C-SSRS, and β-HCG test, if relevant) can be performed within a 
reasonable time from visit (approximately 2 weeks). 
The week 9 and week 12 visits can be completed as remote visits if the previous vital signs and 
ECGs were acceptable as per protocol requirements. Any other required safety assessments (eg, 
C-SSRS and β-HCG test, if relevant) that are not completed during a remote visit should be 
completed within 2 weeks of the remote visit. 
If patient misses the week 15 visit and is approved by the medical monitor to have a remote visit 
and continue on drug, and if patient cannot arrive at site within 3 weeks, a telephone call will be 
added to assess patient’s condition (ie, adverse event, tolerability, sufficient investigational 
medicinal product [IMP]).
The week 16 visit can be completed as a remote visit.
The test and placebo IMP (as applicable) will continue to be administered at home. Following 
the consent of the patient or parent(s)/legally acceptable representative, IMP will be shipped to 
patients if they or their parent/legally acceptable representative cannot visit the site to collect 
IMP. All shipping arrangements will be the site’s responsibility and will occur between site and 
patient or as a direct-to-patient shipment from the site to patient coordinated by the sponsor’s 
third party shipping vendor, where available, and according to local practices and regulations.
Modifications to other procedures and assessments (ECG, laboratory sample collection, etc) will 
be performed per implemented contingency measures according to sponsor instructions and the 
corresponding manual. For example, if central lab samples cannot be collected for safety 
assessments, sites may have patients visit a local reference laboratory, or a home service may 
visit home, to perform the assessments.
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required.
Section 4.3. Withdrawal Criteria and Procedures for the Patient
Patients who cannot complete the required safety assessments within a reasonable time from visit 
(approximately 2 weeks for the week 3 and week 7 visits) will be early terminated from study; 
specifically, these are the vital signs, ECG, C-SSRS, and β-HCG tests at weeks 3 and 7.
Patients who cannot reach the site for a week 15 visit will be allowed to remain on drug for an 
additional 4 weeks. After 3 weeks, if the patient has not yet completed the in-clinic week 
15 visit, the investigator will perform another remote visit to check on the patient’s condition. 
The contract research organization (CRO) will assess with the site if their patient can come to 
complete the week 15 visit in the next week. If not, the sponsor will either allow another 
extension or the patient will be early terminated from the study.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
254
Section 4.5. Rescreening
Patients who screen fail or terminate early from the study due to emergency circumstances (such 
as coronavirus disease 2019 [COVID-19] restrictions) may be allowed to re-screen/re-enter 
(respectively) the study at a later date, depending on the circumstances. Each case should be 
referred to the medical monitor and approved in advance. Patients re-entering the study will be 
manually assigned to their initial treatment group. Patients will have to redo the entire study from 
the start, aside from the blinded CYP2D6 genotyping; these results will carried over from the 
first participation. 
Section 5.9. Randomization and Blinding
Patients re-entering the study will be manually assigned to their initial treatment group by the 
RTSM unblinded vendor. Blinding will be maintained for the patient, investigator, and sponsor 
as described above; the only information that will be available is that the patient was assigned to 
the same treatment group as previously. 
Section 6. Assessments of Efficacy
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, or 
closure of the site clinic), patients will be able to complete the efficacy scales at home using the 
iPhone. The results of the questionnaires completed via patient’s iPhone will be transferred to the 
case report form (CRF) per the usual process. Scales collected as paper forms will be stored in 
patient source file and entered to CRF manually once the CRF has been adapted appropriately.
Section 7. Assessment of Safety
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient’s concern, or 
closure of the site clinic), patients will be allowed to obtain vital signs and ECGs using local 
clinics (primary health care provider) or home nursing service, where available. 
Safety measurements such as vital signs/ECG/β-HCG/C-SSRS are mandatory for weeks 3 and 7 
(during titration) and part of the week 15/16 assessments.
To increase safety assessments, and in anticipation that patients may need to significantly delay 
their week 15 visit, investigators may collect several safety assessments at week 12 that are 
currently not part of the schedule of activities, but are possible using ‘unscheduled’ visits: 
physical examination, neurological examination, 12-lead ECG, and 
chemistry/hematology/urinalysis laboratory tests. These safety measurements are at the 
investigator’s discretion.
Section 7.5.2.1. Beta-Human Chorionic Gonadotropin Tests
If an in-clinic visit is replaced by a remote visit, all efforts will be done to collect the β-HCG (eg, 
at local laboratory or by sending urine β-HCG sticks to the patient and parent/legally acceptable 
representative, so these can be assessed at home). 
Section 7.5.2.2. Urine Drug Screen
If an in-clinic visit is replaced by a remote visit, urine drug screen samples will not be collected, 
until a next in-clinic visit is possible.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Clinical Study Protocol Amendment 05
Study TV50717-CNS-30080
255
Section 9. STATISTICS
Depending on the impact of COVID-19 on the study assessments, additional analyses or 
modifications of planned analyses will be considered and detailed in a possible amendment to the 
statistical analysis plan.
Section 10. Quality Control and Quality Assurance
Deviations from the study conduct due to emergency situations (eg, the COVID-19 pandemic), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational product and/or study, alternative procedures used to collect critical 
safety and/or efficacy data, etc), will be described in the appropriate sections of the clinical study 
report (CSR) as applicable.
Appendix D. Quality Control and Quality Assurance
Protocol Deviations
Deviations from the study conduct due to emergency situations (eg, the COVID-19 pandemic), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational product and/or study, alternative procedures used to collect critical 
safety and/or efficacy data, etc), will be described in the appropriate sections of the CSR as 
applicable.
Study Monitoring
In case of an emergency situation (eg, the COVID-19 pandemic), where study monitors may not 
be able to access the investigational centers for on-site visits, sites will be monitored remotely 
where allowed and in accordance with the local regulations. Additional details are provided in 
the monitoring plan.
Audit and Inspection
In case of an emergency situation (eg, the COVID-19 pandemic), where auditors may not be able 
to access the investigational centers for on-site visits, investigational centers will be audited 
remotely where allowed and in accordance with local regulations.
Appendix E. Ethics
A COVID-19 addendum informed consent will be created to inform patients of the planned 
changes. The site will be allowed to conduct remote assent and consent by phone. Site will 
obtain and document a verbal confirmation from patient and parent/legally acceptable 
representative that they received this information and understood it. The informed consent 
addendum will be signed by the patient and family as applicable at the first next in-clinic visit. 
Any updates prior to the updated consent form should be consented verbally and documented in 
the medical sources. 
Appendix H. List of Allowed and Prohibited Medications
Hydroxychloroquine is contraindicated in this trial due to the risk of QT prolongation and should 
be considered as not allowed. If there is a medical decision to initiate chloroquine, 
hydroxychloroquine, mefloquine, or other drugs related to chloroquine, the IMP should be 
suspended or discontinued and an ECG should be obtained. The medical monitor should be 
consulted for further advice.

SAP_003.pdf: 




6WDWLVWLFDO$QDO\VLV3ODQ


$5DQGRPL]HG'RXEOH%OLQG3ODFHER&RQWUROOHG6WXG\RI7(9
'HXWHWUDEHQD]LQHIRUWKH7UHDWPHQWRI'\VNLQHVLDLQ&HUHEUDO3DOV\LQ&KLOGUHQ
DQG$GROHVFHQWV


6WXG\1XPEHU79&16


1&7


6$3$SSURYDO'DWH0D\


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
1
 
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
(RECLAIM-DCP)
A Randomized, Double-Blind, Placebo-Controlled Study of TEV-50717 (Deutetrabenazine) 
for the Treatment of Dyskinesia in Cerebral Palsy in Children and Adolescents
Short title: Reduction of Childhood and Adolescent Abnormal Involuntary Movements in 
Patients with Dyskinetic Cerebral Palsy in Children and Adolescents (RECLAIM-DCP)
Lay person title: A Study to Test if TEV-50717 is Effective in Relieving Abnormal 
Involuntary Movements in Cerebral Palsy
Phase 3
IND Number: 139700; NDA Number: NA; EudraCT Number: 2018-003742-17
Approval Date: 25 March 2019
Amendment 01 Approval Date: 23 March 2021
Amendment 02 Approval Date: 07 June 2021
Amendment 03 Approval Date: 04 May 2022
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
United States of America
Prepared by:
Global Statistics, Teva 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
2
STATISTICAL ANALYSIS PLAN APPROVAL
Study No.:
TV50717-CNS-30080
A Randomized, Double-Blind, Placebo-Controlled Study of TEV-50717 (Deutetrabenazine) 
for the Treatment of Dyskinesia in Cerebral Palsy in Children and Adolescents
Short title: Reduction of Childhood and Adolescent Abnormal Involuntary Movements in 
Patients with Dyskinetic Cerebral Palsy in Children and Adolescents (RECLAIM-DCP)
Statistical Analysis Plan for:
Interim Analysis
Integrated Summary of Efficacy
Final Analysis
Integrated Summary of Safety
Amendment: 03
Author:
, Teva Global Statistics
, Teva Global Statistics
Executed signature pages are maintained separately within the Trial Master File


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
AMENDMENT HISTORY .............................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................10
INTRODUCTION .........................................................................................................................12
1.
STUDY OBJECTIVES ..............................................................................................13
1.1.
Primary Estimand .......................................................................................................13
1.2.
Secondary Estimands..................................................................................................13
1.3.
Primary and Secondary Study Objectives and Endpoints ..........................................14
1.4.
Exploratory Objectives ...............................................................................................15
2.
STUDY DESIGN .......................................................................................................17
2.1.
General Design ...........................................................................................................17
2.2.
Randomization and Blinding......................................................................................20
2.3.
Data Monitoring Committee.......................................................................................20
2.4.
Sample Size and Power Considerations .....................................................................21
2.5.
Sequence of Planned Analyses ...................................................................................21
2.5.1.
Planned Interim Analyses...........................................................................................21
2.5.2.
Final Analyses and Reporting.....................................................................................22
3.
ANALYSIS SETS ......................................................................................................23
3.1.
Intent-to-Treat Analysis Set........................................................................................23
3.2.
Modified Intent-to-Treat Analysis Set........................................................................23
3.3.
Safety Analysis Set.....................................................................................................23
3.4.
Per-Protocol Analysis Set...........................................................................................23
3.5.
Modified Intent-to-Treat Analysis A Set....................................................................24
3.6.
Modified Intent-to-Treat Analysis B Set ....................................................................24
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................25
4.1.
General........................................................................................................................25
4.2.
Specification of Baseline Values................................................................................25
4.3.
Handling Withdrawals and Missing Data...................................................................25
4.3.1.
Specification of Baseline Value for Centrally-Read MD-CRS II ..............................26
4.3.2.
Specification of Baseline Value for Centrally-Read MD-CRS I................................26


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
4
4.3.3.
Specification of Baseline Value For Clinical Global Impression of Severity............26
4.3.4.
Specification of Baseline Value for Centrally-Read UHDRS-TMC and TMD .........26
4.3.5.
Missing Items in Rating Scales...................................................................................27
4.3.5.1.
Missing Items in MD-CRS.........................................................................................27
4.3.5.2.
Other Missing Items in Rating Scales ........................................................................27
4.4.
Study Days and Visits.................................................................................................28
4.5.
Handling Data From Patients Withdraw and Re-Enter the Study..............................30
4.5.1.
Baseline Values ..........................................................................................................30
4.5.2.
Efficacy Data ..............................................................................................................30
4.5.3.
Safety Data..................................................................................................................31
5.
STUDY POPULATION.............................................................................................32
5.1.
General........................................................................................................................32
5.2.
Patient Disposition......................................................................................................32
5.3.
Demographics and Baseline Characteristics...............................................................32
5.4.
Disease Characteristics...............................................................................................33
5.5.
Medical History ..........................................................................................................33
5.6.
Prior Therapy and Medication....................................................................................33
5.7.
Study Drug Titration...................................................................................................33
5.8.
Study Drug Compliance .............................................................................................33
5.9.
Study Protocol Deviations..........................................................................................35
6.
EFFICACY ANALYSIS ............................................................................................36
6.1.
General........................................................................................................................36
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................36
6.2.1.
Primary Endpoint........................................................................................................36
6.2.2.
Definition....................................................................................................................36
6.2.3.
Primary Efficacy Analysis..........................................................................................36
6.2.4.
Sensitivity Analysis ....................................................................................................37
6.2.4.1.
Sensitivity Analyses for Assumptions of Missing Data Mechanism..........................38
6.2.4.2.
Sensitivity Analysis for the Statistical Model ............................................................39
6.2.4.3.
Other Sensitivity Analyses .........................................................................................39
6.2.5.
Retrospective Power and Sample Size .......................................................................40
6.3.
Secondary Efficacy Endpoints and Analysis..............................................................40
6.3.1.
Key Secondary Efficacy Endpoints............................................................................40


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
5
6.3.1.1.
Key Secondary Efficacy Endpoints Analysis.............................................................40
6.3.1.2.
Key Secondary Efficacy Endpoints Sensitivity Analysis...........................................41
6.4.
Subgroup Analyses .....................................................................................................41
6.5.
Other Efficacy Endpoints and Analysis......................................................................42
6.5.1.
MD-CRS Global Index (calculated from MD-CRS parts I and II total scores, 
centrally read) .............................................................................................................43
6.5.1.1.
Definition....................................................................................................................43
6.5.1.2.
Analysis ......................................................................................................................43
6.5.2.
MD-CRS Physician Rated..........................................................................................44
6.5.2.1.
Definition....................................................................................................................44
6.5.2.2.
Analysis ......................................................................................................................44
6.5.3.
Unified Huntington’s Disease Rating Scale ...............................................................44
6.5.3.1.
Definition....................................................................................................................44
6.5.3.2.
Analysis ......................................................................................................................45
6.5.4.
Pediatric Evaluation of Disability Inventory Computer Adaptive Test 
Definition....................................................................................................................45
6.5.4.1.
PED-CAT Analysis ....................................................................................................45
6.5.5.
The CP module of the PedsQL (QoL, patient/caregiver) ...........................................46
6.5.5.1.
Definition....................................................................................................................46
6.5.5.2.
Analysis ......................................................................................................................46
6.5.6.
PGI-I Scale (global, patient/caregiver).......................................................................47
6.5.6.1.
Definition....................................................................................................................47
6.5.6.2.
Analysis ......................................................................................................................47
6.5.7.
CGI-S Scale (global, physician rated) ........................................................................47
6.5.7.1.
Definition....................................................................................................................47
6.5.7.2.
Analysis ......................................................................................................................47
6.5.8.
Response Analysis......................................................................................................47
6.6.
Minimal Clinically Important Difference (MCID) and Miminal Clinically 
Important Change (MCIC) Exploratory Analysis ......................................................48
6.6.1.
Descriptive Statistics of MD-CRS part II vs Global Impression of 
Improvement at Week 15............................................................................................48
6.6.2.
MCID Analysis...........................................................................................................49
6.6.3.
MCIC Analysis ...........................................................................................................50
6.6.4.
Descriptive Statistics of Improvement in MD-CRS part II ........................................50


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
6
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................51
8.
SAFETY ANALYSIS ................................................................................................52
8.1.
General........................................................................................................................52
8.2.
Duration of Exposure to Study Drug..........................................................................52
8.3.
Adverse Events ...........................................................................................................52
8.4.
Deaths .........................................................................................................................53
8.5.
Clinical Laboratory Tests ...........................................................................................53
8.6.
Physical Examinations................................................................................................53
8.7.
Vital Signs ..................................................................................................................53
8.8.
Electrocardiography....................................................................................................55
8.9.
Concomitant Medications or Therapies......................................................................56
8.10.
Children’s Columbia-Suicide Severity Rating Scale..................................................57
8.11.
Child Behavior Checklist for Ages 6-18 (CBCL) ......................................................58
8.11.1.
Competence Scale.......................................................................................................58
8.11.2.
Syndrome Scale ..........................................................................................................60
8.12.
Epworth Sleepiness Scale...........................................................................................62
8.13.
Extrapyramidal Symptom Rating Scale......................................................................62
8.13.1.
ESRS I ........................................................................................................................62
8.13.2.
ESRS II.......................................................................................................................63
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................64
10.
PLANNED INTERIM ANALYSIS ...........................................................................65
10.1.
General........................................................................................................................65
10.2.
Interim Analysis Procedure ........................................................................................65
10.3.
Data Cut for Interim Analysis.....................................................................................66
10.4.
Estimation of Conditional Power................................................................................66
10.5.
Sample Size ................................................................................................................67
10.6.
Decision Rules............................................................................................................67
11.
STATISTICAL SOFTWARE ....................................................................................68
12.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............69
13.
REFERENCES ...........................................................................................................70
APPENDIX 1.
MAR/MNAR JUMP TO REFERENCE MULTIPLE IMPUTATION 
METHODOLOGY .....................................................................................................71
APPENDIX 2.
TIPPING POINT ANALYSIS ...........................................................................73


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
7
List of Tables
Table 1:
Possible Types of Major Protocol Deviations that May Lead to Exclusion 
from the Per-Protocol Analysis Set ............................................................................24
Table 2:
Visit Windows for Early Termination Visit for Efficacy Assessments......................28
Table 3:
Visit Windows for Early Termination Visit for Safety Assessments.........................29
Table 4:
Drug Kits based on Titration Scheme – Non-Impaired CYP2D6 
Metabolizers ...............................................................................................................34
Table 5:
Drug Kits based on Titration Scheme –Impaired CYP2D6 Metabolizers..................34
Table 6:
Criteria for Potentially Clinically Significant Vital Signs..........................................54
Table 7: 
Potentially Clinically Significant Values for ECG Variables by Age........................56
Table 8:
Suicidal Ideation Category .........................................................................................57
Table 9:
Suicidal Behavior Category........................................................................................58
Table 10:
CBCL Competence Scale ...........................................................................................58
Table 11:
CBCL Competence Scale Scoring..............................................................................59
Table 12:
CBCL Syndrome Scale...............................................................................................61
Table 13:
Decision Rules According to the Promising Zone Method for IA .............................67
LIST OF FIGURES
Figure 1: Overall Study Schematic Diagram.................................................................................19


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
8
AMENDMENT HISTORY
The Statistical Analysis Plan for study TV50717-CNS-30080 (original study protocol dated 27 
September 2018) has been amended and reissued as follows:
Amendment 
number
Date
Author(s)
Summary of changes
Reason for amendment
03
04 May 2022
, 
Teva Global Statistics
,
Teva Global Statistics
- Sample size reduction to 
approximately 65 patients 
due to slow enrollment
- Remove the second 
interim analysis for futility 
and sample size 
reassessment
- Add UHDRS-TMC and 
UHDRS-TMD (centrally 
read) for the scoring of 
chorea and dystonia, 
respectively, as key 
secondary endpoints
- Add MCID and MCIC
supportive primary 
analysis
Adjust the sample size 
and add new endpoints
02
06 June 2021
, 
Teva Global Statistics
,
Teva Global Statistics
The Wald statistic should 
be:
 =
−	
se	
Instead of what is 
currently written in the 
SAP: 
 =
	
se	
Typo correction
01
23 March 2021
, 
Teva Global Statistics
,
Teva Global Statistics
- An additional interim 
analysis for futility when
approximately 50 patients
complete the study was 
added
- A section for handling 
data from patients who 
terminate early from the 
study due to emergency 
circumstances (such as 
coronavirus disease 2019 
[COVID-19] restrictions) 
Update interim analyses 
based on protocol 
amendment 04


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
9
Amendment 
number
Date
Author(s)
Summary of changes
Reason for amendment
and re-enter the study was 
added
- Rules for missing items 
for MD-CRS I were 
clarified
- Minor updates based on 
protocol amendment 04
- Editorial changes were 
made throughout the 
document for the purpose 
of clarification
Original 
Statistical 
Analysis 
Plan
25 March 2019
, 
Teva Global Statistics
,
Teva Global Statistics
Not applicable
Not applicable


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADL
activities of daily living
BMI
body mass index
bpm
beats per minute
C-SSRS
Columbia-Suicide Severity Rating Scale
CaGI-I
Caregiver Global Impression of Improvement 
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clinical Global Impression of Severity
CI
confidence interval
CP
cerebral palsy
CRF
case report form
CSR
clinical study report
CTMS
Clinical Trial Management System
CYP2D6
cytochrome P450 2D6
DCP
dyskinesia in cerebral palsy
EAB
Enrollment Adjudication Board
ECG
Electrocardiogram/Electrocardiography
ET
early termination
FCS
fully conditional specification
HR
heart rate
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
ITT
Intent-to-Treat
LS
least squares
MAR
missing at random
MCIC
minimal clinically important change
MCID
minimal clinically important difference
MD-CRS
Movement Disorder-Childhood Rating Scale
MD‑CRS I 
Movement Disorder-Childhood Rating Scale Index I 
MD‑CRS II
Movement Disorder-Childhood Rating Scale Index II


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
11
Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
MMRM
mixed-effects model repeat measurement
MNAR
missing not at random
n
number
PEDI-CAT
Pediatric Evaluation Disability Inventory-Computer Adapted Test
PedsQL
Pediatric Quality of Life Inventory
PGI-I
Patient Global Impression of Improvement
PP
Per-Protocol
PR
Time from the beginning of the P wave to the beginning of the QRS complex in 
electrocardiogram
QRS
Graphical deflections corresponding to ventricular depolarization in a typical 
electrocardiogram
QTc
QT corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
Time between the start of one R wave and the start of the next R wave in the ECG
RTSM
Randomization and Trial Supply Management
SD
Standard Deviation
SDR
Statistical Data Review
SE
Standard Error
SOC
system organ class
SOP
standard operating procedure
UHDRS-TMC
Unified Huntington’s Disease Rating Scale -Total Maximal Chorea
UHDRS-TMD
Unified Huntington’s Disease Rating Scale -Total Maximal Dystonia
UHDRS-TMS
Unified Huntington’s Disease Rating Scale - Total Motor Score
US
United States
WHO
World Health Organization
α-HTBZ
alpha-dihydrotetrabenazine
β-HTBZ
beta-dihydrotetrabenazine


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
12
INTRODUCTION
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. Study TV50717-CNS-30080, A Randomized, Double-Blind, 
Placebo-Controlled Study of TEV-50717 (Deutetrabenazine) for the Treatment of Dyskinesia in 
Cerebral Palsy in Children and Adolescents, and was written in accordance with SOP GSD-SOP-
702 (Statistical Analysis Plan).
The reader of this Statistical Analysis Plan is encouraged to read the study protocol for details on 
the conduct of this study, the operational aspects of clinical assessments, and the timing for 
completing the participation of a patient in this study. 
The Statistical Analysis Plan is intended to be in agreement with the protocol, especially with 
regards to the primary and all secondary endpoints and their respective analyses. However, the 
Statistical Analysis Plan may contain more details regarding these particular points of interest, or 
other types of analyses (e.g. other endpoints).When differences exist in descriptions or 
explanations provided in the study protocol and this Statistical Analysis Plan, the Statistical 
Analysis Plan prevails; the differences will be explained in the Clinical Study Report (CSR).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
13
1.
STUDY OBJECTIVES
1.1.
Primary Estimand 
The primary estimand is the difference in means between TEV-50717 and placebo in the target 
patient population for the change from baseline to week 15 in centrally read Movement Disorder-
Childhood Rating Scale (MD-CRS) part II total score, regardless of whether or not dose 
reduction, suspension, or discontinuation occurred, and regardless of treatment-related adverse 
events. 
The primary estimand assesses the effectiveness in the reduction of choreiform movements in 
patients with dyskinesia in cerebral palsy (DCP) with predominant choreiform movement 
disorder, focusing on the causal effects attributable to the investigational medicinal product 
(IMP).
The target patient population for this study is patients with DCP with predominant choreiform 
movement disorder and severity of DCP represented by the following:
a.
total score of ≥10 in centrally read MD-CRS part II items at baseline, and 
b. Clinical Global Impression of Severity (CGI-S) ≥4 at baseline.
This population is expected to have the sensitivity to demonstrate clinically meaningful 
improvement following treatment with TEV-50717.
Due to practical reasons (periodical assessments), it is not possible to obtain a central reading of 
MD-CRS part II items at the time of the baseline visit prior to randomization; therefore, 
inclusion of the patient to the study is based on investigator scoring of MD-CRS part II items at 
baseline.
1.2.
Secondary Estimands
The secondary estimands are the differences in means between TEV-50717 and placebo in the 
target patient population for:
(1) Change from baseline to week 15 in centrally read MD-CRS part I total score;
(2) Caregiver Global Impression of Improvement (CaGI-I) at week 15;
(3) Clinical Global Impression of Improvement (CGI-I) at week 15; 
(4) Change from baseline to week 15 in centrally-read Unified Huntington’s Disease Rating 
Scale –Total Maximal Chorea (UHDRS-TMC), and
(5) Change from baseline to week 15 in centrally-read Unified Huntington’s Disease Rating 
Scale – Total Motor Dystonia (UHDRS-TMD)
Regardless of whether or not dose reduction, suspension, or discontinuation occurred, and 
regardless of treatment-related adverse events.
The secondary estimands assess the effectiveness on patients’ ability to perform daily functions,
the improvement in dyskinesia evaluated by the caregiver and the investigator, and the reduction 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
14
in chorea and dystonia evaluated by the central reviewers, all with a focus on the causal effects 
attributable to the IMP.
1.3.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are the following:
Objectives
Measures/Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of TEV-50717 to reduce the 
severity of dyskinetic 
involuntary movements 
associated with CP.
The primary efficacy endpoint is the change from baseline to 
week 15 in the MD-CRS part II total score (movement 
disorder severity, centrally read) (TEV-50717 versus placebo).
A secondary objective is to 
evaluate the specific efficacy 
parameters of TEV-50717 
beyond the measure of the 
primary objective.
The key secondary efficacy endpoints (TEV-50717 versus 
placebo) are the following:

MD-CRS part I total score (general assessment, 
centrally read) change from baseline to week 15

CaGI-I (global, caregiver rated) at week 15

CGI-I (global, physician rated) at week 15

UHDRS-TMC (centrally read) at week 15

UHDRS-TMD (centrally read) at week 15
Other efficacy measures and endpoints (TEV-50717 versus 
placebo) include the following:

MD-CRS part I total score (general assessment, 
physician rated) change from baseline to week 15

MD-CRS part II total score (general assessment, 
physician rated) change from baseline to week 15

MD-CRS Global Index (calculated from MD-CRS
parts I and II total scores, centrally read)

MD-CRS Global Index (calculated from MD-CRS
parts I and II total scores, physician rated)

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

PEDI-CAT (ADL, parent/caregiver completed, 
content-balanced version)

The CP module of the PedsQL (QoL, 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
15
Objectives
Measures/Endpoints
patient/caregiver)

PGI-I (global, patient/caregiver)

CGI-S (global, physician rated)

CaGI-I response, defined as patients who are 
described by the caregiver as “Much Improved” or 
“Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are
described as “Much Improved” or “Very Much 
Improved” in the CGI-I score

CGI-S response, defined as patients who have a 
reduction of ≥1 point in the CGI-S score

PGI-I response, defined as patients who are
described as “Much Improved” or “Somewhat 
Improved” in the PGI-I score
A secondary objective of the 
study is to evaluate the safety 
and tolerability of TEV-50717.
The safety variables include adverse events (and the number of 
patients who withdraw from the study due to adverse events), 
vital signs, laboratory tests (hematology, chemistry, and 
urinalysis), ECG measurements, CBCL, ESRS, ESS, and the 
children’s C-SSRS.
ADL=activities of daily living; CaGI-I=Caregiver Global Impression of Improvement; CBCL=Child Behavior 
Checklist (for ages 6-18); CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of 
Severity; CP=cerebral palsy; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS=Epworth Sleepiness Scale (for children and 
adolescents); MD-CRS=Movement Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability 
Inventory-Computer Adapted Test; PedsQL=Pediatric Quality of Life Inventory; PGI-I=Patient Global Impression 
of Improvement; QoL=quality of life; UHDRS-TMC=Unified Huntington’s Disease Rating Scale-Total Maximal 
Chorea; UHDRS-TMD=Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia; UHDRS-
TMS=Unified Huntington’s Disease Rating Scale-Total Motor Score.
1.4.
Exploratory Objectives
 
 
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
16
 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
17
2.
STUDY DESIGN
2.1.
General Design
This is a Phase 3, 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel 
group study to evaluate the efficacy and safety of TEV-50717 administered as oral tablets at a 
starting dose of 6 mg once daily in patients (age 6 through 18 years, inclusive) with DCP with 
predominant choreiform movement disorder, who have had cerebral palsy (CP) symptoms, of a 
non-progressive nature, since infancy (≤2 years of age). 
The study will consist of a screening period (up to 31 days) and a double-blind treatment period 
including a titration period (7 weeks) and a maintenance period (8 weeks), followed by a 
washout period of 1 week, and a follow-up telephone contact 1 week after the washout period. 
At the baseline visit (day 1), patients will be randomly assigned to 1 of 2 treatment groups with 
TEV-50717 IMP or placebo IMP in a 2:1 ratio stratified by age at baseline (6 to <12 years; 12 
through 18 years, inclusive) and region (US; non-US). 
Titration period (7 weeks): The titration scheme and maximum dose will be determined by body 
weight and cytochrome P450 2D6 (CYP2D6) impairment status at baseline1; patients will be 
classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor or are a 
CYP2D6 poor metabolizer. IMP will be titrated during the double-blind treatment period starting 
with 6 mg of TEV-50717 or matching placebo IMP. During the titration period, patients and 
their caregiver/adult will interact weekly with the investigator/staff from week 1 through week 7:
in-person (in-clinic) study visits will be scheduled at weeks 3 and 7, and telephone contacts (with 
non-recording live video) will be scheduled for weeks 1, 2, 4, 5, and 6 in order to assess 
dyskinesia and adverse events. The telephone contacts to the patient will be supported by live 
video stream, without recording, to provide visual confirmation to the investigator of the verbal 
information provided by the patient or caregiver. The dose of IMP will be adjusted according to 
the titration scheme to identify a dose level that optimally reduces dyskinesia (as determined by 
the investigator) and is well tolerated. If a patient experiences a “clinically significant” adverse 
event attributable to the IMP, the investigator will first determine if a dose reduction (to the 
previous dose level) or suspension is necessary and possible. 
Maintenance period (8 weeks): Patients will continue to receive their maintenance dose over the 
next 8 weeks, although a 1-time dose reduction (to the previous dose level for the remainder of 
the study) for adverse events is allowed. Patients will return to the clinic at weeks 9, 12, and 15 
for assessments of efficacy and safety. 
Washout period and follow-up: All patients will discontinue IMP at the week 15 visit and will 
return 1 week later for the end-of-study (EOS) visit. Patients who complete the study may be 
eligible to begin participation in the open label safety extension Study TV50717-CNS-30081 at 
that time. At the week 16 visit, patients may choose to enter Study TV50717-CNS-30081 (on 
                                                
1 The titration scheme is presented in Tables 4 and 5 in the study protocol.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
18
that day) or up to 1 week later (2 weeks from the week 15 visit). Patients who complete 
treatment but choose not to participate in the open-label safety extension Study TV50717-CNS-
30081 before week 17 of Study TV50717-CNS-30080 will be contacted for a safety evaluation 
call occurring 2 weeks after their last dose of IMP. 
The study scheme is presented in Figure 1.
At the time of informed consent, the parent/legal guardian will be counseled that, once 
randomized to treatment, patients are to remain in the study and complete all study procedures 
unless the choice is made to withdraw consent. Patients who withdraw from the study before 
completing the 15 week treatment period should have an early termination (ET) visit 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 ET; evaluations will be as described for 
week 17.
Patients who screen fail or terminate early from the study due to emergency circumstances (such 
as coronavirus disease 2019 [COVID-19]) may be allowed to re-screen/re-enter (respectively) 
the study at a later date, depending on the circumstances.
Study procedures and assessments with their timing are summarized in Table 3 of the study
protocol.
Interim Analysis: When approximately 50 patients have completed the study (including follow-
up), an independent Data Monitoring Committee (iDMC) will perform an unblinded non-binding 
IA for futility based on centrally read MD-CRS part II total score. 
An iDMC charter will be developed for the IA, and the procedures to ensure the integrity of the 
study will be provided in the charter, see details in Section 10. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
19
Figure 1: Overall Study Schematic Diagram
AE=adverse event; CGI=Clinical Global Impression; CYP2D6=cytochrome P450 2D6; ET=early termination; max=maximum.
Note: If a patient is CYP2D6-impaired, the dose administered is indicated in parentheses. The dose of the IMP should be increased on a weekly basis until any of 
the following events occur: clinically meaningful reduction in dyskinesia (ie, CGI-I) as determined by the investigator, clinically significant AE, or the maximum 
allowable dose is reached.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
20
2.2.
Randomization and Blinding
This is a double-blind study. Patients will be randomized to either TEV 50717 or matching 
placebo in a 2:1 ratio using Randomization and Trial Supply Management (RTSM). Patients will 
be stratified by age at baseline (6 to <12 years; 12 through 18 years, inclusive) and region (US; 
non-US). 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 
RTSM vendor) will be blinded to the IMP identity until the database has been locked for analysis 
and the treatment assignments are revealed.
Patients re-entering the study will be manually assigned to their initial treatment group by the 
RTSM unblinded vendor. Blinding will be maintained for the patient, investigator, and sponsor 
as described above; the only information that will be available is that the patient was assigned to 
the same treatment group as previously.
The iDMC will perform an unblinded non-binding IA for futility and will monitor safety 
throughout the study based on unblinded data. An iDMC charter will be developed for the IA, 
and the procedures to ensure the integrity of the study will be provided in the charter.
In the event of an emergency, it will be possible to determine to which treatment group and dose 
the patient has been allocated by accessing the RTSM system. All investigational centers will be 
provided with details of how to access the system for code breaking at the start of the study. The 
medical monitor or equivalent should be notified following unblinding. Any unblinding of the 
IMP performed by the investigator must be recorded in the source documents.
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider (eg, via an RTSM system). The generation of the randomization list and 
management of the RTSM system will be done by a qualified service provider under the 
oversight of the responsible function at Teva.
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. 
At the time of IA analysis, after receiving unblinding request from a Teva statistician, the service 
provider will provide the unblinded treatment assignment to an independent statistician 
according to the processes defined in the relevant standard operating procedure. The independent 
statistician will perform the IA and prepare unblinded outputs for the iDMC safety monitoring 
sessions. The treatment codes should remain undisclosed to the sponsor in order to ensure the 
integrity of the ongoing study conduct.
At the time of final analysis, after receiving unblinding request from a Teva statistician, the 
service provider will provide the Teva statistician with the unblinded IMP assignment according 
to the processes defined in the relevant standard operating procedure.
2.3.
Data Monitoring Committee
There will be an iDMC in this study. When approximately 50 patients have completed the study 
(including follow-up), the iDMC will perform an unblinded non-binding IA for futility based on 
centrally read MD-CRS part II total score (see Section 10). 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
21
The iDMC will also perform regular safety monitoring throughout the study.
Details on how the iDMC chairperson will communicate with the sponsor in regard to issues 
resulting from the conduct and clinical aspects of the study are described in the iDMC charter. 
The iDMC charter will be developed for the IA, and the procedures to ensure the integrity of the 
study will be provided in the charter. The sponsor will work closely with the iDMC to provide 
the necessary safety and efficacy data for review. In addition, results of the IA will be 
communicated to the sponsor as outlined in the iDMC charter.
2.4.
Sample Size and Power Considerations
The initial sample size estimation of approximately 185 patients randomized to TEV-50717 
versus placebo in a 2:1 ratio (approximately 124 in the TEV-50717 group; approximately 61 in 
the placebo group) is the sample size required to obtain a statistically significant result in the 
primary analysis based on a 1-sided test for mean difference at a significance level of α=0.025 
with a power of approximately 90%, assuming a mean difference of 1.8 and a standard deviation 
(SD) of 3.5 in each treatment group. 
Based on Protocol Amendment 05, the initial planned sample size has been reduced to 
approximately 65 patients randomized to TEV-50717 versus placebo in a 2:1 ratio 
(approximately 43 in the TEV-50717 group; approximately 22 in the placebo group).
The initial assumptions regarding the mean difference and SD are based on the change from 
baseline to month 6 in patients treated with trihexyphenidyl reported by Battini et al (2014),
assuming an effect size of 55% for TEV-50717 versus placebo. The effect size of 55% was 
assumed based on the observed effect sizes of TEV-50717 in the pivotal studies in Huntington’s 
disease and tardive dyskinesia. In the current study, these assumptions correspond to a mean 
difference of 2.0 in MD-CRS part II total score and an SD of 3.5 in each treatment group.
The rate of missing not at random (MNAR) data for the primary analysis is expected to be 10%. 
MNAR data will be imputed in a conservative manner as if they were obtained from patients in 
the placebo treatment group, regardless of the actual treatment group. As a result, the mean 
difference is expected to be reduced from 2.0 to 1.8 in the primary analysis. The impact of the 
missing data imputation on the SD is negligible.
2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
This is the first study to evaluate the efficacy of TEV-50717 to reduce the severity of dyskinetic 
involuntary movements associated with CP in pediatric patients with DCP. Moreover, limited 
data are available on the effect of active treatment on MD-CRS part II total score in DCP that 
can support sample size calculations. Therefore, an IA for futility is planned.
When approximately 50 patients have completed the study (including follow-up), an iDMC will 
perform an unblinded non-binding IA for futility based on centrally read MD-CRS part II total 
score. 
The rules for futility will be included in the iDMC charter. The iDMC charter will also provide 
the wording that will be used to communicate the iDMC recommendation. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
22
The Statistical Analysis Plan will be approved before the IA will be performed, in accordance to 
SOP GBP_RD_702 (Statistical Analysis Plan). Any changes in the main analysis of the primary 
and key secondary endpoints (eg, model specifications) will not be allowed after the IA.
2.5.2.
Final Analyses and Reporting
All analyses identified in this Statistical Analysis Plan will be performed after the end of study as 
defined in the study protocol.
This final version of the Statistical Analysis Plan and any corresponding amendments will be 
approved before database lock, in accordance to SOP GBP_RD_702 (Statistical Analysis Plan).
The randomization codes will not be unblinded until this Statistical Analysis Plan has been 
approved and issued.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
23
3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent to treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
For patients who discontinue the study and re-enter it (repeating the study from baseline; see 
Section 4.5), only the data from the repeated participation will be included in the ITT analysis 
set.
3.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including all 
randomized patients with at least 1 post-baseline centrally read MD-CRS part II assessment.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.
3.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
Rules for assignment of treatment in case of mixed actual treatments:

If a patient received placebo throughout the entire treatment period, then actual 
treatment is placebo.

If a patient was randomized to placebo and received TEV-50717 for up to 7 days, 
then actual treatment is placebo

Otherwise, actual treatment is TEV-50717.
For patients who discontinue the study and re-enter it (repeating the study from baseline; see 
Section 4.5) only the data from the repeated participation will be included in the safety analysis 
set.  
3.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
who meet the following criteria:

compliant with study medication (80% to 105%)

complete the study without any major protocol deviations that may impact efficacy 

centrally read baseline MD-CRS part II total score ≥10


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
24
Examples of major protocol deviations that may result in patient exclusion from the PP analysis 
set are given in Table 1.
Table 1:
Possible Types of Major Protocol Deviations that May Lead to Exclusion 
from the Per-Protocol Analysis Set
Type of deviation
Description of Deviation
Informed consent
Missing informed consent
Inclusion/Exclusion
Patient did not meet inclusion/exclusion criteria
Compliance
Overall compliance during the treatment period <80% or >105% 
Overall compliance during the maintenance period <80% or >105%
Study drug
Patient took incorrect dose for more than 7 days 
Dosing error
Patient received the incorrect IMP, contrary to the randomization 
schedule (eg, patient randomized to placebo group and received a 
supply of TEV-50717).
Restricted/disallowed 
Concomitant Medication
Patient took a medication that was not permitted during 
participation in this study
MD-CRS part II total 
score
Missing centrally-read MD-CRS part II assessment at baseline
Patient does not have at least 1 post-baseline centrally read MD-
CRS part II assessment
Evaluation of exclusion from the PP analysis set will be discussed on a case-by-case basis and 
documented prior to database lock and unblinding of the study for final analysis.
3.5.
Modified Intent-to-Treat Analysis A Set
The modified intent-to-treat A (mITTA) analysis set is a subset of the mITT analysis set 
including all patients that received at least 1 dose of IMP.
In the mITTA analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.
3.6.
Modified Intent-to-Treat Analysis B Set
The modified intent-to-treat B (mITTB) analysis set is a subset of the mITT analysis set 
including all patients that received at least 1 dose of IMP and have centrally-read MD-CRS part
II total score ≥10 at baseline.
In the mITTB analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
25
4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include number (n), mean, standard deviation 
(SD), standard error (SE), median, minimum, and maximum. Mean, SD and SE will not be 
presented if the number of patients in the analysis is less than 5 (n < 5).
Descriptive statistics for categorical variables include patient counts and percentages. Missing 
category will be displayed as appropriate.
The following variables are used as stratification factors for randomization or determination of 
titration scheme and maximal dose: CYP2D6 impairment status; weight category; age group; 
region. For the purpose of analysis, the actual baseline values as derived from the Case Report 
Form (CRF), or from the CRF and the laboratory database in case of CYP2D6 impairment status, 
will be used in the case of discrepancy between Randomization and Trial Supply Management
(RTSM) and CRF data. 
4.2.
Specification of Baseline Values
Generally, the baseline value is the last observed data before the first dose of IMP, unless 
otherwise noted. If the baseline assessments occur on the same day as the first dose of IMP, it is 
assumed that the patients follow study procedure and those baseline assessments will be used.
For patients in the ITT population who took no IMP, the baseline value is the last observed data 
on or prior to the randomization date. Electrocardiogram/Electrocardiography (ECG) data will 
follow this rule, unless specified otherwise.
MD-CRS part I and II central reading: for specification of baseline values in case of missing 
centrally-read MD-CRS part I or II at baseline, see Sections 4.3.1 and 4.3.2.
Baseline values for patients withdrawals and re-enter the study will be defined in Section 4.5.
4.3.
Handling Withdrawals and Missing Data
For this study design and population, it is unlikely that patients who withdraw from IMP will be 
willing to attend the remaining scheduled study visits and, in particular, the week 15 visit. 
Therefore, patients will not be required to return to the clinic at week 15 for efficacy evaluations, 
and the primary analysis of the primary and key secondary efficacy endpoints will be based on a 
multiple imputation method for missing data.
For the primary efficacy and key secondary analyses, missing data will be classified as missing 
at random (MAR) and MNAR. The following cases will be considered as MNAR: 

early terminations related to tolerability

early terminations related to treatment-related adverse events

early terminations related to lack of efficacy 
The following cases will be considered as MAR:

intermittent missing data


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
26

early termination for patients who are lost to follow-up 

early termination due to COVID-19
For all other cases, and for cases classified as above, classification as MAR/MNAR will be 
done/revisited in a blinded manner on a case-by-case basis prior to the IA for futility and prior to 
database lock for final analysis and will be documented in a dedicated document.
Multiple imputation methods will be used in the primary and secondary efficacy analyses. 
See Sections 6.2 - 6.3 for details.
Note: imputation of missing baseline values will be performed prior to implementation of 
multiple imputations in the analysis model.
4.3.1.
Specification of Baseline Value for Centrally-Read MD-CRS II 

General rule: baseline assessment (central reading)

If above not available, then Enrollment Adjudication Board (EAB) screening 
assessment;

If above not available, then impute from the local reading of baseline using 
Regression imputation (see details below);

If above not available, then the average of the centrally-read baseline MD-CRS part II 
total score across all patients from the ITT analysis set (Section 3.1) with baseline 
value.
Regression imputation is a single imputation method. Let Y1 be the local reading of baseline 
MD-CRS II total score; Y2 be the centrally-read MD-CRS II. On the observed pairs (Y1, Y2), fit
Y2 based on Y1 as  =  +  using linear regression. Impute the missing Y2 values using the 
predicted value for a given Y1.
4.3.2.
Specification of Baseline Value for Centrally-Read MD-CRS I 

General rule: baseline assessment (central reading);

If above not available, then impute from the local reading of baseline using 
Regression Imputation (see Section 4.3.1 for details);

If above not available, then the average of the centrally-read baseline MD-CRS part I 
total score across all patients from the ITT analysis set (Section 3.1) with baseline 
value.
4.3.3.
Specification of Baseline Value For Clinical Global Impression of Severity
If the baseline assessment of the Clinical Global Impression of Severity (CGI-S) is not available, 
then the average of the baseline CGI-S assessments across all patients from the ITT analysis set 
(Section 3.1) with baseline value will be used instead. Note that this imputation rule will only be 
applied for the analysis of the Clinical Global Impression of Improvement (CGI-I).
4.3.4.
Specification of Baseline Value for Centrally-Read UHDRS-TMC and TMD

General rule: baseline assessment (central reading);


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
27

If above not available, then impute from the local reading of baseline using 
Regression Imputation (see Section 4.3.1 for details);

If above not available, then the average of the centrally-read baseline value across all 
patients from the ITT analysis set (Section 3.1) with baseline value.
4.3.5.
Missing Items in Rating Scales
4.3.5.1.
Missing Items in MD-CRS
The MD-CRS has 2 parts: part I for general assessment of the patient’s functioning and impact of 
cerebral palsy on the activities of the patient, and part II for a specific motor assessment of the 
severity of the movement disorder. 
There are 15 items in MD-CRS Part I. Items A1-A7 (Motor function), C1 (Self-dressing) and D1 
(Attention/alertness during the observation) are scored by the rater in the clinic and these are 
video recorded for central reading, all other Part I items are scored by the rater based on the 
parent/caregiver interview. The centrally-read MD-CRS Part I total score is obtained by 
summing the centrally-read items and the items that are scored only by the rater in the clinic. 
Each item is on a 0 (present) to 4 (absent) scale. The minimum score is 0 and the maximum score 
is 60. 
There are 7 items in MD-CRS Part II. All items are scored by the rater in the clinic and are 
centrally read based on video recording. The minimum score is 0 (absent) and the maximum 
score is 28 (marked/prolonged).
The MD-CRS part I total score: in case of any missing items, the total score will be derived by 
calculating the MD-CRS I index (see Section 6.5.1.1), and multiplying by the maximum score of 
60.
The MD-CRS part II total score: in case of any missing items, the total score will be derived by 
calculating the MD-CRS II index (see Section 6.5.1.1), and multiplying by the maximum score 
of 28. 
Missing items will be discussed in the blinded statistical data review (SDR) meeting prior to 
database lock.
4.3.5.2.
Other Missing Items in Rating Scales
Rules for handling missing items in efficacy and safety rating scales are presented in Section 6.4  
(Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), Unified 
Huntington’s Disease Rating Scale-Total Maximal Chorea (UHDRS-TMC), Unified 
Huntington’s Disease Rating Scale-Total Maximal Dystonia (UHDRS-TMD), Pediatric 
Evaluation Disability Inventory-Computer Adapted Test (PEDI-CAT), Pediatric Quality of Life 
Inventory (PedsQL) and Patient Global Impression of Improvement (PGI-I)) and Section 8
(Columbia-Suicide Severity Rating Scale [C-SSRS], Child Behavior Checklist [CBCL], 
Extrapyramidal Symptom Rating Scale [ESRS] and Epworth Sleepiness Scale [ESS]).
Unless otherwise specified, only those observed data from the patients will be used in the 
statistical analyses, ie, no estimation of missing data.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
28
4.4.
Study Days and Visits
Study days will be numbered relative to the baseline visit date. Day 1 is defined as the date of the 
baseline visit, and the first dose of the IMP will be taken the next morning (day 2). Days will be 
numbered relative to baseline (ie, ..., –2, –1, 1, 2, ...; day –1 being the day before the baseline 
visit).
For efficacy and safety by-visit analyses, data collected at post-baseline scheduled visits will be 
included using their scheduled visit.
Data collected at early termination and unscheduled visits will be included and assigned to a visit 
window as described below. 
Table 2:
Visit Windows for Early Termination Visit for Efficacy Assessments
Assessmenta
Study Day Window
Scheduled Day  
Scheduled Visit/Week
MD-CRS
Day 2 - 73
Day 63
Week 9
Day 74 - 94
Day 84
Week 12
Day 95 - EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
CaGI-I, CGI-S, 
PGI-I
Day 2 - 35
Day 21
Week 3
Day 36 - 53
Day 49
Week 7
Day 54 - 73
Day 63
Week 9
Day 74 - 94
Day 84
Week 12
Day 95 - EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
CGI-I
Day 2 - 10
Day 7
Week 1
Day 11 - 17
Day 14
Week 2
Day 18 – 24
Day 21
Week 3
Day 25 - 31
Day 28
Week 4
Day 32 - 38
Day 35
Week 5
Day 39 - 45
Day 42
Week 6
Day 46 - 53
Day 49
Week 7
Day 54 - 73
Day 63
Week 9
Day 74 - 94
Day 84
Week 12
Day 95 - EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
PEDI-CAT, PedsQL
Day 2 – EOT 
Day 105
Week 15


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
29
Assessmenta
Study Day Window
Scheduled Day  
Scheduled Visit/Week
UHDRS-TMS,
UHDRS-TMC,
UHDRS-TMD
Day 2 - 73
Day 63
Week 9
Day 74 - 94
Day 84
Week 12
Day 95 - EOT
Day 105
Week 15
a CaGI-I=Caregiver Global Impression of Improvement; CGI-I=Clinical Global Impression of Improvement;
CGI-S=Clinical Global Impression of Severity; PGI-I=Patient Global Impression of Improvement; UHDRS-
TMS=Unified Huntington’s Disease Rating Scale-Total Motor Score; UHDRS-TMC=Unified Huntington’s Disease 
Rating Scale-Total Maximal Chorea; UHDRS-TMD=Unified Huntington’s Disease Rating Scale-Total Maximal 
Dystonia; EOT=end of treatment
Table 3:
Visit Windows for Early Termination Visit for Safety Assessments
Assessmenta
Study Day Window
Scheduled day  
Scheduled Visit/Week
Vital signs, Weight, 
C-SSRS, ESRS, 
CBCL- Syndrome Scale, 
ESS
Day 2 - 35
Day 21
Week 3
Day 36 - 53
Day 49
Week 7
Day 54 - 74
Day 63
Week 9
Day 75 - 94
Day 84
Week 12
Day 95 – EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
ECG
Day 2 - 35
Day 21
Week 3
Day 36 - 67
Day 49
Week 7
Day 68 – EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
Laboratory tests other 
than pregnancy and drug 
screen
Day 2 – EOT
Day 105
Week 15
Day after EOT
Day 112
Week 16
Orthostatic blood 
pressure, Physical exam, 
Neurological exam, 
height, CBCL-full 
assessment
Day 2 – EOT
Day 105
Week 15
a CBCL=Child Behavior Checklist (for ages 6-18); C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ESRS=Extrapyramidal Symptom Rating Scale (subscales I and II); ESS =Epworth 
Sleepiness Scale (for children and adolescents); EOT=end of treatment
After mapping the data to the analysis visits of unscheduled and early termination visits, the 
following rules will apply unless other handling is specified for a particular analysis:

If there is a scheduled visit in the analysis window, the last non- missing scheduled 
visit will be selected.

If there is no scheduled visit, but early termination visit, early termination visit will be 
selected. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
30

If there are no scheduled or early termination visits, the record closest to the planned 
assessment day will be selected for analysis. 

If there are no scheduled or early termination visits, and 2 records are equidistant 
from the scheduled day, then the later record will be selected. 

If a patient has no scheduled record or early termination/unscheduled visits in an 
analysis window, the patient will be considered missing at that visit.
For these analyses performed by time period, eg, adverse events, the following definitions will 
be used:

Titration Period - from the first dose of treatment until the day of the week 7 visit. For 
patients discontinued before the week 7, the Titration Period is until the later of the 
last dose of treatment and the early termination visit.

Maintenance Period - from the day after the week 7 visit until the day of the week 15
visit. If a patient enters the Maintenance Period but discontinues treatment early, the 
Maintenance Period is until the later of the last dose of treatment and the early 
termination visit. 

Overall Treatment Period - includes the Titration and the Maintenance Periods, if 
applicable.

Follow-up Period - from the end of the Overall Treatment Period through the end of 
the study.
For last assessment, the last available non-missing value will be used. Unscheduled visits that 
could not be mapped will not be displayed in the safety by-visit summaries, but they will be 
considered for the endpoint/last assessment visit.
4.5.
Handling Data From Patients Withdraw and Re-Enter the Study
Patients who terminate early from the study due to emergency circumstances (such as 
coronavirus disease 2019 [COVID-19]) may be allowed to re-enter the study at a later date. 
Patients re-entering the study will be manually assigned to their initial treatment group and will 
redo the entire study from the start.
4.5.1.
Baseline Values
In general, baseline values from the re-entered participation will be used. Missing baseline 
values will be handled in the same method as other non-withdrawal patients. 
The blinded CYP2D6 genotyping is the only measurement that is not required for re-entering 
patients. Results from the original participation of the CYP2D6 impairment status at baseline 
will be carried over to the repeated participation (re-entered) portion. 
4.5.2.
Efficacy Data
For each patient that re-entered the study, only data from the repeated participation will be 
included in the ITT, mITT, PP, mITTA, and mITTB analysis sets. The original participation data 
will be listed separately and will not be included in any summary tables or statistical analysis.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
31
Missing postbaseline efficacy values will be handled in the same method as other non-
withdrawal patients. 
4.5.3.
Safety Data
For each patient that re-entered the study, only data from the repeated participation will be 
included in the ITT and safety analysis sets. The original participation data will be listed 
separately and will not be included in any summary tables. In case of a SAE that occurred during 
the original participation and resolved prior to re-entering, the SAE will be documented in 
medical history database. Missing postbaseline safety values will be handled in the same method 
as other non-withdrawal patients.  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
32
5.
STUDY POPULATION
5.1.
General
The ITT analysis set (Section 3.1) will be used for all study population summaries, unless 
otherwise specified. The summaries might be presented using the mITT analysis set 
(Section 3.2), in case >10% of ITT patients were excluded from the mITT analysis set. 
Summaries will be presented by treatment group and for all patients.
5.2.
Patient Disposition
Data from patients screened; patients screened but not randomized (and reason not randomized); 
patients who are randomized; patients randomized but not treated; patients re-randomized (if 
applicable); patients in the ITT, mITT, safety, PP, mITTA and mITTB analysis sets; patients 
who complete the treatment period; patients who withdraw from the study during the treatment 
period; patients who complete the EOS visit; and patients who withdraw from the study will be 
summarized using descriptive statistics. 
Data from patients who withdraw from the study during the treatment period, and from the study
overall will be summarized by reason for withdrawal.
Data from patients who withdraw during the treatment period will be summarized by 
classification to MAR/MNAR overall, for the titration and maintenance periods, and by visit 
using descriptive statistics.
5.3.
Demographics and Baseline Characteristics
Patient demographic and baseline characteristics will be summarized using descriptive statistics. 
The continuous variables of patient age, weight, height, and body mass index (BMI) will be 
summarized using descriptive statistics. 
BMI at baseline will be computed as:
BMI (kg/m2) = Weight at baseline (kg)/[Height at screening (m)2].
Height, weight, and BMI at baseline will also be presented by age group and sex using 
descriptive statistics. In addition, normal age and sex-based z-scores and percentiles for BMI will 
be determined using the World Health Organization (WHO) growth charts, and summarized
descriptively.
The categorical variables of patient weight group, sex, race, ethnicity, and region (United States 
(US) and non- US) and country for non-US will be summarized using descriptive statistics for 
each category. The categorical variables of age group at baseline (6 to <12 years, 12 through 18
years, inclusive), use of a strong CYP2D6 inhibitor, as appears in Table 9 of the study protocol
(Yes/No), CYP2D6 genotype (Poor CYP2D6 metabolizer/ Non-poor CYP2D6 metabolizer), and 
CYP2D6 impairment status (Impaired/Not impaired) will be summarized using descriptive 
statistics for each category. In addition, age and sex-based BMI categories include: Underweight 
(< 5 percentile), Normal (≥ 5 - < 85 percentile), Overweight (≥85 - < 95 percentile), Obese (≥ 95 
percentile), will be tabulated for each category.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
33
5.4.
Disease Characteristics
Post-hoc analysis will be provided for disease characteristics. 
5.5.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each preferred term and SOC category. Summaries will be presented by treatment group 
and for all patients.
5.6.
Prior Therapy and Medication
Any prior or concomitant medication a patient has had within 3 months prior to baseline and up 
to the end of study, including follow up, will be recorded on the CRF. Generic or trade name, 
indication, dose, and start and end dates of the administered medication will be recorded. The 
sponsor will encode all medication according to the WHO drug dictionary.
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class, preferred base name and preferred term. Patients are counted only once in 
each therapeutic class category, and only once in each preferred term category. Prior therapies 
and medications will include all medications taken and therapies administered before the first 
day of IMP administration.
5.7.
Study Drug Titration
The number and percent of patients at each dose level by weight group and CYP2D6 impairment 
status during the titration period will be summarized by week. The latest administered dose in 
each study week will be used.
Reasons for the deviation from the IMP dosing scheme (see Protocol Sections 5.1.1.1 and 
5.1.1.2) will be summarized overall and by period (titration and maintenance). Patient data will 
be reviewed in the blinded SDR meeting prior to database lock to determine the reason for 
deviation in each period and overall.
Descriptive statistics of the maintenance dose (last dose taken in the maintenance period); 
nominal and as percent of the maximal planned dose for the patient) will be presented.
The safety analysis set will be used for IMP titration summaries.
5.8.
Study Drug Compliance
Study drug compliance during the treatment period will be assessed as described in the protocol
Section 5.7.
Study drug compliance will be determined by presenting the number of tablets taken as a 
percentage of the expected number of tablets based on the dose(s) of the patient at the relevant 
time period (see Table 4 and Table 5; study protocol Section 5.1).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
34
Table 4:
Drug Kits based on Titration Scheme – Non-Impaired CYP2D6 Metabolizers 
Weight 
Group
12kg to <17kg
17kg to <30kg
30kg to <40kg
≥40kg
Visit
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Day 2
6 
6
6 
6
6 
6
6 
6
Week 1
6 
6
6 
6
6 
6
12 
6,6
Week 2
6 
6
12 
6,6
12 
6,6
18 
9,9
Week 3
12
6,6
18 
9,9
18 
9,9
24 
12,12
Week 4
12 
6,6
18 
9,9
24 
12,12
30 
15,15
Week 5
18 
9,9
24 
12,12
30 
15,15
36  
18,18
Week 6
18 
9,9
24 
12,12
36  
18,18
42 
15,6 AM
15,6 PM
Week 7
24  
12,12
30 
15,15
42 
15,6 AM
15,6 PM
48 
12,12 AM
12,12 PM
Dose and tablets refer to IMP, either TEV-50717 or matching placebo. Maximal dose according to the titration 
scheme is presented.
Table 5:
Drug Kits based on Titration Scheme –Impaired CYP2D6 Metabolizers 
Weight 
Group
12kg to <17kg
17kg to <30kg
30kg to <40kg
≥40kg
Visit
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Dose
(mg/day)
Tablets
(mg)
Day 2
6 
6
6 
6
6 
6
6 
6
Week 1
6 
6
6 
6
6 
6
12 
6,6
Week 2
6 
6
12 
6,6
12 
6,6
18 
9,9
Week 3
12
6,6
18 
9,9
18 
9,9
24 
12,12
Week 4
12 
6,6
18 
9,9
24 
12,12
30 
15,15
Week 5
12 
6,6
18 
9,9
24 
12,12
36  
18,18
Week 6
12 
6,6
18 
9,9
24 
12,12
36
9,9 AM
9,9 PM
Week 7
12 
6,6
18 
9,9
24
6,6 AM
6,6 PM
36
9,9 AM
9,9 PM
Dose and tablets refer to IMP, either TEV-50717 or matching placebo. Maximal dose according to the titration 
scheme is presented. 
The number of tablets used is the number of tablets dispensed minus the number of tablets 
returned. If a patient does not return a pill bottle, it will be assumed that the patient took no IMP
from that bottle for the purposes of calculating compliance.  
The denominator of “expected number of tablets” will be calculated based on patients’ 
participation in the study (ie, last day of study drug – first day of study drug + 1) and the 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
35
expected dose according to the RTSM system. Adjustments may be required for the doses split 
between the morning and the evening dose. Of note, the protocol allows the investigator not to 
titrate a patient up to the maximal possible dose by weight group and CYP2D6 impairment
status; therefore the expected number of tablets will be calculated individually. Moreover, drug 
suspensions and reductions based on investigator instructions are considered as change in the 
expected number of tablets and are not considered non-compliance. For patients who complete 
the study, the last day of study drug used in the denominator calculation will be the last expected 
dosing day. For early termination patients, the last day of study drug used in the denominator 
calculation will be the last expected dosing day before termination day.
A patient will be deemed compliant over the treatment period if the patient has taken 80% to 
105% of the expected tablets of study drug.
Treatment compliance (%) will be summarized as continuous data using descriptive statistics. In 
addition, treatment compliance will be summarized as categorical data using descriptive statistics 
for the following categories: <80%, 80% to 105%, >105%. Compliance will be presented by 
visit, by overall in the titration and maintenance periods, and by overall in the treatment period.
An additional assessment of the IMP compliance may be performed while taking into account 
the patient’s dose. 
5.9.
Study Protocol Deviations
Data from patients with any important protocol deviations (as recorded in the Clinical Trial 
Management System) during the study will be summarized overall and for each category using 
descriptive statistics. All protocol deviations will be listed.
In addition, patients with any COVID-19 related protocol deviations will be summarized and 
listed separately. 
Reasons for exclusion from the PP analysis set (as evaluated in the final blinded statistical data 
review meeting; see Section 3.4) will be summarized using descriptive statistics.  


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
36
6.
EFFICACY ANALYSIS
6.1.
General
The mITT, mITTA, mITTB, ITT, and PP analysis sets (Section 3) will be used for all the
efficacy analyses.
The mITT analysis set will be regarded as the main set for the analysis of the primary endpoint. 
It will also be used for all the efficacy endpoints unless otherwise specified. In addition, the 
mITTA, mITTB, ITT, and PP analysis sets will be used for the sensitivity analyses of the 
primary and key secondary endpoints.
Summaries will be presented by each scheduled visit (until Week 15) and treatment group,
unless specified otherwise.
All p-values for treatment effect (TEV-50717 vs. placebo) will correspond to a 1-sided test for 
superiority.
6.2.
Primary Efficacy Endpoint and Analysis
6.2.1.
Primary Endpoint
6.2.2.
Definition
The primary efficacy endpoint is the change from baseline to week 15 in the MD-CRS part II
total score (movement disorder severity, centrally read) (TEV-50717 versus placebo).
6.2.3.
Primary Efficacy Analysis
The primary analysis will be a mixed-model repeated-measures (MMRM) with the change in 
MD-CRS part II total score as the dependent variable. The model will include fixed effects for 
treatment group, week (as a categorical variable with 3 levels: weeks 9, 12, and 15), and 
treatment group by week interaction. The baseline MD-CRS part II total score, age group at 
baseline (2 levels: 6 to <12 years; 12 through 18 years, inclusive), and region (US; non-US) will
be included as covariates. The unstructured covariance matrix will be used in the model. In cases
where the model does not converge, the Maximum-Likelihood estimation method will be used 
instead of the default Restricted Maximum-Likelihood. If the model still does not converge, then 
a simpler covariance structure with fewer parameters will be used, according to the following 
order: Heterogeneous Autoregressive (1), Heterogeneous Compound Symmetry, Autoregressive 
(1), and Compound Symmetry. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.
Missing data will be classified as MAR and MNAR, as described in Section 4.3. MNAR data 
will be imputed using the jump-to-reference method, and MAR data will be imputed based on
the randomized treatment group. The details are described below:


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
37
1. Missing data will be imputed in 2 separate subgroups. The MAR subgroup will 
contain all patients randomized to a TEV-50717 treatment group without missing data 
at week 15 or have a MAR missing data mechanism. The MNAR subgroup will 
contain all patients randomized to placebo as well as patients randomized to receive 
TEV-50717 with missing data at week 15 with an MNAR missing data mechanism. 
2. Data will be imputed for patients with missing data at week 15 using a predictive 
mean matching multiple imputation method. Multiple imputations will be performed 
within each subgroup: 
a.
Under a MNAR data assumption, patients in the MNAR subgroup will have 
their missing data at week 15 imputed as if they behaved like placebo treated 
patients after dropping out. Only placebo patients with complete data will be 
included in the imputation model.
b. All other patients will have data imputed from a model derived from their 
assigned treatment group (imputation under MAR assumption). 
The imputation models will include age group at baseline, region, baseline MD-CRS 
part II total score, and MD-CRS part II total scores at week 9 and week 12. After 
obtaining complete data sets for both subgroups, they will be combined and the 
complete data set will be used in the analysis.
3. The resulting complete, imputed datasets will each be analyzed using the analysis 
model described above and the resulting statistics combined using methodology 
presented by Rubin (1987) and Little and Rubin (2002).
The complete multiple imputation methodology, along with SAS code, is detailed in Appendix 1.
Difference in least squares (LS) mean of the change in MD-CRS part II total score from baseline 
to week 15 (TEV-50717 versus placebo) will be compared using a 1-sided test for superiority at 
a nominal significance level of α=0.025. 
The LS mean and SE for the treatment groups, the LS mean difference, 2-sided 95% confidence 
interval, and p-value for the comparison (TEV-50717 versus placebo) at week 15 will be 
presented.
6.2.4.
Sensitivity Analysis
To assess the robustness of the primary efficacy analysis, sensitivity analyses will include the 
following:
Sensitivity analyses for assumptions of missing data mechanism:

tipping point (MNAR)

MAR multiple imputation 
Sensitivity analysis for the statistical model:

analysis of covariance (ANCOVA)

primary model, including only the following covariates: treatment group, week, and 
treatment group by week interaction


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
38
Other:

primary model repeated for the ITT analysis set;

primary model repeated for the mITTA analysis set;

primary model repeated for the mITTB analysis set;

primary model repeated for the PP analysis set;

ANCOVA models for MD-CRS part II total score change from baseline to week 9 
and to week 12.
6.2.4.1.
Sensitivity Analyses for Assumptions of Missing Data Mechanism
Sensitivity analyses for assumptions of missing data mechanism include the MNAR tipping point 
analysis and the MAR multiple imputations.
6.2.4.1.1. MNAR Tipping Point Analysis
Details for tipping point analysis are described below:
a.
For patients that completed the study, intermittent missing data are considered as 
MAR and will be imputed by the predictive mean matching multiple imputation 
method (Heitjan and Little 1991, Schenker and Taylor 1996). The imputation model 
will include age group at baseline, region, treatment group and MD-CRS part II total 
score at baseline, week 9 and week 12.
b. For patients who discontinued due to any reason, all missing data will be imputed 
using the same predictive mean matching multiple imputation method. The imputed 
values will be adjusted under a MNAR assumption: 

Patients randomized to TEV-50717: the first missing value after patients drop out 
will be analyzed assuming the treatment effect is worsened by δ (where δ1 = 0 to 2
or estimated treatment effect based on the primary analysis, whichever is higher, 
in step of 0.2) compared to the patients who have no missing value.  ≥0 will be 
used as a shift to adjust the imputed values, since higher MD-CRS score
corresponds to the more severe movement disorder.

Patients treated with placebo: the observed treatment effect for placebo-treated 
patients will be used for imputing missing value in the placebo population for all 
shift parameters.
The shift will be applied only for the first visit with missing data and will not be 
applied for later time points as these values are shifted through the condition on the 
previous time points. For each δ value, 500 imputed datasets will be obtained. 
c.
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). Refer 
to Appendix 1; start at Step 2.
The complete multiple imputation methodology, along with the SAS code, is detailed 
in Appendix 2.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
39
6.2.4.1.2.
MAR Multiple Imputation
All missing data will be imputed using the predictive mean matching multiple imputation 
method (Heitjan and Little 1991, Schenker and Taylor 1996) under MAR data assumption using 
fully conditional specification (FCS) method. The imputation model will include age group at 
baseline, region, treatment arm, MD-CRS part II total score at baseline, week 9 and week 12. 
The imputation under the MAR assumption corresponds to a full treatment effect observed in the 
mITT population. Therefore, the results from the tipping point analysis with δ = 0 will be used 
for this sensitivity analysis; see Section 6.2.4.1.1 for details.
6.2.4.2.
Sensitivity Analysis for the Statistical Model
Sensitivity analyses for the statistical model include the analysis of covariance (ANCOVA) and 
the primary model rerun with a reduced number of covariates.
6.2.4.2.1. Analysis of Covariance
The ANCOVA model will be used for week 15 MD-CRS part II total score change from baseline 
data following imputation using the same approach as described in Section 6.2.3, steps 1-2. The 
ANCOVA model will replace the MMRM analysis in step 3 of Section 6.2.3 and will include 
age group at baseline, region, baseline MD-CRS part II total score, and treatment as covariates.
The SAS code for this model is as follows:
proc mixed;
   class arm agegrp region;
   model chg=arm agegrp region base;
   lsmeans arm / diff cl; 
where avisitn=15;
run;
6.2.4.2.2. Primary Analysis With Reduced Number of Covariates
Primary analysis, including only the following covariates: treatment group, week, and treatment 
group by week interaction will be run as described in Section 6.2.3. The MAR/MNAR multiple 
imputation models will include only these limited covariates. After obtaining complete data sets 
for MAR/MNAR subgroups, they will be combined and the complete data set will be used in the 
analysis with the same covariates.
6.2.4.3.
Other Sensitivity Analyses
Other sensitivity analyses will include the primary model repeated on the different subsets of 
patients and at the different time points.
The primary model as described in Section 6.2.3 will be repeated using

ITT analysis set;

mITTA analysis set;

mITTB analysis set;

PP analysis set.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
40
ANCOVA model, as described in Section 6.2.4.2.1, but without the multiple imputation, will be 
applied for MD-CRS part II total score change from baseline to 

week 9;

week 12;

week 15.
6.2.5.
Retrospective Power and Sample Size
The following analyses will be performed to quantify the impact of the reduction in sample size 
on the power, based on the actual final data: 

Conditional power for n=185 (the initially planned minimal sample size), based on 
the observed effect size at the end of the study

Sample size required to power the study (90%) at α=0.025, based on the observed 
effect size at the end of the study

Effect size and difference in change in MD-CRS II based on the observed SD needed 
in order to be powered (90%) for the given final sample size
The retrospective analyses will be conducted using the definitions and methods that were used in 
the interim analysis, see Section 10.4 and 10.5.
6.3.
Secondary Efficacy Endpoints and Analysis
6.3.1.
Key Secondary Efficacy Endpoints
The key secondary endpoints are the following:
1. change from baseline to week 15 in centrally read MD-CRS part I total score
(TEV-50717 versus placebo) 
2. CaGI-I at week 15 (TEV-50717 versus placebo)
3. CGI-I at week 15 (TEV-50717 versus placebo)
4. change from baseline to week 15 in centrally read UHDRS-TMC (TEV-50717 versus 
placebo)
5. change from baseline to week 15 in centrally read UHDRS-TMD (TEV-50717 versus 
placebo)
For a detailed description of scales, refer to the Section 6.2 of the study protocol.
6.3.1.1.
Key Secondary Efficacy Endpoints Analysis
Analyses of the key secondary endpoints will be performed in a hierarchical manner as follows:  
1. MD-CRS part I total score change from baseline to week 15 will be analyzed using a 
MMRM in the same fashion as the primary analysis, with the exception that the 
baseline value of MD-CRS part I total score will be included as the covariate instead 
of MD-CRS part II total score.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
41
2. CaGI-I at week 15 will be analyzed using an MMRM model in the same fashion as 
the primary analysis, with the exceptions that the baseline value of CGI-S will be 
included as the covariate instead of MD-CRS part II total score and that the week 
variable will include 5 levels (weeks 3, 7, 9, 12, and 15).
3. CGI-I at week 15 will be analyzed using an MMRM model in the same fashion as the 
primary analysis, with the exceptions that the baseline value of CGI-S will be 
included as the covariate instead of MD-CRS part II total score and that the week 
variable will include 5 levels (weeks 3, 7, 9, 12, and 15).
4. UHDRS-TMC (centrally-read) change from baseline to week 15 will be analyzed 
using an MMRM model in the same fashion as the primary analysis, with the 
exception that the baseline value of UHDRS-TMC (centrally-read) will be included 
as the covariate instead of MD-CRS part II total score.
5. UHDRS-TMD (centrally-read) change from baseline to week 15 will be analyzed 
using an MMRM model in the same fashion as the primary analysis, with the 
exception that the baseline value of UHDRS-TMD (centrally-read) will be included 
as the covariate instead of MD-CRS part II total score. 
For CaGI-I and CGI-I, in Appendix 1, Step 1 should begin with week 3, week 7 and only then 
continue to week 9.
See Section 6.5.3 for definition of UHDRS-TMC and TMD, and Section 7 for description of 
multiplicity control of the key secondary endpoints.
6.3.1.2.
Key Secondary Efficacy Endpoints Sensitivity Analysis
Sensitivity analyses for the key secondary endpoints will be performed in the same fashion as the 
primary endpoint. See Section 6.2.4 for details. 
Some specific notes:

The corresponding baseline or post-baseline assessment will be used for each 
secondary endpoint.

Tipping point (MNAR) – For CaGI-I and CGI-I, the imputation model will include 
age group at baseline, region, treatment group, and CGI-S core at baseline, as well as 
the CaGI-I or CGI-I score at week 3, 7, 9 and week 12. MAR multiple imputation 
will be analyzed in a similar fashion with the same covariates.

ANCOVA models will be fitted for change from baseline in MD-CRS part I total 
score to weeks 9, 12 and 15, and CaGI-I and CGI-I scores at weeks 3, 7, 9, 12 and 15.
6.4.
Subgroup Analyses
Analyses of the primary and key secondary endpoints by subgroup below will be conducted 
using the mITT population:

Gender: male and female;

Race Group: white, black or African American, and other;


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
42

Baseline Age Group (6-<12 years, 12-18 years inclusive);

CYP2D6 impairment status (Yes/No);

US vs outside of US (non-US).
As the total sample size is approximately 65 patients, the sub-group analysis will include 
descriptive statistics by subgroup, and no statistical models will be fitted. The subgroup analyses 
will be performed provided the minimum size of the smaller subgroup is at least 5 patients. 
Otherwise, the main analysis will be repeated on the larger subgroup.
6.5.
Other Efficacy Endpoints and Analysis
Other efficacy endpoints (change from baseline to week 15/proportion at week 15; TEV-50717 
versus placebo) are the following:

MD-CRS physician rated:

MD-CRS part I total score change from baseline to week 15

MD-CRS part II total score change from baseline to week 15

MD-CRS Global Index (calculated from MD CRS parts I and II total scores as 
assessed by physician)

MD-CRS Global Index (calculated from MD-CRS parts I and II total scores, centrally 
read)

UHDRS:

UHDRS-TMS (physician rated)

UHDRS-TMC (physician rated)

UHDRS-TMD (physician rated)

PEDI CAT

PedsQL 

PGI-I

CGI-S

Response Analysis

CaGI-I response, defined as patients who are described by the caregiver as “Much 
Improved” or “Very Much Improved” in the CaGI-I score

CGI-I response, defined as patients who are described as “Much Improved” or 
“Very Much Improved” in the CGI-I score

CGI-S response, defined as patients who have a reduction of ≥1 point in the 
CGI-S score

PGI-I response, defined as patients who are described as “Much Improved” or 
“Somewhat Improved” in the PGI-I score


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
43
The mITT analysis set will be used for the analysis.
6.5.1.
MD-CRS Global Index (calculated from MD-CRS parts I and II total scores, 
centrally read) 
6.5.1.1.
Definition
The MD-CRS Global Index is a global measure of the MD-CRS that consolidates the 
information from parts I and II using the method of weighted means of the 2 normalized indexes 
obtained from each part. The minimum score is 0 and the maximum score is 1.
The standardized/normalized score for each item of MD-CRS parts I and II with value  is 
calculated using the formula
 =
 −
 −
where  is the maximum value for the score, and  is the minimum value for the score, or 
4 and 0 respectively.
The normalized index for the scale, MD-CRS parts I or II, Index I or II, is calculated as the mean 
value of .
The MD-CRS Global Index is the weighted mean of the normalized indexes for centrally read 
MD-CRS parts I and II using the formula:
 !"#$! %&'() = &* × %&'()* + &** × %&'()**
&* + &**
where &* and &** are the numbers of items in MD-CRS parts I and II respectively.
6.5.1.2.
Analysis
The MD-CRS Global Index change from baseline to week 15 data will be analyzed using 
MMRM. The MMRM model will include age group at baseline, week (3 levels: weeks 9, 12, and 
15), region, corresponding baseline value and treatment as fixed effects. The SAS code is below:
proc mixed Method=REML;
   class usubjid arm avisitn agegrp region;
   model chg=arm | avisitn agegrp region base / ddfm=kr;
   repeated avisitn / type=un subject=usubjid;
   lsmeans arm*avisitn / diff cl;
   ods output diffs=diff(where=(avisitn=_avisitn) lsmeans=lsm; 
Run;
The LS mean and SE for the treatment groups, the LS mean difference, 2-sided 95% confidence 
interval (CI), and 1-sided p-value for the comparison (TEV-50717 versus placebo) at Week 15
will be presented. The p-value will be considered to be a nominal p-value.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
44
A descriptive summary will be provided for all assessments and change from baseline, including 
the follow-up period.
6.5.2.
MD-CRS Physician Rated
6.5.2.1.
Definition
The local, physician rated MD-CRS part I and MD-CRS part II are additional efficacy endpoints 
of the study. The physician rated MD-CRS part I and MD-CRS part II endpoints include:

MD-CRS part I total score (general assessment, physician rated) change from 
baseline to week 15

MD-CRS part II total score (general assessment, physician rated) change from 
baseline to week 15

MD-CRS Global Index (calculated from MD CRS parts I and II total scores as 
assessed by physician) change from baseline to Week 15
The calculation as described in Section 6.5.1.1 will be performed for physician-rated MD-CRS
assessments to yield the MD-CRS Global Index.
6.5.2.2.
Analysis
The data will be analyzed using MMRM similarly to the description in Section 6.5.1.2.
6.5.3.
Unified Huntington’s Disease Rating Scale 
6.5.3.1.
Definition
UHDRS-TMS:
The UHDRS-TMS (physician rated) comprises a broad assessment of features associated with 
HD. The TMS component of UHDRS comprises 31 assessments from the 15 items of the 
UHDRS. The TMS is calculated as the sum of the 31 motor assessments, each of which range 
between 0 to 4. The minimum score is 0 (absent) and the maximum score is 124 (worst). 
The UHDRS-TMS is administered at baseline and weeks 9, 12, and 15/ET visits.
UHDRS-TMC:
The UHDRS-TMC is part of the UHDRS-TMS assessment and evaluates the severity of chorea 
in the face, mouth, trunk, and the 4 extremities. The minimum score is 0 (absent) and the 
maximum score is 28 (marked/prolonged).
UHDRS-TMD: 
The UHDRS-TMD is part of the UHDRS-TMS assessment and assesses the severity of dystonia 
in the trunk and the 4 extremities. The minimum score is 0 (absent) and the maximum score is 20 
(marked/prolonged).
If responses of up to 25% of items are missing in UHDRS-TMS, UHDRS-TMC, or UHDRS-
TMD (“scale”), the missing responses will be replaced by the average of the remaining responses 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
45
within each of the scales. If 8 or more of the items are missing, the missing items will not be 
replaced and the scale will be set to missing.
The UHDRS-TMC and TMD are administered at baseline and at weeks 9, 12, and 15/ET visits.
6.5.3.2.
Analysis
The UHDRS-TMS, UHDRS-TMC (physician rated) and UHDRS-TMD (physician rated) change 
from baseline to week 15 data will be analyzed using MMRM similarly to the description in 
Section 6.5.1.2.
6.5.4.
Pediatric Evaluation of Disability Inventory Computer Adaptive Test Definition
The PEDI-CAT is a clinical assessment for children and youth. The PEDI-CAT (activities of 
daily living [ADL], parent/caregiver completed, content balanced version) measures function in 
4 domains: (1) Daily Activities; (2) Mobility; (3) Social/Cognitive, and (4) Responsibility. Each 
domain is self-contained and can be used separately or with other domains. The content balanced 
version presents a balance of items from each of the Daily Activities domain’s content areas 
(Getting Dressed, Keeping Clean, Home Tasks, and Eating & Mealtime). A total of 
approximately 30 items are administered (total number of items administered is dependent upon 
the responses and decision tree path). The PEDI-CAT software utilizes Item Response Theory 
statistical models to estimate a child’s abilities from a minimal number of the most relevant 
items or from a set number of items within each domain. All respondents begin with the same 
item in each domain in the middle of the range of difficulty or responsibility and the response to 
that item then dictates which item will appear next (a harder or easier item), thus tailoring the 
items to the child and avoiding irrelevant items. The CAT program then displays the results: 
normative standard scores, scaled scores and the SE. The scales are available for 21 age groups 
as intervals of 1 year. 
Normative (fit) scores are based on a child’s chronological age and intended for use by clinicians 
so that they may interpret a particular child’s functioning relative to others of the same age. This 
metric is of less relevance for the studied population and therefore will not be assessed.
Scaled scores provide a way to look at a child’s current functional skills and progress in these 
skills over time. Scaled scores are especially helpful in documenting improvements in functional 
skills for children not expected to exhibit or regain normative levels of functioning. The scaled 
scores are based on an estimate of the placement of an individual child along the hierarchical 
scale within each domain. The PEDI-CAT scaled scores are currently on a 20 to 80 scale metric.
See PEDI-CAT (Version 1.3.6) Development, Standardization and Administration Manual.
The SE scores indicate the level of the test precision, and are expected to be up to 0.5.
The PEDI-CAT (ADL, parent/caregiver completed, content balanced version) is administered at 
baseline and at week 15/ET visits.
6.5.4.1.
PED-CAT Analysis
The PEDI-CAT scaled score change from baseline to week 15 data will be analyzed using an 
ANCOVA model with age group at baseline, region, baseline score, and treatment as fixed 
effects based on the mITT analysis set. The ANCOVA model will be applied as in 
Section 6.2.4.2.1.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
46
A descriptive summary of the PEDI-CAT scaled score will be provided for all measurements and 
change from baseline.
6.5.5.
The CP module of the PedsQL (QoL, patient/caregiver)
6.5.5.1.
Definition
The Pediatric Quality of Life Inventory (PedsQL™) is a health-related quality-of-life instrument 
that consists of a well-validated generic core measure and some condition and disease-specific 
modules (Varni et al 2006). The 35-item PedsQL 3.0 CP module encompasses 7 scales: (1) Daily 
Activities (9 items); (2) School Activities (4 items); (3) Movement and Balance (5 items); 
(4) Pain and Hurt (4 items); (5) Fatigue (4 items); (6) Eating Activities (5 items); and (7) Speech 
and Communication (4 items).
The scales comprise parallel child self-report and parent proxy-report formats. Child self-report 
includes ages 5 to 7 years, 8 to 12 years, and 13 to 18 years. A parent proxy report is included in 
reports for ages 2 to 4 years (toddler), 5 to 7 years (young child), 8 to 12 years (child), and 13 to 
18 years (adolescent, not administered in the study), and assesses parents’ perceptions of their 
child’s health-related quality of life (QoL). The instructions ask how much of a problem each 
item has been during the past 1 month. A 5-point response scale is utilized across child self-
report and parent proxy report as follows:
0=never a problem; 
1=almost never a problem;
2=sometimes a problem; 
3=often a problem; 
4=almost always a problem.
To further increase the ease of use for the young child self-report (ages 5–7 years), the response 
scale is reworded and simplified to a 3-point scale (0=not at all a problem; 2=sometimes a 
problem; 4=a lot of a problem).
Items are reverse scored and linearly transformed to a 0–100 scale (0=100, 1=75, 2=50, 3=25, 
4=0), so that higher scores indicate better quality of life, i.e. fewer symptoms or problems. Scale 
Scores are computed as the sum of the items divided by the number of items answered (this 
accounts for missing data). If more than 50% of the items in the scale are missing, the Scale 
Score is not computed. This computation is consistent with the previous PedsQL peer-reviewed 
publications as well as other well-established Health-related quality of life measures. 
A total score will be computed as the sum of the 35 items divided by the number of items 
answered and will not be computed if more than 50% of the items are missing. Each teen/child 
self-report and parent proxy-report will be assessed separately.
The PedsQL is administered at baseline and at week 15/ET visits. 
6.5.5.2.
Analysis
The PedsQL total score per each teen/child self-report /parent proxy-report and change from
baseline to week 15 will be analyzed using an ANCOVA model with region, baseline score, and 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
47
treatment as fixed effects based on the mITT analysis set. The ANCOVA model will be applied 
as in Section 6.2.4.2.1.
A descriptive summary of each PedsQL teen/child self-report /parent proxy-report total and scale 
scores and change from baseline will be provided.
6.5.6.
PGI-I Scale (global, patient/caregiver)
6.5.6.1.
Definition
For a detailed description of scales, refer to the Section 6.3.7 of the study protocol.
The PGI-I is administered at week 3, week 7, week 9, week 12, week 15/ET, and week 16/EOS 
visits. Input from the caregiver/adult is permitted.
6.5.6.2.
Analysis
The PGI-I at week 15 data will be analyzed using MMRM based on the mITT analysis set
similarly to the description in Section 6.5.1.2 (except that the value at week 15 will be analyzed 
rather than the change from baseline). The MMRM model will include age group at baseline, 
week (3 levels: weeks 9, 12, and 15), region, and treatment as fixed effects. No baseline 
assessment will be used in the model.
6.5.7.
CGI-S Scale (global, physician rated)
6.5.7.1.
Definition
For a detailed description of the scale, refer to the Section 6.3.8 of the study protocol.
The CGI-S is administered at screening, baseline, week 3, week 7, week 9, week 12, week 
15/ET, and week 16/EOS visits. 
6.5.7.2.
Analysis
The CGI-S change from baseline to week 15 data will be analyzed using MMRM similarly to the 
description in Section 6.5.1.2. CGI-S baseline assessment will be used as the corresponding 
baseline value.
6.5.8.
Response Analysis
The following response analyses will be performed:

CaGI-I response, defined as patients who are described by the caregiver as “Much 
Improved” or “Very Much Improved” in the CaGI-I score;

CGI-I response, defined as patients who are described as “Much Improved” or “Very 
Much Improved” in the CGI-I score;

CGI-S response, defined as patients who have a reduction of ≥1 point in the CGI-S 
score;

PGI-I response, defined as patients who are described as “Much Improved” or 
“Somewhat Improved” in the PGI-I score.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
48
The proportion of patients answering each response definition above will be calculated as the 
number of patients answering each response definition above in each treatment group divided by 
the number of patients in the given treatment group at each visit where the corresponding scale 
was assessed. The proportion of responder patients will be compared between groups using the 
Cochran–Mantel–Haenszel test adjusting for age group at baseline and region.
The responder patient counts and percentages will be presented at each visit.
As a sensitivity analysis, proportion of responder patients for each criterion will also be 
summarized and analyzed as described above by classifying patients with missing data at a visit 
as a non-responder, meaning the entire mITT analysis set population participates in the analysis.
6.6.
Minimal Clinically Important Difference (MCID) and Miminal 
Clinically Important Change (MCIC) Exploratory Analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
6.6.1.
Descriptive Statistics of MD-CRS part II vs Global Impression of Improvement
at Week 15
For each anchor, the change from baseline in MD-CRS part II vs CaGI-I, CGI-I, and PGI-I at 
week 15 will be presented graphically.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
49
In addition, the mean change from baseline in MD-CRS part II vs global impression of 
improvement at week 15 will be summarized by treatment group as follows: 
For CaGI-I, CGI-I as anchors:
Mean Change from Baseline in MD-CRS part II
TEV-50717
Placebo
All
N
Mean (SE)
N
Mean (SE)
N
Mean (SE)
Very Much Improved
Much Improved
Minimally Improved
Not Changed
Minimally Worse
Much Worse
For PGI-I as anchor:
Mean Change from Baseline in MD-CRS part II
TEV-50717
Placebo
All
N
Mean (SE)
N
Mean (SE)
N
Mean (SE)
Much Improved
Somewhat Improved
Not Changed
Somewhat Worse
Much Worse
6.6.2.
MCID Analysis
The MCID analysis will be based on the method described by Hauser et al (2014). According to 
this method, the MCID is defined as the difference between patients in the TEV-50717 group 
who were rated “Minimally Improved” and patients in the placebo group who were rated “No 
Change”. The calculation will be performed for each anchor (CaGI-I, CGI-I and PGI-I) 
separately2.
The MCID analyses will be performed if there are at least 5 patients in the TEV-50717 group 
and at least 5 patients in the placebo group who contribute to the calculation.
                                                
2 For PGI-I, the level “Somewhat Improved” will be used instead of “Minimally Improved”.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
50
6.6.3.
MCIC Analysis
The MCIC analysis will be based on the method described by Hauser et al (2022). According to 
this method, the MCIC is defined as the mean change from baseline in MD-CRS part II in 
patients treated with TEV-50717 who were rated “Minimally Improved”.
If the mean change from baseline in MD-CRS part II at week 15 for the patients in the placebo 
group who were rated “No Change” is negative, indicating a placebo effect in this subgroup, then 
the MCIC analysis will not be carried out. 
The MCIC analyses will be performed if there are at least 5 patients in the TEV-50717 group 
who contribute to the calculation.
6.6.4.
Descriptive Statistics of Improvement in MD-CRS part II
The following descriptive statistics for the change from baseline in MD-CRS part II by treatment 
group will be added: a histogram of the change; cumulative distribution of improvement (i.e., 
proportion of patients with change ≤ 0; change ≤ -1 ; change ≤ -2; change ≤ -3, change ≤ -4, …).


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
51
7.
MULTIPLE COMPARISONS AND MULTIPLICITY
The primary efficacy endpoint will be tested at the 1-sided significance level of α=0.025. 
If the primary endpoint is statistically significant (p-value ≤0.025), the 5 key secondary 
hypotheses will be tested using a hierarchical approach at the 1-sided significance level of 
α=0.025, in the following order: (1) MD-CRS part I total score, (2) CaGI-I, (3) CGI-I, (4) 
UHDRS-TMC (centrally-read), and (5) UHDRS-TMD (centrally-read)
 
 
 
 
No multiplicity control will be applied to the sensitivity analysis or other endpoints.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
52
8.
SAFETY ANALYSIS
8.1.
General
Safety analyses will be performed on the safety analysis set (Section 3.3), unless otherwise 
noted. Summaries will be presented by treatment group and for all patients, unless otherwise 
stated. Selected safety data might also be presented by age group, as applicable.
For continuous variables, descriptive statistics will be provided for actual values and changes 
from baseline to each time point. For categorical variables, patient counts and percentages will 
be provided.
Safety assessments and time points are provided in Table 3 of the study protocol.
8.2.
Duration of Exposure to Study Drug
Duration of exposure to study drug (days) for individual patients is the number of days patient 
received drug (last day of study drug – first day of study drug + 1). Duration of treatment (days) 
will be summarized using descriptive statistics. Weeks on treatment using the categories ≤3
weeks, >3 to ≤7 weeks, >7 to ≤9 weeks, >9 to ≤12 weeks, >12 to ≤15 and >15 weeks will also be 
summarized using descriptive statistics.
8.3.
Adverse Events
Adverse events will be collected and recorded from the time a patient signs the informed consent 
to the end of follow-up period. For this study, the follow-up period for recording of adverse 
events is defined as 2 weeks after the last dose of IMP or up to baseline/day 1 in the open-label 
safety extension study TV50717-CNS-30081 (whichever comes first) or 2 weeks after last site 
visit for patients who terminated early from the study.
All adverse events will be coded using MedDRA. Each patient will be counted only once in each 
preferred term or SOC category for the analyses of safety. Unless otherwise specified, adverse 
events will be summarized by SOC and preferred term, with SOCs and preferred terms within 
SOCs presented in descending order of patient incidence. Summaries will be presented for all 
adverse events (overall and by severity), adverse events determined by the investigator to be 
related to test IMP (ie, reasonable possibility; see Table 7 of the study protocol - defined as 
related or with missing relationship), overall and by severity, serious adverse events, and adverse 
events causing withdrawal from the study; Most common adverse events, defined as occurring in 
> 4% of the patients in either of the treatment groups overall, and by preferred term. Summaries 
will be presented by treatment group and for all patients. 
Summaries will include treatment-emergent adverse events which are defined as adverse events 
occurring at or after the first dose of the IMP. The listings will include all adverse events 
recorded.
Patient listings of all adverse events, serious adverse events, adverse events leading to study drug 
discontinuation, adverse events leading to dose interruption and adverse events leading to death 
will be presented. Patient’s dose at the time of the AE onset will be included in all listings. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
53
8.4.
Deaths
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
8.5.
Clinical Laboratory Tests
Summary statistics for chemistry, hematology and coagulation, and urinalysis laboratory tests are 
assessed at screening and week 15. The assessment will be repeated at week 16 visit for patients 
with clinically significant laboratory abnormalities at week 15. Laboratory values and changes 
from baseline to week 15 and the last assessment as defined in Section 4.4 will be presented. 
A list of laboratory tests is included in Table 8 of the study protocol.
Shifts (below, within, and above the normal range) from baseline to last assessment will be 
summarized using patient counts for all the laboratory tests as applicable. Only patients with 
both baseline and post-baseline assessments will be summarized in the shift tables.
Only central laboratory assessments will be summarized; local laboratory assessments will be 
listed. Values below the lower limit of quantification or above the upper limit of quantification 
will be assessed on a case-by-case basis if present in the data and discussed in the final blinded 
SDR meeting. 
8.6.
Physical Examinations
Physical examinations will be performed at the time points detailed in Table 3 of the study 
protocol. Physical examinations will not be summarized. Any finding will be listed.
Weight, height and BMI will be assessed as a part of the vital signs (Section 8.7).
8.7.
Vital Signs
Vital signs (blood pressure [BP; systolic/diastolic], respiratory rate, body temperature, and pulse)
will be measured at the time points detailed in Table 3 of the study protocol.
Vital signs (supine or semi erect/seated) values and changes from baseline to each visit will be 
summarized using descriptive statistics. The last assessment will be defined as in Section 4.4.
Orthostatic systolic and diastolic BP and pulse will be calculated as supine or semi erect/seated 
measurement minus standing measurement and values and changes from baseline to each visit 
will be summarized using descriptive statistics. Any cases where standing measurements were 
taken less than 3 minutes after the supine or semi erect/seated measurement will be excluded 
from the analysis.
Orthostatic hypotension (determined by BP measurements only; positive value in case of 
abnormality) is defined as having either a ≥20 mmHg reduction from supine to standing position 
in systolic blood pressure (SBP) or ≥10-mmHg reduction from supine to standing position in 
diastolic blood pressure (DBP) or both. Orthostatic tachycardia is defined as pulse increase ≥20 
beats per minute (bpm) from supine to standing position.
Summaries of potentially clinically significant abnormal values will include all post-baseline
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
54
clinically significant abnormal values will be summarized using descriptive statistics with the 
criteria specified in Table 6.
Table 6 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. 
Table 6:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign (unit)
Age
Potentially Clinically 
Significant  Low Criterion 
value
Potentially Clinically 
Significant High Criterion 
value
SBP (supine/ seated/ 
semi-erect) (mmHg)
6-12
Value ≤70 and≥20 decrease from 
baseline
Value ≥120 and
≥20 increase from baseline
13-18
Value ≤ 90 and
≥20 decrease from baseline
Value ≥135 and
≥20 increase from baseline
DBP (supine/ seated/ 
semi-erect) (mmHg)
6-12
Value ≤40 and
≥15 decrease from baseline
Value ≥80 and
≥15 increase from baseline
13-18
Value ≤50 and
≥15 decrease from baseline
Value ≥90 and
≥15 increase from baseline
Pulse rate (supine/ 
seated/ semi-erect) 
(bpm)
6-10
Value ≤60 and
≥15 decrease from baseline
Value ≥135 and
≥15 increase from baseline
11-18
Value ≤50 and
≥15 decrease from baseline
Value ≥120 and
≥15 increase from baseline
SBP orthostatic criteria 
(mmHg)
~
≥20 decrease from supine to 
standing position
NA
DBP orthostatic criteria 
(mmHg)
~
≥10 decrease from supine to 
standing position
NA
Pulse rate orthostatic 
criteria (bpm)
~
NA
≥20 increase from supine to 
standing position
Temperature (˚C)
~
NA
Value ≥38.3°C and ≥0.8°C 
increase from baseline
The BMI will be computed similarly to description in Section 5.3 at post-baseline visits using
weight at visit and last available height measurement.
In addition, normal age and sex-based z-scores and percentiles for BMI will be determined using 
the WHO growth charts. Age and sex-based BMI categories include: Underweight (< 5 
percentile), Normal (≥ 5 - < 85 percentile), Overweight (≥ 85 - < 95 percentile), Obese (≥ 95 
percentile).
Descriptive statistics for weight, height, BMI, BMI World Health Organization adjusted z-scores 
and percentile will be provided. The categorical variables of BMI categories will be tabulated for 
each category as mentioned above. Data will be listed.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
55
8.8.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 3 of the study protocol. 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. A central ECG 
Standard 12-lead ECG will record heart rate (HR), PR interval (Time from the beginning of the 
P wave to the beginning of the QRS complex in electrocardiogram), RR interval (Time between 
the start of one R wave and the start of the next R wave in the ECG), QT interval, Fridericia’s 
corrected QT interval (QTcF), and QRS duration (Graphical deflections corresponding to 
ventricular depolarization in a typical electrocardiogram). 
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
If an abnormal post-baseline QTcF value >500 msec or change from screening >60 msec is 
found, the investigator must further evaluate QTcF based on protocol section 7.8. 
Shifts (normal and abnormal) from baseline to overall result interpretation, each visit and last 
assessment, will be summarized using patient counts for the centrally-read interpretation. For 
overall result interpretation the worst post-baseline finding for the patient (the abnormal finding 
if there are both normal and abnormal findings) will be used in the summaries. Summary 
statistics for ECG variables values will be presented. Actual values and changes from baseline to 
each scheduled visit and last assessment will be summarized using descriptive statistics.
QTcF values will be classified as having QTc prolongation if any of the following conditions are 
met.

Confirmed QTcF >450 msec 

Confirmed QTcF>480 msec

Confirmed QTcF>500 msec

Increase from screening QTcF > 60 msec 

Increase from screening confirmed QTcF > 60 msec
Screening is defined as the last non-missing ECG value prior to first dose IMP and the confirmed 
QTcF is defined as the average of up to 3 standard ECG values at a visit, or a single summary 
ECG. If there are more than 3 standard or more than one summary ECG at a visit, then use the 
last ECGs for the confirmed QTcF.
The number and percentage of patients with QTc prolongation will be summarized by treatment 
and overall, and by visit and last assessment. 
The incidence of potentially clinically significant abnormal values for ECG variables will be 
summarized using descriptive statistics with the criteria presented in Table 7. The summary will 
be completed by treatment and overall, and age groups (6 to < 8 years, 8 to < 12 years, 12 to < 16 
years, and ≥16 years), and overall using the age at screening.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
56
Table 7:
Potentially Clinically Significant Values for ECG Variables by Age
ECG parameter 
(unit) a
Age (years old)
Potentially 
Clinically 
Significant Low
Potentially 
Clinically 
Significant High
HR (bpm)
6 to <8
< 65
> 115
8 to <12
< 55
> 110
12 to <16
< 50
> 105
≥16
< 50
> 100
PR interval (msec)
6 to <8
--
> 160
8 to <12
--
> 175
12 to <16
--
> 180
≥16
--
> 200
QRS interval (msec)
6 to <8
--
> 100
8 to <12
--
> 105
12 to <16
--
> 110
≥16
--
> 120
a bpm=beats per minute; HR=heart rate; PR interval =Time from the beginning of the P wave to the beginning of 
the QRS complex in electrocardiogram; RR interval =Time between the start of one R wave and the start of the 
next R wave in the ECG; QRS duration =Graphical deflections corresponding to ventricular depolarization in a 
typical electrocardiogram
8.9.
Concomitant Medications or Therapies 
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in Section 5.7 of the study protocol. All concomitant medications will 
be coded using the WHO Drug.
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category, preferred base name and preferred term. Patients are 
counted only once in each therapeutic class, once in each preferred base name, and only once in 
each preferred term category. Concomitant therapies and medications will include all 
medications taken after the first administration of the IMP up to the end of study as defined in 
the study protocol.
In order to determine whether a medication is concomitant, partial start dates with missing day 
and/or month will be imputed with the first day of the month/first month of the year, respectively 
and partial end dates with missing day and/or month will be imputed with the 28th day of the 
month/last month of the year respectively. Imputed dates will be used for calculations only, 
actual dates will be listed.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
57
Prohibited medications that are associated with QTc prolongation are listed in Appendix H, 
Table 11, of the study protocol. Any incidence of these prohibited medications will be listed
separately.
8.10.
Children’s Columbia-Suicide Severity Rating Scale 
The frequency and severity of suicidal ideation or behavior according to the children’s C-SSRS 
questionnaire will be presented for all patients aged ≥12 years by visit and by treatment group. A 
shift table to examine changes in children’s C-SSRS categories from baseline (using the lifetime 
version of the questions), compared to the worst (highest) category during the treatment period 
will be presented by treatment and overall.
Patients will be placed into categories for suicidal ideation and suicidal behavior based on their 
responses to various questions. The suicidal ideation categories will be determined by the 
following 5 questions.
Table 8:
Suicidal Ideation Category
Type
Category
Suicidal Ideation
(0) None – if response is No to Questions 1 and 2 
(1) Wish to be Dead – if response to Question 1 is Yes and responses 
to Question 2 is No. 
(2) Non-Specific Active Suicidal Thoughts – if response to Question 
2 is Yes and response to Questions 3-5 are No.
(3) Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act – if response to question 3 is Yes and response to 
questions 4 and 5 are No. 
(4) Active Suicidal Ideation with Some Intent to Act, without 
Specific Plan – if response to Question 4 is Yes and response to 
Question 5 is No. 
(5) Active Suicidal Ideation with Specific Plan and Intent – if 
response to Question 5 is Yes.
For suicidal behavior, the following categories will be used. The categories will be determined 
based on the response to the questions. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
58
Table 9:
Suicidal Behavior Category
Type
Category
Suicidal Behavior
(6) Preparatory Acts or Behavior – if response to Preparatory Acts 
and Behavior is Yes and responses to Actual Attempt, Interrupted 
Attempt, Aborted Attempt, and Completed Suicide are No
(7) Aborted Attempt – if response to Aborted Attempt is Yes and 
responses to Actual Attempt, Interrupted Attempt, and Completed 
Suicide are No.
(8) Interrupted Attempt – if response to Interrupted Attempt is Yes 
and response to Actual Attempt, and Completed Suicide are No.
(9) Actual Attempt – if response to Actual Attempt is Yes and 
Completed Suicide is No.
(10) Completed Suicide - if response to Completed Suicide is Yes
(0) None – if responses to all the above  questions are No.
Suicidal ideation or behavior will be derived as the highest suicidal ideation or behavior score at 
the visit. Score of 0 represent “No Suicidal Ideation/Behavior”.
The frequency and percentage of suicidal ideation, suicidal behavior, suicidal ideation or 
behavior, and self-injurious behavior without suicidal intent will be summarized by treatment 
and overall, and visit.
8.11.
Child Behavior Checklist for Ages 6-18 (CBCL)
The CBCL assesses behavioral and emotional status in children ages 6 through 18 years of age as 
reported by the parent/caregiver (Achenbach and Ruffle 2000; Achenbach 2005). The full CBCL 
has 2 parts, a Competence Scale (Parts I to VII) and a Syndrome Scale (behavioral items).
8.11.1.
Competence Scale
The Competence Scale (Parts I to VII) assesses various activities, interpersonal relationships, and 
academic performance. Competence assessment will be performed at screening and week 15/ET.
The competence scale is divided into 3 subscales – see Table 10.
Table 10:
CBCL Competence Scale
Activities
Social
School
I.A. number of sports
I.B. Mean part/skills
II.A. number of activities
II.B. Mean part/skills
IV.A. number of jobs
IV.B. Mean job quality
III.A. number of organizations
III.B. Mean Participation
V.1 number of friends
V.2 Frequency of contact
VI.A. Behavior with others
VI.B. Behavior alone
VII.1. Mean performance 
VII.2. Special class
VII.3. Repeated grade
VII.4. School problems


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
59
Total score and change from baseline for each subscale separately and a total score and change 
from baseline for all items will be summarized for each time point using descriptive statistics for 
continuous variables. Total scores are rounded to nearest 0.5.
Scores per item are calculated as follows in Table 11:
Table 11:
CBCL Competence Scale Scoring
Subscale
Item
Scoring
Activities
I.A. number of 
sports
count the number of sports
I.B. Mean part/skills
mean of up to 6 rates, 2 for each sport activity. Where 'below average' or ’Less 
than average’=0, 'Average'=1, 'above average' or ‘More than average’=2
II.A. number of 
activities
count the number of activities.
II.B. Mean part/skills
mean of up to 6 rates, 2 for each activity. Where 'below average' or ’Less than 
average’=0, 'Average'=1, 'above average' or ‘More than average’=2
IV.A. number of 
jobs
count the number of jobs
IV.B. Mean job 
quality
mean of up to 3 rates, 1 for each job. Where: 'below average'=0, 'Average'=1, 
'above average’'=2.
Social
III.A. number of 
organizations
count the number of organizations.
III.B. Mean 
Participation
mean of up to 3 rates, 1 for each organization. Where: 'Less active'=0, 
'Average'=1, ‘More active'=2.
V.1 number of 
friends
None’=0, '1'=1, '2 or 3' =2, '4 or more'=3.
V.2 Frequency of 
contact
'Less than 1'=0, '1 or 2'=1, '3 or more'=2. 
VI.A. Behavior with 
others
mean of items a-c. Where: 'Worse'=0, 'Average'=1, 'Better'=2.
VI.B. Behavior alone
rate for item d. Where: 'Worse'=0, 'Average'=1, 'Better'=2.  
School
VII.1. Mean 
performance
Mean of up to 7 performance items. Where 'failing'=0, 'below average'=1, 
'average'=2,'above average'=3.
VII.2. Special class
'Yes='0', 'No='1'.
VII.3. Repeated 
grade
'Yes='0', 'No='1'.
VII.4. School 
problems
'Yes='0', 'No='1'.
Values of ‘Do not know’, ‘Not applicable’, or ‘Has no brothers or sisters’ will be ignored for 
mean calculations and logically skipped items will be imputed as 0 or none.
A subscale score is calculated as the sum of the item scores and the total score is calculated as 
the sum of the subscale scores. If one or more subscale scores are missing, the total score is not
calculated.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
60
If 1 item from activities and social subscales has a missing value, the mean of the other items of 
that subscale is substituted for that item. If more than 1 item is missing from either of these 
scales or any item is missing from the school scale, the respective scale is not to be scored.  
Results will be listed.
8.11.2.
Syndrome Scale
The Syndrome Scale comprises 113 questions related to problem behaviors. Syndrome 
assessment will be performed at screening, baseline, weeks 3, 7, 9, 12, 15/ET, 16/EOS. 
For each item, the parent/caregiver will circle “0” if the item is not true of their child, “1” if the 
item is somewhat or sometimes true, and “2” if the item is very true or often true.
The Syndrome scale is divided into 8 subscales – see Table 12.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
61
Table 12:
CBCL Syndrome Scale
Anxious / Depressed
Withdrawn /
Depressed
Somatic
Complaints
Social Problems
Thought Problems
14.Cries           
30.FearsSchool
32.Perfect          
35.Worthless     
50.Fearful             
71.SelfConsc  
112.Worries
29.Fears
31.FearDoBad
33.Unloved 
45.Nervous  
52.Guilty 
91.ThinksSuicide 
5.EnjoysLittle  
42.RatherBeAlone  
65.Won'tTalk   
69.Secretive             
75.Shy      
102.LacksEnergy    
103.Sad       
111.Withdrawn
47.Nightmares
49.Constipated      
51.Dizzy                
54.Tired  
56a-g.Physical 
Problems without 
known medical 
causea            
11.Dependent   
12.Lonely  
25.NotGetAlong 
27.Jealous    
34.OutToGet  
36.Accidents    
38.Teased     
48.NotLiked   
62.Clumsy 
64.PreferYoung 
79.SpeechProb
9.MindOff     
40.HearsThings  
58.PicksSkin  
60.SexPartsM  
70.SeesThings  
83.StoresUp 
85.StrangeIdeas 
100.SleepProb
18.HarmsSelf
46.Twitches
59.SexPartsP  
66.RepeatsActs
76.SleepsLess
84.StrangeBehav
92.SleepWalk  
Rule-Breaking Behavior 
Attention 
Problems
Aggressive Behavior
Other Problems
2.Alcohol 
28.BreaksRules 
43.LiesCheats  
67.RunAway  
73.SexProbs  
82.StealsOther 
96.ThinksSex  
101.Truant 
106.Vandalism
26.LacksGuilt  
39.BadFriends
63.PreferOlder
72.SetsFires 
81.StealsHome 
90.Swears
99.Tobacco
105.UsesDrugs  
1.ActsYoung 
4.FailsToFinish
8.Concentrate   
10.SitStill     
13.Confused 
17.Daydreams
41.Impulsive 
61.PoorSchool
78.Inattentive    
80.Stares
3.Argues         
19.DemAtten  
21.DestroyOther  
23.DisobeySchl  
57.Attacks  
86.Stubborn 
88.Sulks  
94.Teases    
97.Threaten    
16.Mean  
20.DestroyOwn
22.DisobeyHome  
37.Fights  
68.Screams  
87.MoodChang
89.Suspicious
95.Temper 
104.Loud    
6.BMOut  
15.CruelAnimal
44.BiteNail
55.Overweight
74.ShowsOff
93.TalkMuch
107.WetsSelf
109.Whining
113.OtherProbb
7.Brags
24.NoEatWell
53.Overeat
56h.OtherPhys
77.SleepsMore    
98.ThumbSuck
108.WetsBed
110.WishOppSex
a Item 56 stands for “Physical Problems without known medical cause: other” and may not be filled in by the responder. 
b Similarly, item 113 that stands for “Any problems that were not listed above” may be missing, for the same reason.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
62
Total score for each subscale separately, total score for all items, change from baseline for the 
total score for each subscale separately and change from baseline for total score for all items will 
be summarized for each time point using descriptive statistics for continuous variables.
Total score is calculated as the sum of item scores.
If more than 20 items have missing values, excluding items 56h and 113, which may be left 
blank by structure (see Table 12 for details), then no scores will be provided. For calculating 
subscale scores, if one or more items, excluding items 56h and 113, are missing in a subscale, the 
subscale score will not be calculated.      
Data will be listed.
In addition, individual plots will be provided.
8.12.
Epworth Sleepiness Scale
The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire composed of 8 
questions that provide a measure of a patient’s general level of daytime sleepiness (Johns 1991).
The ESS is administrated at screening, baseline, weeks 3, 7, 9, 12, 15/ET and 16/EOS.
The ESS is composed of 8 items. The responders are asked to rate their chances of falling asleep 
while engaged at 8 different activities, on a 4-point scale (0-3). Therefore, the total score can 
range from 0 to 24.
If at least 1 item has a missing value, then the entire questionnaire is not valid.
Total score of the 8 items and total scores change from baseline will be summarized by time 
point, using descriptive statistics. In the case of both caregiver and self-administered versions of 
the ESS are presented at the same visit, caregiver version will be used for patients who are 6 to 
12 years old and self-administered version will be used for patients 13 years of age and older. 
Total score is calculated as the sum of item scores.
Data will be listed.
8.13.
Extrapyramidal Symptom Rating Scale 
The Extrapyramidal Symptom Rating Scale (ESRS) consists of 2 subscales, ESRS I and ESRS 
II.
ESRS I and II are administrated at screening, baseline, weeks 3, 7, 9, 12, 15/ET and 16/EOS.
8.13.1.
ESRS I
The first subscale (ESRS I) is a 7 item subjective questionnaire to evaluate parkinsonism, 
akathisia, dystonia and dyskinesia. The ESRS I is scored on for point scale (0=absent, 1=Mild, 
2=Moderate, Severe=3) for each item. 
Total score of the 7 items and total scores change from baseline will be summarized by time 
point, using descriptive statistics.
Total score will be the sum of the 7 items. Missing items will be replaced by the average of the 
remaining responses within each item. 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
63
Data will be listed.
8.13.2.
ESRS II
The second subscale (ESRS II) is a 17-item questionnaire to evaluate parkinsonism and 
akathisia.
ESRS II consists of the following parts:
1. Tremor: scored on a 7-point item scale for 8 parts of the body. For each part of the 
body, frequency and amplitude are selected, assigning each one of the 8 items a 
score from 0=none to 6=severe. Therefore, the total score for tremor can ranged 
from 0 to 48. 
2. Bradykinesia: scored on a 7-point item scale (0-6).
3. Gait and Posture: scored on a 7-point item scale (0-6).
4. Postural stability: scored on a 7-point item scale (0-6).
5. Rigidity: scored on a 7-point item scale (0-6) for 4 parts of the body. Therefore, 
the total score for rigidity can ranged from 0 to 24. 
6. Expressive automatic movements: scored on a 7-point item scale (0-6).
7. Akathisia: scored on a 7-point item scale (0-6).
The total score of the 17 items can ranged from 0 to 102.
Total score of the 17 items and total scores change from baseline will be summarized by time 
point, using descriptive statistics for continuous variables.
Total score will be the sum of the 17 items. Missing items will be replaced by the average of the 
remaining responses within each item. 
Data will be listed.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
64
9.
TOLERABILITY VARIABLES AND ANALYSIS
If more than 15% of the patients withdraw from the study before the end of the treatment period, 
the number of days until study discontinuation will be analyzed using Kaplan-Meier 
methodology with the ITT analysis set.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
65
10.
PLANNED INTERIM ANALYSIS
10.1.
General
When approximately 50 patients have completed the study (including follow-up), an iDMC will 
perform an unblinded non-binding IA for futility based on centrally read MD- CRS part II total 
score. 
A blinded SDR meeting will be performed prior to the IA to determine eligibility to the mITT 
analysis set and to classify missing data to MAR/MNAR.
Calculation of conditional power will be performed by an independent unblinded statistician, and 
the IA will be presented and discussed in a closed session of the iDMC. Release of 
randomization codes to the unblinded statistician will follow SOP GBP-RD-703. 
Once the unblinded statistician and iDMC members are exposed to unblinded data, they will not 
be involved in decision making regarding the planned analysis of the study, or classification of 
missing data to MAR/MNAR.
Unblinded analysis datasets, TLGs, or simulation outputs will not be disclosed to the study team 
until the study is completed, database is locked and randomization codes are released for final 
analysis. The study team will be informed of the IA decision; communication format is described 
in the iDMC charter. 
In order to minimize potential bias, investigators will not be informed on the parameters of the 
promising zone method, or on decision to increase the sample size.
The Statistical Analysis Plan and iDMC charter will be finalized before the IA is performed. Any 
changes in the main analysis of the primary and key secondary endpoints (eg, model 
specifications) will not be allowed after the IA. 
10.2.
Interim Analysis Procedure
The IA will include the following steps:
1. A blinded statistical data review meeting will be convened to review patient-blinded data 
from the patients that completed the study (including early termination). For patients that 
terminated early from the study, classification to MAR/MNAR will be performed. In 
addition, exclusion of patients from the mITT analysis set will be reviewed.
The meeting will include blinded members only; iDMC members and the unblinded 
statistician will not take part in the discussions.
2. The sponsor will provide to the unblinded statistician the following data: disposition, 
demography, MD-CRS part II total scores (centrally read), the list of patients included in 
the mITT analysis set, and classification of missing data to MAR/MNAR. The unblinded 
statistician will have received the randomization codes from the randomization codes 
generator according to SOP GBP-RD-703.
3. The unblinded statistician will estimate the conditional power (see Section 10.4 for
details) and provide the results to the iDMC.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
66
4. The iDMC will apply futility rule (see Section 10.6) to provide recommendation to the 
sponsor to continue the study or stop the study for futility. This recommendation will be 
communicated with the sponsor while keeping the sponsor blinded, as specified in the 
iDMC Charter.
5. The sponsor will follow the iDMC recommendation for futility recommendations.
10.3.
Data Cut for Interim Analysis
When the target number of patients (approximately 50 patients) complete the study (including 
follow-up; including patients that withdraw from the study) and the central reading of MD-CRS 
part II is available, the data will be cleaned for the IA. The IA data cut will not include data from 
patients that are ongoing. 
Assessment of eligibility to the mITT analysis set and classification of missing data to 
MAR/MNAR will be performed in a blinded manner in a SDR meeting prior to the IA.
The following data will be used for the IA: disposition, demography, MD-CRS part II total 
scores (centrally read), the list of patients included in the mITT analysis set, and classification of 
missing data to MAR/MNAR.
10.4.
Estimation of Conditional Power
The conditional power is the probability of rejecting the null hypothesis at the final analysis, 
assuming the alternative hypothesis is true given the data accumulated in the interim analysis.
Conditional power will be estimated given the observed data, under the following assumptions:

effect size (true difference and standard error) is as estimated in the observed data (point 
estimates)

proportion of missing data MNAR in the TEV-50717 treatment group is as in the 
observed data

proportion of patients excluded from the mITT analysis set is as in the observed data
Note: the conditional power is estimated based on the observed data and does not take into 
account the initial assumptions that were used for estimating the initial sample size.
The primary analysis is a 1-sided test of the null hypothesis H0: δ ≥ 0 versus the alternative 
hypothesis .:  < 0 , where δ is the difference between TEV-50717 and placebo in change 
from baseline in centrally-read MD-CRS part II total score (higher score represents a more 
severe movement disorder, thus negative change from baseline is a good outcome).
Let & be the number of patients included in the mITT analysis set in the IA, and let & be the 
incremental number of patients between the IA and the final analysis that will be included in the 
mITT analysis set, such that the total number of patients in the analysis will be & = & + & .
Let  be the Wald statistic at the IA. The conditional power is given by (Mehta and Pocock 
2011):
CPow(&|&, ) = 1 −Φ :;√& −√&
√&
−√&
√&
=


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
67
Calculation of the Wald statistic:
 =
−	
se	
Where, 	 is the estimated mean difference between TEV-50717 and placebo and se	 is the 
estimated SE of the mean difference, both obtained from the primary analysis model (MMRM 
applying MAR/MNAR multiple imputation; see Section 6.2.3) fitted to the IA mITT data.
10.5.
Sample Size
Let &
∗be the total sample size at the IA (ITT analysis set). Assuming that the proportion of 
patients that will be excluded from the mITT analysis set for the primary analysis (ie, do not 
have at least 1 post-baseline central reading of MD-CRS part II total score) will be as estimated 
in the IA, the total sample size of the study is given by
&∗= &
∗
&
& = &
∗+ &
∗
&
&
The sample size recommendation will be presented in terms of the total sample size &∗.
10.6.
Decision Rules
The following zone and corresponding actions are defined for all possible results of conditional 
power (CPow) is provided in Table 13.
Table 13:
Decision Rules According to the Promising Zone Method for IA
Zone
Conditional Power
Decision
Futility 
CPow <3%
Stop the study for futility
The futility decision is considered non-binding.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
68
11.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
69
12.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
No changes to the analyses specified in the protocol are planned at the time of writing this SAP 
amendment.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
70
13.
REFERENCES
Achenbach TM. Advancing assessment of children and adolescents: commentary on evidence-
based assessment of child and adolescent disorders. J Clin Child Adolesc Psychol 
2005;34:541-7.
Achenbach TM, and Ruffle TM. The Child Behavior Checklist and Related Forms for
Assessing Behavioral/Emotional Problems and Competencies. Pediatrics in Review. 2000; 21(1): 
265-271.
Battini R, Sgandurra G, Petacchi E, Guzzetta A, Di Pietro R, Giannini MT, et al. Movement 
Disorder-Childhood Rating Scale: reliability and validity. Pediatr Neurol 2008;39(4):259-65.
Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. 
Sleep 1991;14:50-55.
Little RJA, Rubin DB. Statistical Analysis with Missing Data, Second Edition. 2002, New York: 
John Wiley & Sons.
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med 2011;30(28):3267-84.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987, New York: John Wiley & 
Sons.
Heitjan F and Little RJA. Multiple Imputation for the Fatal Accident Reporting System. Applied 
Statistics 1991;40:13–29.
PEDI-CAT (Version 1.3.6) Development, Standardization and Administration Manual, Trustees 
of Boston University, under license to CREcare, LLC, 2011.
Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, et al Minimal clinically 
important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended 
release. Parkinson's disease 2014, 467131. https://doi.org/10.1155/2014/467131
Hauser RA, Barkay H, Wilhelm A, Wieman M, Savola J-M, Gordon MF. Minimal clinically 
important change in abnormal involuntary movement scale score in tardive dyskinesia as 
assessed in pivotal trials of deutetrabenazine. Parkinsonism Relat Disord 2022;97:47-51.
Schenker N and Taylor JMG. Partially Parametric Techniques for Multiple Imputation. 
Computational Statistics and Data Analysis 1996;22:425-446.
Varni JW, Burwinkle TM, Berrin SJ, Sherman SA, Artavia K, Malcarne VL, et al. The 
PedsQL™ in pediatric cerebral palsy: Reliability, validity, and sensitivity of the Generic Core 
Scales and Cerebral Palsy Module. Developmental Medicine and Child Neurology 2006;48:442-
49.


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
71
APPENDIX 1.
MAR/MNAR JUMP TO REFERENCE MULTIPLE 
IMPUTATION METHODOLOGY 
The following 3 steps will be performed to the do the multiple imputation analysis:
1. Create complete data sets using imputation for each subgroup.
2. Analyze the imputed complete data sets for the combined subgroups.
3. Combine analysis results into a final result.
Step 1
In order to induce monotonicity, an imputation model will first be used to impute missing values 
for MD-CRS part II total score week 9, 12, and 15 change values and will use age group at 
baseline and baseline MD-CRS part II total score to determine the scores (500 imputations will be 
created).
The SAS code for the imputation is as follows:
proc mi data=final out=mitv1 seed=987 nimpute=500;   
where arm=’TEV-50717’ & (missdm in (''MAR'') or _9^=.);   /* 1st subgroup */
class agegrp region; 
var agegrp region base _9;
monotone regpmm; run;
proc mi data=final out=miplb1 seed=876 nimpute=500;
where arm=’PLACEBO’ or (arm=’TEV-50717’ & missdm='MNAR' & _9=.);   /* 2nd subgroup */
class agegrp region; 
var agegrp region base _9;
monotone regpmm; run;
data mi1; set mitv1 miplb1; run;
proc sort data=mi1; by _imputation_; run;
proc mi data=mi1 out=mitv2 seed=9876 nimpute=1; by _imputation_;
where arm=’TEV-50717’ & (missdm in ('' 'MAR') or _12^=.);
class agegrp region; 
var agegrp region base _9 _12;
monotone regpmm; run;
proc mi data=mi1 out=miplb2 seed=8765 nimpute=1; by _imputation_;
where arm=’PLACEBO’ or (arm=’TEV-50717’ & missdm='NMAR' & _12=.);
class agegrp region; 
var agegrp region base _9 _12;
monotone regpmm; run;
data mi2; set mitv2 miplb2; run;
proc sort data=mi2; by _imputation_; run;
proc mi data=mi2 out=mitv3 seed=98765 nimpute=1; by _imputation_;
where arm=’TEV-50717’ & (missdm in ('' 'MAR') or _15^=.);
class agegrp region; 


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
72
var agegrp region base _9 _12 _15;
monotone regpmm; run;
proc mi data=mi2 out=miplb3 seed=87654 nimpute=1; by imputation; 
where arm=’PLACEBO’ or (arm=’TEV-50717’ & missdm='NMAR' & _15=.);
class agegrp region; 
var agegrp region base _9 _12 _15;
monotone regpmm; run;
Step 2
The resultant complete data sets will be combined for the 2 subgroups and then analyzed using 
mixed-model, repeated-measures with the change in MD-CRS part II total score as the dependent 
variable (the primary analysis). The SAS code is as follows:
data all; set mitv3 miplb3;
      avisitn=9; chg=_9; output; avisitn=12; chg=_12; output; avisitn=15; chg=_15; output; run;
proc sort data=all; by _imputation_ descending arm avisitn; run;
proc mixed data=all order=data; by _imputation_;
   class usubjid arm avisitn agegrp region;
   model chg=arm avisitn arm*avisitn agegrp region base / ddfm=kr;
   repeated avisitn / type=un subject=usubjid;
   lsmeans arm*avisitn / diff cl;
   ods output diffs=diff(where=(avisitn=_avisitn) lsmeans=lsm; run;
Step 3
The results from the imputed data analysis will be combined using PROC MIANALYZE which 
will provide the LS mean and standard error of the LS mean for each treatment group at each 
visit as well as the LS mean difference, 95% CI and resultant p-value between the TEV-50717 
and placebo groups at each visit. The SAS code is as follows:
proc sort data=diff; by avisitn arm; run;
proc sort data=lsm; by avisitn arm; run;
proc mianalyze data=diff; by avisitn arm; 
modeleffects estimate;
stderr stderr; 
ods output ParameterEstimates=estdiff; run;
proc mianalyze data=lsm; by avisitn arm;
modeleffects estimate;
stderr stderr; 
ods output ParameterEstimates=estlsm; run;


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
73
APPENDIX 2.
TIPPING POINT ANALYSIS
Let delta (shift) be the penalty to TEV-50717 group, ie. the worsening of effect for the patients in 
TEV-50717 group who early dropped out, compared to patients with full data, assuming MNAR.
Delta will be in the range of 0 to 2 (or estimated treatment effect from primary analysis if it is 
larger than 2) in step of 0.2. The following 3 steps will be performed to do the multiple 
imputation analysis:
1. Create complete data sets using imputation for each shift in treatment effect.
2. Analyze the imputed complete data sets for each shift in treatment effect.
3. Combine analysis results into a final result for each shift in treatment effect.
Step 1:
The fully conditional specification (FCS) method will be used to impute missing values for MD-
CRS part II total score change values and will use age group at baseline, treatment arm, and 
baseline MD-CRS part II total score to determine the scores (500 imputations will be created).
The SAS code for the imputation is as follows:
%macro midata(data=, smin=, smax=, sinc=, out=);
data &out; set _null_; run;
%let ncase=%sysevalf((&smax-&smin)/&sinc, ceil);
%do jc=0 %to &ncase;
%let sj=%sysevalf(&smin + &jc*&sinc);
proc mi data=&data out=outmi seed=724375 nimpute=500;   
class arm agegrp region; 
fcs regpmm; 
mnar adjust (_9 /shift=&sj adjustobs= ( arm=’TEV-50717’));
mnar adjust (_12 /shift=&sj adjustobs=( arm=’TEV-50717’));
mnar adjust (_15 /shift=&sj adjustobs=( arm=’TEV-50717’));
var arm agegrp region base _9 _12 _15; run;
data outmi; set outmi; shift=&sj; run;
data &out; set &out outmi; run;
%end;
%mend midata;
%midata(data=final, smin=, smax=, sinc=, out=out1);
Values should be added for smin, smax, and sinc. Per current definitions, these should be 
smin=0, smax=2.0 (or estimated treatment effect from primary analysis if it is larger than 2) and 
sinc=0.2.
Step 2
The resultant complete data sets will be analyzed using the same model as the primary analysis –
see Appendix 1 - Step 2. The SAS code is as follows:


Placebo-Controlled Study–Dyskinesia in Cerebral Palsy
Statistical Analysis Plan Amendment 03
Study TV50717-CNS-30080
74
data all; set out1;
   avisitn=9; chg=_9; output; avisitn=8; chg=_8; output; avisitn=12; chg=_12; output; run;
proc sort data=all; by shift _imputation_ arm avisitn; run;
proc mixed data=all order=data; by shift _imputation_;
   class usubjid arm avisitn agegrp region;
model chg=arm avisitn arm*avisitn agegrp region base / ddfm=kr;
   repeated avisitn / type=un subject=usubjid;
   lsmeans arm*avisitn / diff cl;
   ods output diffs=diff(where=(avisitn=_avisitn )) lsmeans=lsm; run;
Step 3
The results from the imputed data analysis will be combined using PROC MIANALYZE which 
will provide the LS mean and standard error of the LS mean for each treatment group at each 
visit as well as the LS mean difference, 95% CI and resultant p-value between the TEV-50717 
and placebo groups at each visit. The SAS code is as follows:
proc sort data=diff; by shift avisitn arm; run;
proc sort data=lsm; by shift avisitn arm; run;
proc mianalyze data=diff; by shift avisitn arm;  
modeleffects estimate;
stderr stderr; 
ods output ParameterEstimates=estdiff; run;
proc mianalyze data=lsm; by shift avisitn arm;
modeleffects estimate;
stderr stderr; 
ods output ParameterEstimates=estlsm; run;