Conditions: Cerebral Palsy, Dyskinetic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
Study TV50717-CNS-30081 is a 55-week study in which participants who have successfully completed the parent study (Study TV50717-CNS-30080) may be eligible to enroll in this study.

The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with TEV-50717 in children and adolescents with DCP.

The secondary objective of this study is to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the severity of DCP.

Detailed description:

Arms:
arm 1: The dose of the TEV-50717 should be increased on a weekly basis to reach a clinically meaningful reduction in dyskinesia, as indicated by a reduction in the Clinical Global Impression of Improvement;(CGI-I).

Interventions: intervention 1: TEV-50717
Intervention descriptions: intervention 1: Oral tablets are 6, 9, and 12 mg.

Protocol document:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-
50717 (Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in 
Children and Adolescents (Open RECLAIM-DCP) 
 
 
Study Number TV50717-CNS-30081 
 
 
NCT04200352 
 
 
Protocol with Amendment 04 Approval Date: 01 June 2022 


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
1 
 
  
Clinical Study Protocol with Amendment 04 
Study Number TV50717-CNS-30081 
An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and 
Adolescents (Open RECLAIM-DCP) 
Short title: Reduction of Childhood and Adolescent Abnormal Involuntary Movements in 
Patients with Dyskinetic Cerebral Palsy in Children and Adolescents (Open 
RECLAIM-DCP) 
Lay person title: A Study to Test if TEV-50717 is Safe and Effective in Relieving Abnormal 
Involuntary Movements in Cerebral Palsy 
Phase 3 
IND Number: 139700; NDA Number: NA; EudraCT Number: 2019-001807-19 
EMA Decision Number of Pediatric Investigation Plan: Not Applicable 
Article 45 or 46 of 1901/2006 does not apply 
Original Protocol Approval Date: 07 March 2019 
Protocol Amendment 04 Approval Date: 01 June 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
2 
AMENDMENT HISTORY  
The protocol for Study TV50717-CNS-30081 (original protocol dated 07 March 2019) has been 
amended and reissued as follows: 
Amendment 04 
01 June 2022 
42 patients enrolled to date 
Administrative Letter 06 
11 June 2021 
Administrative Letter 05 
23 February 2021 
Administrative Letter 04 
14 November 2020 
Administrative Letter 03 
14 July 2020 
Amendment 03 
23 June 2020 
8 patients enrolled to date 
Amendment 02 
19 March 2020 
3 patients enrolled to date 
Amendment 01 
02 October 2019 
0 patients randomized/enrolled to date 
Letter of Clarification 02 
02 July 2019 
Letter of Clarification 01 
07 June 2019 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
3 
 
 
INVESTIGATOR AGREEMENT   
Original Protocol Dated 07 March 2019 
Amendment 04 Dated: 01 June 2022 
IND Number: 139700; NDA Number: NA; EudraCT Number: 2019-001807-19 
EMA Decision Number of Pediatric Investigation Plan: Not Applicable 
Article 45 or 46 of 1901/2006 does not apply 
An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and 
Adolescents (Open RECLAIM-DCP) 
Principal Investigator:   
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
 
I have read the protocol with amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, investigational medicinal products (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 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
4 
 
SPONSOR PROTOCOL APPROVAL  
Sponsor’s Authorized 
Representative 
 
 
 
Signature 
Date 
Executed signature pages are maintained separately within the Trial Master File 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
5 
COORDINATING INVESTIGATOR AGREEMENT  
Original Protocol Dated 07 March 2019 
Amendment 04 Dated: 01 June 2022 
IND Number: 139700; NDA Number: NA; EudraCT Number: 2019-001807-19 
EMA Decision Number of Pediatric Investigation Plan: Not Applicable 
Article 45 or 46 of 1901/2006 does not apply 
An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and 
Adolescents (Open RECLAIM-DCP) 
I have read the protocol with amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national 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 Signed page is retained 
in the sponsor’s official repository. 
Date 
Executed signature pages are maintained within the Investigator Site File and Trial Master File. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
6 
COORDINATING INVESTIGATOR AGREEMENT  
Original Protocol Dated 07 March 2019 
Amendment 04 Dated: 01 June 2022 
IND Number: 139700; NDA Number: NA; EudraCT Number: 2019-001807-19 
EMA Decision Number of Pediatric Investigation Plan: Not Applicable 
Article 45 or 46 of 1901/2006 does not apply 
An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of TEV-50717 
(Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and 
Adolescents (Open RECLAIM-DCP) 
I have read the protocol with amendment 04 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national 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 Signed page is retained 
in the sponsor’s official repository. 
Date 
Executed signature pages are maintained within the Investigator Site File and Trial Master File. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
7 
CLINICAL STUDY PROTOCOL SYNOPSIS  
Study TV50717-CNS-30081 
Title of Study: An Open-Label, Long-Term Safety, Tolerability, and Efficacy Study of 
TEV-50717 (Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children 
and Adolescents (Open RECLAIM-DCP) 
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: 2019-001807-19 
EMA Decision Number of Pediatric Investigation Plan: Does not apply 
Name of Active Ingredient: Deutetrabenazine 
Name of Test Investigational Medicinal Product (IMP): TEV-50717 (deutetrabenazine, 
previously SD-809) 
Type of Study: Safety and Efficacy (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 35 investigational centers. 
Countries Planned: Global (per Study TV50717-CNS-30080) 
Planned Study Period: Q1 2020 to Q4 2023 with a duration of approximately 55 weeks 
Number of Patients Planned (total): Approximately 45 patients 
Study Population: Male and female children and adolescents diagnosed with DCP who have 
previously completed participation in parent Study TV50717-CNS-30080. 
Primary and Secondary Objectives and Endpoints: The primary and secondary study 
objectives and endpoints are presented in Table 1. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
8 
Table 1: 
Primary and Secondary Study Objectives and Endpoints  
Objectives 
Measures/Endpoints 
The primary objective of this study 
is to evaluate the safety and 
tolerability of long-term therapy with 
TEV-50717 in children and 
adolescents with DCP. 
The safety measures/endpoints are as follows: 
• 
adverse events 
• 
vital signs 
• 
children’s C-SSRS 
• 
ECG parameters 
• 
clinical laboratory parameters (hematology, serum chemistry, and 
urinalysis) 
• 
ESRS (subscales I and II) 
• 
CBCL 
• 
ESS 
The secondary objective of this 
study is to evaluate the efficacy of 
long-term therapy with TEV-50717 in 
reducing the severity of DCP. 
The efficacy measures/endpoints are as follows: 
• 
MD-CRS part I total score (centrally read) 
• 
MD-CRS part II total score (centrally read) 
• 
MD-CRS part I total score (physician rated) 
• 
MD-CRS part II total score (physician rated) 
• 
MD-CRS Global Index (calculated from MD-CRS parts I and II 
total scores) 
• 
CaGI-I (global, caregiver rated) 
• 
CGI-I (global, physician rated) 
• 
CGI-S (global, physician rated) 
• 
PEDI-CAT (activities of daily living, caregiver completed, 
content-balanced version) 
• 
UHDRS-TMC (centrally read) 
• 
UHDRS-TMD (centrally read) 
• 
UHDRS-TMS (physician rated) 
• 
UHDRS-TMC (physician rated) 
• 
UHDRS-TMD (physician rated) 
• 
COPM (physician rated) 
CaGI-I=Caregiver Global Impression of Improvement; CBCL=Child Behavior Checklist (for ages 6 to 18); 
CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; 
COPM=Canadian Occupational Performance Measure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
DCP=dyskinesia in cerebral palsy; ECG=electrocardiogram; ESRS=Extrapyramidal Symptom Rating Scale 
(subscales I and II); ESS=Epworth Sleepiness Scale (for children and adolescents); MD-CRS=Movement 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
9 
Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability Inventory-Computer Adapted Test; 
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. 
General Study Design: This is a 55-week, open-label, single-arm study in which patients who 
have successfully completed the parent study (TV50717-CNS-30080) may be eligible to enroll in 
this study after they complete a 1-week washout period and the final evaluation at week 16. For 
patients rolling over from Study TV50717-CNS-30080, the week 16 visit may be the day 1 visit 
for Study TV50717-CNS-30081. If the patient does not wish to enroll in 
Study TV50717-CNS-30081 at that visit, or for any other reason, the patient can enroll up to 
4 weeks following the week 15 visit of Study TV50717-CNS-30080. Any patient who cannot 
enroll within this timeframe, for any justified reason, must be discussed and pre-approved by the 
medical monitor prior to enrolling the patient. The end of Study TV50717-CNS-30081 is defined 
as the date of the week 55 follow-up telephone contact of the last participant. 
This study will include children and adolescents between 6 and 18 years of age at the time when 
they enrolled in the parent study (Study TV50717-CNS-30080). Informed consent/assent, as 
appropriate, based on the patient’s age and condition, will be obtained from the 
patient/parent(s)/legally acceptable representative and caregiver (as applicable) at baseline/day 1 
or screening visit (whichever comes first), and before any study procedures are performed. 
Informed consent/assent process can begin within 4 weeks before possible participation in the 
open-label study to allow patients adequate time to engage and ask questions. 
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 legally acceptable 
representative. In some countries, an adult (such as grandparent or nurse) may be appointed by 
the parent or legally acceptable representative (as per local regulations and laws) and would take 
over this responsibility as caregiver. The parent or legally acceptable representative only has to 
sign the parent/legally acceptable representative informed consent form (ICF) and not the 
caregiver ICF. 
For adult patients, a caregiver must be appointed by the patient. The caregiver can be the parent 
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 acceptable representative; 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 the child’s health, or where “parent/legally 
acceptable representative” is specifically indicated in the protocol. 
Site-administered scales include the Movement Disorder-Childhood Rating Scale (MD-CRS) 
parts I and II (physician rated, with video recording), Caregiver Global Impression of 
Improvement (CaGI-I), Clinical Global Impression of Improvement (CGI-I), Clinical Global 
Impression of Severity (CGI-S), Pediatric Evaluation Disability Inventory-Computer Adapted 
Test (PEDI-CAT), Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-
TMS), Unified Huntington’s Disease Rating Scale-Total Maximal Chorea (UHDRS-TMC), 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
10 
Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia (UHDRS-TMD), Canadian 
Occupational Performance Measure (COPM), children’s Columbia-Suicide Severity Rating 
Scale (C-SSRS), Extrapyramidal Symptom Rating Scale (ESRS) subscales I and II, Child 
Behavior Checklist (CBCL) for ages 6 to 18 years, and Epworth Sleepiness Scale (for children 
and adolescents) (ESS) questionnaire. Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, questions should be directed to 
the child; however, caregiver involvement is strongly encouraged to add relevant information.  
In the study period descriptions below, “week X” refers to the end of that week, which coincides 
with the study visit, unless stated otherwise. Some dose changes will occur at the start of a week 
rather than at the end of a week and will be indicated as such. 
Patients can either enroll in the study at the week 16 visit of Study TV50717-CNS-30080 or up 
to 4 weeks following the week 15 visit of Study TV50717-CNS-30080. The time when the 
patient enrolls (baseline/day 1) in this study will determine the assessments that will need to be 
performed at the initial visit for the study (Figure 2). 
Day 1: Between 1 and <2 weeks after Study TV50717-CNS-30080 week 15 visit: 
To reduce patient burden and not collect duplicate information, after obtaining appropriate 
informed consent/assent, relevant data collected in Study TV50717-CNS-30080 will be used to 
provide corresponding data in this open-label study baseline/day 1 visit.  
Day 1 assessments for Study TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/week 16 visit assessments, whichever is the most current, do not need to be 
repeated, except for orthostatic pulse rate and blood pressure, electrocardiogram (ECG), 
beta-human chorionic gonadotropin (β-HCG) tests in urine, the site-administered scales, and the 
patient/caregiver-completed questionnaires, which need to be repeated at day 1.  
Any scales/questionnaires administered at the week 16 visit for Study TV50717-CNS-30080 do 
not need to be repeated if the day 1 visit of Study TV50717-CNS-30081 is the same day as the 
week 16 visit Study TV50717-CNS-30080. 
In addition, the following applies for day 1 baseline assessments for this study: 
• clinically significant laboratory abnormalities identified at week 15 in 
Study TV50717-CNS-30080 are to be repeated at week 16 of the parent study for 
eligibility in Study TV50717-CNS-30081 and will serve as day 1 baseline values in 
this study. Any abnormalities which are listed in the inclusion/exclusion criteria must 
be discussed with the medical monitor prior to patient enrollment into the study.  
• urine drug screen is performed at week 16 in study TV50717-CNS-30080 and will 
serve as day 1 baseline values in this study. 
• if the day 1 visit in Study TV50717-CNS-30081 is on the same day as the week 16 
visit of Study TV50717-CNS-30080, the results of β-HCG tests in urine will be 
carried over from the week 16 visit.  Otherwise, the β HCG tests in urine will be 
administered at day 1.  
• weight is performed at week 16 in Study TV50717-CNS-30080 and height is 
performed at week 15 in study TV50717-CNS-30080; these assessments will serve as 
day 1 baseline values in this study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
11 
• vital signs (respiratory rate and body temperature) are performed at week 16 in 
Study TV50717-CNS-30080. If the day 1 visit in Study TV50717-CNS-30081 is on 
the same day as the week 16 visit of Study TV50717-CNS-30080, these assessments 
will serve as day 1 baseline values in this study. Otherwise, these assessments will be 
performed at day 1. 
• physical and neurological examinations are performed at week 15 (and week 16, if 
applicable) in Study TV50717-CNS-30080. The findings from the last assessment 
taken will serve as day 1 baseline values in this study.  
• ECG is to be performed on day 1 of Study TV50717-CNS-30081 and will serve as 
day 1 baseline values in this study.  
• medical and psychiatric history are to be assessed on day 1 of Study 
TV50717-CNS-30081 and will serve as day 1 baseline values in this study. 
• COPM (an assessment included only in Study TV50717-CNS-30081) will also be 
performed at day 1. 
At the investigator’s discretion, abnormal findings can be discussed with the medical monitor. 
Day 1: Between 2 and ≤4 weeks after Study TV50717-CNS-30080 week 15 visit: 
If, in the judgment of the investigator, the patient has not had any clinically significant change 
since the week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, 
clinical assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo 
all day 1 assessments outlined in Table 4, except hematology, chemistry, and urinalysis 
laboratories and urine drug screen, which can be carried over from Study TV50717-CNS-30080 
week 15 or week 16 visit, whichever is more current. 
If, in the judgment of the investigator, the patient has had a clinically significant change since the 
week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, clinical 
assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo all 
screening procedures outlined in Table 4. Patients who remain eligible for participation in the 
study will be asked to return for day 1 assessments. 
Study drug will be dispensed at day 1 once all procedures and investigator-related assessments 
are completed and patient eligibility is confirmed. 
For patients who enroll in the study between 2 and ≤4 weeks after the Study TV50717-
CNS‑30080 week 15 visit, the investigator is required to consult with the medical monitor 
regarding eligibility prior to baseline/day 1. The patient’s file should include all related 
correspondence with the medical monitor.  
Titration period (7 weeks): Because the patients from parent Study TV50717-CNS-30080 have 
discontinued TEV-50717 treatment for at least 1 week at completion of the parent study or 
received placebo in the parent study, all patients will undergo TEV-50717 dose titration in this 
study in order to maintain the blind of the parent Study TV50717-CNS-30080. Patients will 
receive 6 mg of TEV-50717 (Table 2). This dose will be administered in the morning on days 2 
and 3, followed by evening administration starting on day 3 for the remainder of the week (if 
body weight is ≥40 kg/88 lbs). TEV-50717 daily doses of 12 mg and higher will be administered 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
12 
as 2 divided equal doses, approximately 8 to 10 hours apart during the day. A minimum of 
6 hours should elapse between doses. 
The TEV-50717 tablets cannot be crushed or split but should be swallowed whole; the TEV-
50717 tablets should be taken with food (eg, a snack) and should not be taken on an empty 
stomach. The titration scheme and maximum dose will be determined by body weight at day 1 
and cytochrome P450 2D6 (CYP2D6) impairment status, as shown in Table 2 and Table 3, 
respectively. Patients will be classified as CYP2D6 impaired if they are receiving a strong 
CYP2D6 inhibitor. Patients who are CYP2D6 impaired will have a dose cap in the open-label 
study, as shown in Table 3.  
Patients and their caregiver will interact weekly with the clinical research staff, either by 
telephone contact (with non-recording live video) or in-clinic visits from week 1 through week 7 
of the titration period, in order to evaluate safety and establish a dose of TEV-50717 that 
optimally reduces dyskinesia (as indicated by a reduction in the CGI-I) and is well tolerated 
(optimal dose). 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. Safety evaluations during the titration period include 
assessment of vital signs, monitoring for adverse events and concomitant medications, 12-lead 
ECGs, identifying patients at risk for suicide, 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.  
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 dose of TEV-50717 should be increased to reach a clinically meaningful reduction in 
dyskinesia, as indicated by a reduction in the CGI-I (see Table 2). The dose of TEV-50717 
should not be increased further if either of the following occurs: 
• the patient experiences a “clinically significant” adverse event (defined as an adverse 
event that is related to TEV-50717 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 day 1. Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. 
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 TEV-50717 should not be increased 
further, but the patient should continue on that dose for the remainder of the titration period. If a 
patient experiences a “clinically significant” adverse event attributable to TEV-50717, 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.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
13 
Dose adjustments should be made based on all available information, including the patient and 
caregiver reports of adverse events and dyskinesia reduction, the clinical assessment of safety 
and efficacy by the investigator, and the information from rating scales. 
Table 2: 
Maximum Daily Dose of TEV-50717 by Week and Weight Category on Day 1 
for Titration at Study Initiation  
 
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 mg 
18 mg 
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 a 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 5 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, 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 3). 
CYP2D6=cytochrome P450 2D6. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
14 
Table 3: 
Maximum Daily Dose of TEV-50717 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. 
Note: Patients will be classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor. Strong CYP2D6 inhibitors 
include paroxetine, fluoxetine, and bupropion. 
Maintenance period (46 weeks): At the end of the titration period (week 7 visit), the patient’s 
initial dose for the maintenance period (up to week 53) will be established. Dose adjustments of 
TEV-50717 (upward or downward) may be made during the maintenance period, if necessary, 
based on efficacy, safety, and/or tolerability considerations but not more often than every 5 days 
and only in increments of 6 mg up to the maximum allowed dose. As during titration, dose 
adjustments should be made based on all available information. Dose reductions of TEV-50717 
or suspensions of patients for adverse events or tolerability findings are allowed.  
During the maintenance period, in-person (in-clinic) study visits will be scheduled at weeks 14, 
27, 40, and 53 for assessments of safety and efficacy, and telephone contacts (with non-recording 
live video) will be scheduled for weeks 21, 33, and 46 in order to assess adverse events and 
dyskinesia. At week 53/early termination (ET), patients will undergo a complete evaluation, 
including vital signs and weight, physical and neurological examination, height measurement, 
12-lead ECG, safety laboratory testing, urine drug screen, and beta-human chorionic 
gonadotropin (β-HCG) test, when applicable, as well as the MD-CRS parts I and II, CaGI-I, 
CGI-I, CGI-S, PEDI-CAT, UHDRS-TMS, UHDRS-TMC, UHDRS-TMD, COPM, children’s 
C-SSRS assessments, ESRS (subscales I and II), CBCL, and ESS. 
Washout and follow-up period: All patients should continue their usual treatment regimen up to 
week 53 visit (ie, the last dose can be administered until visit completion, if applicable). No 
dosing will be given after the week 53 visit. All patients will discontinue TEV-50717 at the 
week 53 visit and will return 1 week later (week 54) for evaluation of safety. Patients will have a 
follow-up telephone contact (no live video streaming) for safety evaluation 1 week after the end 
of the washout period (2 weeks after their last dose of TEV-50717) (week 55). 
Brief Summary of Study Design for the Trial Registry(s): 
Study TV50717-CNS-30081 is a 55-week study in which patients who have successfully 
completed the parent study (Study TV50717-CNS-30080) may be eligible to enroll in this study 
after they complete a 1-week period where no treatment is administered and the final evaluation 
at week 16. Patients may roll over from Study TV50717-CNS-30080 on the same day as the 
week 16 visit or up to 4 weeks from the week 15 visit of the TV50717-CNS 30080 study. Any 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
15 
patient who cannot enroll within this timeframe, for any justified reason, must be discussed and 
pre-approved by the medical monitor prior to enrolling the patient. The end of Study 
TV50717‑CNS‑30081 is defined as the date of the week 55 follow-up telephone contact of the 
last participant. 
This is an open-label study, and all patients who are enrolled will receive TEV-50717; there is no 
placebo treatment group. The purpose of the study is to determine whether long-term treatment 
with TEV-50717 is safe, tolerable, and effective in the treatment of dyskinetic involuntary 
movements associated with CP. 
This study will include children and adolescents between 6 and 18 years of age at the time when 
they enrolled in the parent study (Study TV50717-CNS-30080). Informed consent/assent, as 
appropriate, based on the patient’s age, will be obtained from the patient/parent/legally 
acceptable representative and caregiver (as applicable) at baseline/day 1 or screening visit 
(whichever comes first), and before any study procedures are performed. Informed 
consent/assent process can begin within 4 weeks before possible participation in the open‑label 
study to allow patients adequate time to engage and ask questions. 
Approximately 45 patients who have completed parent Study TV50717-CNS-30080 are planned 
for enrollment into this study. 
Patients can either enroll in the study at the week 16 visit of Study TV50717-CNS-30080 or up 
to 4 weeks following the week 15 visit. The time when the patient enrolls (baseline/day 1) in this 
study will determine the assessments that will need to be performed at the initial visit for the 
study (Figure 2). 
Day 1: Between 1 and <2 weeks after Study TV50717-CNS-30080 week 15 visit: 
To reduce patient burden and not collect duplicate information, after obtaining appropriate 
informed consent/assent, relevant data collected in Study TV50717-CNS-30080 will be used to 
provide corresponding data in this open-label study baseline/day 1 visit. 
Day 1 assessments for Study TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/week 16 visit assessments, whichever is most current, do not need to be 
repeated, except for orthostatic pulse rate and blood pressure, electrocardiogram (ECG), beta-
human chorionic gonadotropin (β-HCG) tests in urine, the site-administered scales, and the 
patient/caregiver-completed questionnaires, which need to be repeated at day 1.  
Any scales/questionnaires administered at the week 16 visit for Study TV50717-CNS-30080 do 
not need to be repeated if the day 1 visit of Study TV50717-CNS-30081 is the same day as the 
week 16 visit Study TV50717-CNS-30080.  
In addition, the following applies for day 1 baseline assessments for this study: 
• clinically significant laboratory abnormalities identified at week 15 in 
Study TV50717-CNS-30080 are to be repeated at week 16 of the parent study for 
eligibility in Study TV50717-CNS-30081 and will serve as day 1 baseline values in 
this study. Any abnormalities which are listed in the inclusion/exclusion criteria must 
be discussed with the medical monitor prior to patient enrollment into the study.   
• Urine drug screen is performed at week 16 in study TV50717-CNS-30080 and will 
serve as day 1 baseline values in this study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
16 
• If the day 1 visit in Study TV50717-CNS-30081 is on the same day as the week 16 
visit of Study TV50717-CNS-30080, the results of β-HCG tests in urine will be 
carried over from the week 16 visit.  Otherwise, the β HCG tests in urine will be 
administered at day 1. 
• weight is performed at week 16 in Study TV50717-CNS-30080 and height is 
performed at week 15 in study TV50717-CNS-30080; these assessments will serve as 
day 1 baseline values in this study. 
• vital signs (respiratory rate and body temperature) are performed at week 16 in 
Study TV50717-CNS-30080. If the day 1 visit in Study TV50717-CNS-30081 is on 
the same day as the week 16 visit of Study TV50717-CNS-30080, these assessments 
will serve as day 1 baseline values in this study. Otherwise, these assessments will be 
performed at day 1. 
• physical and neurological examinations are performed at week 15 (and week 16, if 
applicable) in Study TV50717-CNS-30080. The findings from the last assessment 
taken will serve as day 1 baseline values in this study.  
• ECG is to be performed on day 1 of Study TV50717-CNS-30081 and will serve as 
day 1 baseline values in this study.  
• medical and psychiatric history are to be assessed on day 1 of Study TV50717-CNS- 
30081 and will serve as day 1 baseline values in this study. 
• COPM (an assessment included only in Study TV50717-CNS-30081) will also be 
performed at day 1. 
At the investigator’s discretion, abnormal findings can be discussed with the medical monitor.  
Day 1: Between 2 and ≤4 weeks after Study TV50717-CNS-30080 week 15 visit: 
If, in the judgment of the investigator, the patient has not had any clinically significant change 
since the week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, 
clinical assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo 
all day 1 assessments outlined in Table 4, except hematology, chemistry, and urinalysis 
laboratories and urine drug screen, which can be carried over from Study TV50717-CNS-30080 
week 15 or week 16 visit, whichever is more current. 
If, in the judgment of the investigator, the patient has had a clinically significant change since the 
week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, clinical 
assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo all 
screening procedures outlined in Table 4. Patients who remain eligible for participation in the 
study will be asked to return for day 1 assessments.  
Study drug will be dispensed at day 1 once all procedures and investigator-related assessments 
are completed and patient eligibility is confirmed. 
For patients who enroll in the study between 2 and ≤4 weeks after the Study TV50717-
CNS-30080 week 15 visit, the investigator is required to consult with the medical monitor 
regarding eligibility prior to baseline/day 1. The patient’s file should include all related 
correspondence with the medical monitor.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
17 
Because the patients from parent Study TV50717-CNS-30080 have discontinued TEV-50717 
treatment for at least 1 week at completion of the parent study or received placebo in the parent 
study, all patients will undergo TEV-50717 dose titration (7 weeks) in this study in order to 
maintain the blind of the parent Study TV50717-CNS-30080. Patients will receive 6 mg of 
TEV-50717 (Table 6). This dose will be administered in the morning on days 2 and 3, followed 
by evening administration starting on day 3 for the remainder of the 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. 
The TEV-50717 tablets cannot be crushed or split, but should be swallowed whole; the TEV-
50717 tablets should be taken with food (eg, a snack) and should not be taken on an empty 
stomach. The titration scheme and maximum dose will be determined by body weight at day 1 
and CYP2D6 impairment status. Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. Patients who are CYP2D6 impaired will have a dose cap in 
this study. Patients and their caregiver will interact weekly with the clinical research staff, either 
by telephone contact or in-clinic visits from week 1 through week 7 of the titration period, in 
order to evaluate safety and establish a dose of TEV-50717 that optimally reduces dyskinesia (as 
indicated by a reduction in the CGI-I) and is well tolerated (optimal dose). 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.  
In-person (in-clinic) study visits will be scheduled at weeks 3 and 7, and telephone contacts will 
be scheduled for weeks 1, 2, 4, 5, and 6 in order to assess dyskinesia and adverse events.  
The dose of TEV-50717 should be increased to reach a clinically meaningful reduction in 
dyskinesia, as indicated by a reduction in the CGI-I (see Table 2). The dose of TEV-50717 
should not be increased further if either of the following occurs: 
• the patient experiences a “clinically significant” adverse event (defined as an adverse 
event that is related to TEV-50717 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 day 1. Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. 
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 TEV-50717 should not be increased 
further, but the patient should continue on that dose for the remainder of the titration period. If a 
patient experiences a “clinically significant” adverse event attributable to TEV-50717, 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.  
Dose adjustments should be made based on all available information, including the patient and 
caregiver reports of adverse events and dyskinesia reduction, the clinical assessment of safety 
and efficacy by the investigator, and the information from rating scales. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
18 
During the maintenance period (week 8 to week 53), dose adjustments of TEV-50717 (upward or 
downward) may be made, if necessary, based on efficacy, safety, and/or tolerability 
considerations but not more often than every 5 days and only in increments of 6 mg up to the 
maximum allowed dose. In-person (in-clinic) study visits will be scheduled at weeks 14, 27, 40, 
and 53 for assessments of safety and efficacy, and telephone contacts will be scheduled for 
weeks 21, 33, and 46 in order to assess adverse events and dyskinesia.  
All patients should continue their usual treatment regimen up to week 53 visit (ie, the last dose 
can be administered until visit completion, if applicable). No dosing will be given after the 
week 53 visit. All patients will discontinue TEV-50717 at the week 53 visit and will return 
1 week later (week 54) for evaluation of safety. Patients will have a follow-up telephone contact 
for safety evaluation 1 week after the end of the washout period (ie, the period where no 
treatment is administered), which will be 2 weeks after their last dose of TEV-50717 (week 55). 
Method of Randomization and Blinding: Not applicable. This is an open-label, single-arm 
study with no blinding. 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate: 
Test IMP is defined as TEV-50717 (deutetrabenazine, previously SD-809) in this study. 
Test IMP will be administered as oral tablets at a starting dose of 6 mg once daily. Titration 
schemes based on body weight at day 1 are shown in Table 2. The maximum daily dose is 
determined by body weight at day 1 and CYP2D6 impairment status (Table 3). Patients will be 
classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor. If a patient 
experiences a “clinically significant” adverse event that is attributed to TEV-50717, 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 initial dose will be 
established for the maintenance period. Dose adjustments of TEV-50717 (upward or downward) 
may be made during the maintenance period, if necessary, based on efficacy, safety, and/or 
tolerability considerations but not more often than every 5 days and only in increments of 6 mg 
up to the maximum allowed dose. As during titration, dose adjustments should be made based on 
all available information. The dose of TEV-50717 may be reduced or suspended if a patient 
experiences an adverse event or tolerability finding during the maintenance period and the 
investigator believes a dose reduction or suspension is warranted. 
TEV-50717 oral tablets (test IMP) are 6, 9, and 12 mg, or other commercially available, dose 
strengths. Each dose strength will have a marking corresponding to the dose strength on the 
label. TEV-50717 will be supplied as 60-count tablets per bottle. Each dose strength will be a 
colored tablet with a marking of “SD” and the corresponding strength. 
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. 
TEV-50717 will be administered as follows: 
• TEV-50717 cannot be crushed or split but should be swallowed whole; the 
TEV-50717 tablets should 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
19 
• Dosing and titration will be based on body weight at the day 1 visit and CYP2D6 
impairment status, as shown in Table 2 and Table 3, respectively. 
• The starting dose is 6 mg in all patients. This dose will be administered in the 
morning on days 2 and 3, followed by evening administration starting on day 3 for the 
remainder of the 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. 
• Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg. For patients ≥40 kg, 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 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 TEV-50717 should be adjusted according to 
Table 2 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 a telephone or in-clinic visit. 
Test IMP: TEV-50717 (deutetrabenazine, previously SD-809) 
Placebo IMP: Not applicable 
Duration of Patient Participation and Maximal Exposure to IMP: All participating patients 
are expected to participate in this study for its entire duration, which is 55 weeks. Patients will 
have a follow-up telephone contact to evaluate safety 1 week after the end of the washout period 
(2 weeks after their last dose of TEV-50717). Any patient that reaches the age of legal 
competence to give informed consent during the course of Study TV50717-CNS-30081 will need 
to be re-consented as an adult. When a patient is a minor advancing to the next age range (new 
assent available and patient is still considered a minor by local law), the patient may need to sign 
on new assent appropriate for that age in order to continue participation in the study (in 
accordance with local laws and regulations). 
Study Duration: Approximately 55 weeks 
End of Study: The end of the study TV50717-CNS-30081 is defined as the date of the week 55 
follow-up telephone contact of the last participant. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
20 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: There 
are no plans to provide further treatment to patients upon completion of the study. An extension 
to the study may be considered on an annual basis. 
Inclusion Criteria: Patients who meet the criteria below are eligible to be included in the study.  
a. Patient has completed week 16 of Study TV50717-CNS-30080. 
b. Patient weighs at least 12 kg (26 lbs) on day 1 of this study. 
c. Patient is able to swallow TEV-50717 whole. 
d. Patient and caregiver are willing to adhere to TEV-50717 regimen and comply with 
all study procedures. 
e. Patient is in good general health, as indicated by medical and psychiatric history and 
physical and neurological examination. 
f. 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. 
g. For a patient who is a minor, the parent(s)/legally acceptable representative(s) 
provides written informed consent, and the patient provides assent (in accordance 
with local regulations). Adult patients provide written informed consent (in 
accordance with local regulations), and the legally acceptable representative will sign, 
if needed. 
In this study, eligible patients with dyskinetic cerebral palsy 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. 
h. A caregiver provides written informed consent after being assigned the role by an 
adult patient or if this role is delegated by the parent/legally acceptable representative 
of a patient who is a minor. 
i. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative β-HCG test on day 1 or are sterile. 
j. 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 day 1) and for 30 days after last dose of 
TEV-50717. 
Exclusion Criteria: Patients will not be randomized/enrolled in this study if they meet any of 
the following criteria: 
a. Patient has clinically significant depression at screening or day 1 of this study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
21 
− Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 6 weeks before screening or day 1 (whichever comes first) and 
anticipated to remain stable (dose and frequency) within the study duration. 
b. Patient has a history of suicidal intent or related behaviors based on medical or 
psychiatric history or the C-SSRS at screening visit, if performed, or at the day 1 
visit, as applicable according to the patient’s age: 
− intent to act on suicidal ideation with a specific plan, irrespective of level of 
ambivalence, at the time of suicidal thought 
− suicidal preparatory acts or behavior 
c. Patient has a history of a previous actual, interrupted, or aborted suicide attempt 
based on medical or psychiatric history or the C-SSRS at screening visit, if 
performed, or at the day 1 visit, as applicable according to the patient’s age. 
d. Patient has a first-degree relative who has completed suicide. 
e. Patient has received any of the following concomitant medications within the 
specified exclusionary windows from screening or day 1 (whichever comes first) of 
this study: 
− within 30 days: tetrabenazine or valbenazine  
− within 21 days: reserpine 
− within 14 days: levodopa, dopamine agonists, and monoamine oxidase inhibitors 
f. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic 
stimulation, or transcranial direct current stimulation for treatment of abnormal 
movements or cerebral palsy since the week 15 visit of Study TV50717-CNS-30080, 
or the patient is not in a stable clinical condition.  
g. Patient had a surgical procedure since the week 15 visit of Study TV50717-
CNS-30080 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. 
h. Patient has a severe mental disability or an unstable or serious medical illness (eg, 
epilepsy) that, in the opinion of the investigator, could jeopardize or would 
compromise the patient’s ability to participate in this study. 
i. Patient has a QT interval corrected for heart rate (QTc) using Fridericia’s formula 
(QTcF) value >450 msec on 12-lead ECG at screening or day 1 (whichever comes 
first) of this study. 
j. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure. 
k. Patient has evidence of hepatic impairment, as indicated by the following: 
− aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× the 
upper limit of the normal range (ULN) at the week 15 or week 16 visit of Study 
TV50717-CNS-30080 or screening of this study, as applicable 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
22 
− alkaline phosphatase (ALP) or total bilirubin (Tbil) >2×ULN at the week 15 or 
week 16 visit of Study TV50717-CNS-30080 or screening of this study, as 
applicable 
− 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 AST, ALT, ALP, and Tbil 
parameters that do not meet the above laboratory criteria for exclusion based on 
hepatic impairment must be approved for enrollment by the medical monitor. 
l. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5×ULN at the week 15 or week 16 visit of Study TV50717-CNS-30080 
or screening of this study, as applicable. 
m. Patient has a known allergy to any of the components of TEV-50717. 
n. Patient has participated in an investigational drug or device study other than Study 
TV50717-CNS-30080 and received IMP/intervention within 30 days or 5 drug 
half-lives of day 1 of this study, whichever is longer. 
o. Patient is pregnant or breastfeeding. 
p. Patient has a history of or acknowledges alcohol or substance abuse. 
q. Patient has a positive urine drug screen test result since the week 15 or week 16 visit 
of Study TV50717-CNS-30080 or at screening (as applicable) of this study (with 
exception of medications listed in Table 11 of Appendix H or a justified medical 
explanation). Any request to include a patient with a positive urine drug screen test 
result should be discussed with, and approved by, the medical monitor.  
Statistical Considerations 
Sample Size Rationale:  
This study is open-label and safety oriented in nature; therefore, no formal hypothesis testing is 
planned. The sample size for this study is not based on statistical considerations; hence, only 
descriptive statistics will be presented. 
Based on the number of patients in the parent study (Study TEV50717-CNS-30080), 
approximately 45 patients who completed the parent study may enroll in this study.  
Analysis Sets 
A single analysis set is defined for this clinical study, the intent to treat (ITT) analysis set. 
Intent-to-Treat Analysis Set:  
The ITT analysis set will include all enrolled patients, regardless of whether or not a patient took 
any TEV-50717. A patient is considered enrolled according to the status reported in the database. 
All analyses will be based on the ITT analysis set. 
Additional Analyses Sets: 
Additional analysis sets may be defined in the Statistical Analysis Plan. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
23 
Analysis of Safety: 
Safety analyses will be presented for the ITT analysis set. Patients that did not receive any 
TEV-50717 will be excluded from the summaries and presented in listings only.  
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events, adverse 
events determined by the investigator to be related to TEV-50717, serious adverse events, and 
adverse events causing withdrawal from the study. Patient listings of serious adverse events and 
adverse events leading to withdrawal will be presented. 
Observed values and changes from day 1 in laboratory results and vital signs will be summarized 
descriptively.  
Observed values in ECG parameters will be summarized, and counts and percentages of 
abnormal findings will be presented. Changes from baseline of the parent study in ECG 
parameters will be summarized descriptively. In addition, the number and percentage of patients 
with on-treatment QTcF values >450, >480, or >500 msec and change from day 1 >30 or 
>60 msec will be presented.  
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with TEV-50717. 
Observed values in the children’s C-SSRS will be presented for all patients. 
Assessments of drug-induced parkinsonism according to the ESRS (subscales I and II), of 
change in behavior according to the CBCL questionnaire, and assessment of sedation according 
to the ESS questionnaire will be summarized descriptively.  
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. 
Analysis of Efficacy: 
Descriptive statistics will be used to summarize efficacy measures.  
Descriptive statistics of change-from-day 1 will utilize day 1 from the present open-label study 
(Study TEV-50717-30081). 
The ITT analysis set will be used for all summaries, unless otherwise noted. 
There is no planned interim analysis of this study. Intermediate analysis may be performed for 
submission of an NDA or other purposes. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
24 
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 ........................................................................................................31 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................33 
1.1. 
Introduction .................................................................................................................33 
1.1.1. 
Background for TEV-50717 .......................................................................................33 
1.1.2. 
Experience with Tetrabenazine in the Treatment of Dyskinesia in Cerebral 
Palsy and Other Hyperkinetic Movement Disorders in Children and 
Adolescents .................................................................................................................34 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................35 
1.2.1. 
Nonclinical Studies .....................................................................................................35 
1.2.1.1. 
Nonclinical Pharmacology ..........................................................................................35 
1.2.1.2. 
Nonclinical Pharmacokinetics and Drug Metabolism ................................................35 
1.2.1.3. 
Toxicology ..................................................................................................................36 
1.2.2. 
Clinical Studies ...........................................................................................................36 
1.2.2.1. 
Clinical Pharmacology Studies ...................................................................................37 
1.2.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................37 
1.2.2.3. 
Pharmacometric Analysis of TEV-50717 Active Metabolites to Support 
Dose Selection and Pharmacokinetic Characterization in a Pediatric 
Population ...................................................................................................................38 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................38 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................38 
1.3.1.1. 
Benefits of TEV-50717 ...............................................................................................38 
1.3.1.2. 
Potential Risks of TEV-50717 ....................................................................................39 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................39 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................40 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................40 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
25 
3. 
STUDY DESIGN .......................................................................................................41 
3.1. 
General Study Design and Study Schematic Diagram ...............................................41 
3.2. 
Planned Number of Patients and Regions ..................................................................48 
3.3. 
Justification for Study Design and Selection of Population .......................................48 
3.4. 
Stopping Rules for the Study ......................................................................................48 
3.5. 
Schedule of Study Procedures and Assessments ........................................................49 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................56 
4.1. 
Patient Inclusion Criteria ............................................................................................56 
4.2. 
Patient Exclusion Criteria ...........................................................................................57 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................59 
4.4. 
Replacement of Patients .............................................................................................60 
4.5. 
Rescreening .................................................................................................................60 
4.6. 
Screening Failure ........................................................................................................60 
5. 
TREATMENTS ..........................................................................................................61 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................61 
5.1.1. 
Test Investigational Medicinal Product ......................................................................61 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................61 
5.1.1.2. 
Dose Modification and Dose Stratification ................................................................61 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for IMPs ...................64 
5.2.1. 
Storage and Security ...................................................................................................64 
5.2.2. 
Labeling ......................................................................................................................64 
5.2.3. 
Accountability .............................................................................................................64 
5.3. 
Justification for Investigational Medicinal Products ..................................................65 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................65 
5.4. 
Treatment after the End of the Study ..........................................................................65 
5.5. 
Restrictions .................................................................................................................66 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................66 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................67 
5.8. 
Temporary Discontinuation of Investigational Medicinal Product ............................67 
5.9. 
Randomization and Blinding ......................................................................................68 
5.10. 
Maintenance of Randomization and Blinding ............................................................68 
5.10.1. 
Maintenance of Randomization ..................................................................................68 
5.10.2. 
Blinding and Unblinding ............................................................................................68 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
26 
5.10.3. 
Data Monitoring Committee .......................................................................................68 
5.11. 
Total Blood Volume ...................................................................................................69 
6. 
ASSESSMENT OF EFFICACY ................................................................................70 
6.1. 
Assessments of Efficacy .............................................................................................70 
6.1.1. 
Movement Disorder-Childhood Rating Scale ............................................................70 
6.1.2. 
Caregiver Global Impression of Improvement Scale .................................................71 
6.1.3. 
Clinical Global Impression of Improvement Scale ....................................................71 
6.1.4. 
Clinical Global Impression of Severity ......................................................................72 
6.1.5. 
Pediatric Evaluation Disability Inventory-Computer Adapted Test (Activities 
of Daily Living, Caregiver Completed, Content-Balanced Version ...........................73 
6.1.6. 
Unified Huntington’s Disease Rating Scale-Total Motor Score ................................73 
6.1.7. 
Canadian Occupational Performance Measure ...........................................................74 
7. 
ASSESSMENT OF SAFETY .....................................................................................75 
7.1. 
Adverse Events ...........................................................................................................75 
7.1.1. 
Definition of an Adverse Event ..................................................................................75 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................76 
7.1.3. 
Severity of an Adverse Event .....................................................................................76 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product .............77 
7.1.5. 
Serious Adverse Events ..............................................................................................77 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................78 
7.1.5.2. 
Expectedness ...............................................................................................................78 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................79 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest ................................................80 
7.1.7. 
Protocol Deviations Because of an Adverse Event ....................................................81 
7.2. 
Safety Rating Scales ...................................................................................................81 
7.2.1. 
Children’s Columbia-Suicide Severity Rating Scale ..................................................81 
7.2.2. 
Extrapyramidal Symptom Rating Scale ......................................................................81 
7.2.3. 
Child Behavior Checklist (for Ages 6 to 18) ..............................................................82 
7.2.4. 
Epworth Sleepiness Scale (for Children and Adolescents) ........................................83 
7.3. 
Pregnancy ...................................................................................................................83 
7.4. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Product .......................................................................................................84 
7.5. 
Clinical Laboratory Tests ...........................................................................................84 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
27 
7.5.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................85 
7.5.2. 
Other Clinical Laboratory Tests .................................................................................86 
7.5.2.1. 
Beta-Human Chorionic Gonadotropin Tests ..............................................................86 
7.5.2.2. 
Urine Drug Screen ......................................................................................................86 
7.6. 
Vital Signs ..................................................................................................................87 
7.7. 
Physical Examination .................................................................................................87 
7.8. 
Neurological Examinations ........................................................................................87 
7.9. 
Electrocardiography ....................................................................................................88 
7.10. 
Assessment of Suicidality ...........................................................................................89 
7.11. 
Assessment of Depression ..........................................................................................90 
7.12. 
Concomitant Medication or Treatment .......................................................................90 
7.13. 
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data .............................................................................................................................91 
8. 
ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS 
AND PHARMACOGENETICS .................................................................................92 
8.1. 
Pharmacokinetic Assessment ......................................................................................92 
8.2. 
Pharmacodynamics Assessment .................................................................................92 
8.3. 
Assessment of Exploratory Biomarkers .....................................................................92 
9. 
STATISTICS ..............................................................................................................93 
9.1. 
Sample Size and Power Considerations .....................................................................93 
9.2. 
Analysis Sets ...............................................................................................................93 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................93 
9.2.2. 
Additional Analyses Sets ............................................................................................93 
9.3. 
Data Handling Conventions ........................................................................................93 
9.4. 
Study Population .........................................................................................................93 
9.4.1. 
Patient Disposition ......................................................................................................93 
9.4.2. 
Demographic and Baseline Characteristics ................................................................94 
9.5. 
Multiple Comparisons and Multiplicity......................................................................94 
9.6. 
Safety Endpoints and Analysis ...................................................................................94 
9.7. 
Efficacy Analysis ........................................................................................................95 
9.8. 
Tolerability Analysis ..................................................................................................96 
9.9. 
Planned Interim Analysis ............................................................................................96 
9.10. 
Reporting Deviations from the Statistical Plan ..........................................................96 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
28 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................97 
11. 
COMPLIANCE STATEMENT ..................................................................................97 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................97 
13. 
FINANCING AND INSURANCE .............................................................................98 
14. 
PUBLICATION POLICY ..........................................................................................98 
15. 
REFERENCES ...........................................................................................................99 
16. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................101 
16.1. 
Amendment 04 Dated 01 June 2022 .........................................................................101 
16.2. 
Administrative Letter 06 Dated 11 June 2021 ..........................................................119 
16.3. 
Administrative Letter 05 Dated 23 February 2021 ...................................................121 
16.4. 
Administrative Letter 04 Dated 14 November 2020 ................................................124 
16.5. 
Administrative Letter 03 Dated 14 July 2020...........................................................126 
16.6. 
Amendment 03 Dated 23 June 2020 .........................................................................128 
16.7. 
Amendment 02 Dated 19 March 2020 ......................................................................136 
16.8. 
Amendment 01 Dated 02 October 2019 ...................................................................174 
16.9. 
Letter of Clarification 02 Dated 02 July 2019 ..........................................................197 
16.10. 
Letter of Clarification 01 Dated 07 June 2019 .........................................................198 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................201 
APPENDIX B. INDEPENDENT DATA MONITORING COMMITTEE ..............................203 
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................204 
APPENDIX D. QUALITY CONTROL AND QUALITY ASSURANCE ..............................217 
APPENDIX E. ETHICS ............................................................................................................219 
APPENDIX F. BIRTH CONTROL METHODS AND PREGNANCY TESTING .................220 
APPENDIX G. LOST TO FOLLOW-UP .................................................................................221 
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS .......................222 
APPENDIX I. TOTAL BLOOD VOLUME .............................................................................224 
APPENDIX J. PRODUCT COMPLAINTS .............................................................................225 
APPENDIX K. DATA MANAGEMENT AND RECORD KEEPING ...................................227 
APPENDIX L. PUBLICATION POLICY................................................................................230 
APPENDIX M. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 .............231 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
29 
LIST OF TABLES 
Table 1: 
Primary and Secondary Study Objectives and Endpoints ............................................8 
Table 2: 
Maximum Daily Dose of TEV-50717 by Week and Weight Category on Day 
1 for Titration at Study Initiation ................................................................................13 
Table 3: 
Maximum Daily Dose of TEV-50717 by CYP2D6 Impairment Status .....................14 
Table 4: 
Study Procedures and Assessments: Screening and/or Day 1 ....................................49 
Table 5: 
Study Procedures and Assessments: Titration, Maintenance, and Follow-up 
Periods ........................................................................................................................52 
Table 6: 
Maximum Daily Dose of TEV-50717 by Week and Weight Category on Day 
1 for Titration at Study Initiation ................................................................................63 
Table 7: 
Maximum Daily Dose of TEV-50717 by CYP2D6 Impairment Status .....................63 
Table 8: 
Investigational Medicinal Products Used in the Study ...............................................64 
Table 9: 
The Relationship of an Adverse Event to the IMP .....................................................77 
Table 10: Clinical Laboratory Tests ...........................................................................................85 
Table 11: Allowed Medications ................................................................................................222 
Table 12: Prohibited QTc-Prolonging Drugs ............................................................................223 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
30 
LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................46 
Figure 2: 
Flow Chart for Patient Screening and Day 1 Visit Assessments ................................47 
  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
31 
LIST OF ABBREVIATIONS  
Abbreviation 
Term 
ADL 
activities of daily living 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BoNT 
botulinum neurotoxin 
CaGI-I 
Caregiver Global Impression of Improvement 
CBCL 
Child Behavior Checklist (for ages 6-18) 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
COPM 
Canadian Occupational Performance Measure 
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 
DSM-V™ 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
ESRS 
Extrapyramidal Symptom Rating Scale (subscales I and II) 
ESS 
Epworth Sleepiness Scale (for children and adolescents) 
ET 
early termination 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HD 
Huntington’s disease 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
32 
Abbreviation 
Term 
ICH 
International Conference on Harmonisation 
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 
IWRS 
Interactive Web Response Systems 
LSO 
local safety officer 
MAOI 
monoamine oxidase inhibitor 
MD-CRS 
Movement Disorder-Childhood Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
PEDI-CAT 
Pediatric Evaluation Disability Inventory-Computer Adapted Test 
PedsQL 
Pediatric Quality of Life Inventory 
PND 
postnatal day 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RSI 
reference safety information 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
Tbil 
total bilirubin 
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 
VMAT2 
vesicular monoamine transporter type 2 
XML 
Extensible Markup Language 
α-HTBZ 
alpha-dihydrotetrabenazine 
β-HCG 
beta-human chorionic gonadotropin 
β-HTBZ 
beta-dihydrotetrabenazine 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
33 
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 (CDC Data and Statistics for Cerebral Palsy 2018, Maenner et al 2016, Monbaliu et al 2017, 
Prevalence of Cerebral Palsy 2018). 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 2018). 
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 (CDC Causes and Risk Factors of 
Cerebral Palsy 2018, Monbaliu et al 2017).  
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 long-term treatment with TEV-50717 is safe, 
tolerable, and 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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
34 
an improved pharmacokinetic and tolerability profile compared with tetrabenazine. TEV-50717 
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. TEV-50717 tablets are 
6, 9, and 12 mg, or other commercially available, dose strengths, all of which are identical in size 
and shape. Each strength will be a colored tablet with a marking of “SD” and the corresponding 
strength. The investigational medicinal product (IMP) will be supplied in 60-count tablets 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.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
35 
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 
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 2017). 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
36 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
37 
• one ongoing Phase 3 efficacy and safety study in patients with DCP 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
38 
The ongoing Study TV50717-CNS-30080 is the first study to assess the safety, tolerability, and 
efficacy of TEV-50717 in patients with DCP. This study (Study TV50717-CNS-30081) is being 
conducted to provide more details on the long-term safety and efficacy of treatment with 
TEV-50717 in patients with DCP. 
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 (+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 (+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 5.1.1.1. 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
39 
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. 
• 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). 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
40 
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 this study 
is to evaluate the safety and 
tolerability of long-term therapy with 
TEV-50717 in children and 
adolescents with DCP. 
The safety measures/endpoints are as follows: 
• 
adverse events 
• 
vital signs 
• 
children’s C-SSRS 
• 
ECG parameters 
• 
clinical laboratory parameters (hematology, serum chemistry, and 
urinalysis) 
• 
ESRS (subscales I and II) 
• 
CBCL 
• 
ESS 
The secondary objective of this 
study is to evaluate the efficacy of 
long-term therapy with TEV-50717 in 
reducing the severity of DCP. 
The efficacy measures/endpoints are as follows: 
• 
MD-CRS part I total score (centrally read) 
• 
MD-CRS part II total score (centrally read) 
• 
MD-CRS part I total score (physician rated) 
• 
MD-CRS part II total score (physician rated) 
• 
MD-CRS Global Index (calculated from MD-CRS parts I and II 
total scores) 
• 
CaGI-I (global, caregiver rated) 
• 
CGI-I (global, physician rated) 
• 
CGI-S (global, physician rated) 
• 
PEDI-CAT (activities of daily living, caregiver completed, 
content-balanced version) 
• 
UHDRS-TMC (centrally read) 
• 
UHDRS-TMD (centrally read) 
• 
UHDRS-TMS (physician rated) 
• 
UHDRS-TMC (physician rated) 
• 
UHDRS-TMD (physician rated) 
• 
COPM (physician rated) 
CaGI-I=Caregiver Global Impression of Improvement; CBCL=Child Behavior Checklist (for ages 6 to 18); 
CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression of Severity; 
COPM=Canadian Occupational Performance Measure; C-SSRS=Columbia-Suicide Severity Rating Scale; 
DCP=dyskinesia in cerebral palsy; 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; 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
41 
3. 
STUDY DESIGN  
3.1. 
General Study Design and Study Schematic Diagram  
This is a 55-week, open-label, single-arm study in which patients who have successfully 
completed the parent study (Study TV50717-CNS-30080) may be eligible to enroll in this study 
after they complete a 1-week washout period and the final evaluation at week 16. For patients 
rolling over from Study TV50717-CNS-30080, the week 16 visit may be the day 1 visit for 
Study TV50717-CNS-30081. If the patient does not wish to enroll in Study TV50717-
CNS-30081 at that visit, or for any other reason, the patient can enroll up to 4 weeks following 
the week 15 visit of the TV50717-CNS-30080 study. Any patient who cannot enroll within this 
timeframe, for any justified reason, must be discussed and pre-approved by the medical monitor 
prior to enrolling the patient. The end of study TV50717-CNS-30081 is defined as the date of the 
week 55 follow-up telephone contact of the last participant. 
This study will include children and adolescents between 6 and 18 years of age at the time when 
they enrolled in the parent study (Study TV50717-CNS-30080). Informed consent/assent, as 
appropriate, based on the patient’s age and condition, will be obtained from the 
patient/parent(s)/legally acceptable representative and caregiver (as applicable) at baseline/day 1 
or screening visit (whichever comes first), and before any study procedures are performed. 
Informed consent/assent process can begin within 4 weeks before possible participation in the 
open-label study to allow patients adequate time to engage and ask questions. 
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 legally acceptable 
representative. In some countries, an adult (such as grandparent or nurse) may be appointed by 
the parent or legally acceptable representative (as per local regulations and laws) and would take 
over this responsibility as caregiver. The parent or legally acceptable representative only has to 
sign the parent/legally acceptable representative informed consent form (ICF) and not the 
caregiver ICF. 
For adult patients, a caregiver must be appointed by the patient. The caregiver can be the parent 
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 acceptable representative, 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 the child’s health, or where “parent/legally 
acceptable representative” is specifically indicated in the protocol. 
Site-administered scales include the Movement Disorder-Childhood Rating Scale (MD-CRS) 
parts I and II (physician rated, with video recording), Caregiver Global Impression of 
Improvement (CaGI-I), Clinical Global Impression of Improvement (CGI-I), Clinical Global 
Impression of Severity (CGI-S), Pediatric Evaluation Disability Inventory-Computer Adapted 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
42 
Test (PEDI-CAT), 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), Canadian 
Occupational Performance Measure (COPM), children’s Columbia-Suicide Severity Rating 
Scale (C-SSRS), Extrapyramidal Symptom Rating Scale (ESRS) subscales I and II, Child 
Behavior Checklist (CBCL) for ages 6 to 18 years, and Epworth Sleepiness Scale (for children 
and adolescents) (ESS) questionnaire. Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, questions should be directed to 
the child; however, caregiver involvement is strongly encouraged to add relevant information.  
In the study period descriptions below, “week X” refers to the end of that week, which coincides 
with the study visit, unless stated otherwise. Some dose changes will occur at the start of a week, 
rather than at the end of a week, and will be indicated as such. 
Patients can either enroll in the study at the week 16 visit of Study TV50717-CNS-30080 or up 
to 4 weeks following the week 15 visit of Study TV50717-CNS-30080. The time when the 
patient enrolls (baseline/day 1) in this study will determine the assessments that will need to be 
performed at the initial visit for the study (Figure 2). 
Day 1: Between 1 and <2 weeks after Study TV50717-CNS-30080 week 15 visit: 
To reduce patient burden and not collect duplicate information, after obtaining appropriate 
informed consent/assent, relevant data collected in Study TV50717-CNS-30080 will be used to 
provide corresponding data in this open-label study baseline/day 1 visit.  
Day 1 assessments for Study TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/week 16 visit assessments, whichever is most current, do not need to be 
repeated, except for orthostatic pulse rate and blood pressure, electrocardiogram (ECG), 
beta-human chorionic gonadotropin (β-HCG) tests in urine, the site-administered scales, and the 
patient/caregiver-completed questionnaires, which need to be repeated at day 1.  
Any scales/questionnaires administered at the week 16 visit for Study TV50717-CNS-30080 do 
not need to be repeated if the day 1 visit of Study TV50717-CNS-30081 is the same day as the 
week 16 visit Study TV50717-CNS-30080. 
In addition, the following applies for day 1 baseline assessments for this study: 
• clinically significant laboratory abnormalities identified at week 15 in 
Study TV50717-CNS-30080 are to be repeated at week 16 of the parent study for 
eligibility in Study TV50717-CNS-30081 and will serve as day 1 baseline values in 
this study. Any abnormalities which are listed in the inclusion/exclusion criteria must 
be discussed with the medical monitor prior to patient enrollment into the study.  
• Urine drug screen is performed at week 16 in study TV50717-CNS-30080 and will 
serve as day 1 baseline values in this study. 
• If the day 1 visit in Study TV50717-CNS-30081 is on the same day as the week 16 
visit of Study TV50717-CNS-30080, the results of β-HCG tests in urine will be 
carried over from the week 16 visit. Otherwise, the β HCG tests in urine will be 
administered at day 1. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
43 
• weight is performed at week 16 in Study TV50717-CNS-30080 and height is 
performed at week 15 in study TV50717-CNS-30080; these assessments will serve as 
day 1 baseline values in this study. 
• vital signs (respiratory rate and body temperature) are performed at week 16 in 
Study TV50717-CNS-30080. If the day 1 visit in Study TV50717-CNS-30081 is on 
the same day as the week 16 visit of Study TV50717-CNS-30080, these assessments 
will serve as day 1 baseline values in this study. Otherwise, these assessments will be 
performed at day 1. 
• physical and neurological examinations are performed at week 15 (and week 16, if 
applicable) in Study TV50717-CNS-30080. The findings from the last assessment 
taken will serve as day 1 baseline values in this study.  
• ECG is to be performed on day 1 of Study TV50717-CNS-30081 and will serve as 
day 1 baseline values in this study.  
• medical and psychiatric history are to be assessed on day 1 of Study 
TV50717-CNS-30081 and will serve as day 1 baseline values in this study. 
• COPM (an assessment included only in Study TV50717-CNS-30081) will also be 
performed at day 1. 
At the investigator’s discretion, abnormal findings can be discussed with the medical monitor. 
Day 1: Between 2 and ≤4 weeks after Study TV50717-CNS-30080 week 15 visit: 
If, in the judgment of the investigator, the patient has not had any clinically significant change 
since the week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, 
clinical assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo 
all day 1 assessments outlined in Table 4, except hematology, chemistry, and urinalysis 
laboratories and urine drug screen, which can be carried over from Study TV50717-CNS-30080 
week 15 or week 16 visit, whichever is more current. 
If, in the judgment of the investigator, the patient has had a clinically significant change since the 
week 15 visit of Study TV50717-CNS-30080 in health, concomitant medications, clinical 
assessments, laboratories, ECGs, or non-medical interventions, the patient will undergo all 
screening procedures outlined in Table 4. Patients who remain eligible for participation in the 
study will be asked to return for day 1 assessments. 
Study drug will be dispensed at day 1 once all procedures and investigator-related assessments 
are completed and patient eligibility is confirmed. 
For patients who enroll in the study between 2 and ≤4 weeks after the Study 
TV50717-CNS-30080 week 15 visit, the investigator is required to consult with the medical 
monitor regarding eligibility prior to baseline/day 1. The patient’s file should include all related 
correspondence with the medical monitor.  
Titration period (7 weeks): Because the patients from parent Study TV50717-CNS-30080 have 
discontinued TEV-50717 treatment for at least 1 week at completion of the parent study or 
received placebo in the parent study, all patients will undergo TEV-50717 dose titration in this 
study in order to maintain the blind of the parent Study TV50717-CNS-30080. Patients will 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
44 
receive 6 mg of TEV-50717 (Table 6). This dose will be administered in the morning on days 2 
and 3, followed by evening administration starting on day 3 for the remainder of the 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. 
The TEV-50717 tablets cannot be crushed or split but should be swallowed whole; the TEV-
50717 tablets should be taken with food (eg, a snack) and should not be taken on an empty 
stomach. The titration scheme and maximum dose will be determined by body weight at day 1 
and CYP2D6 impairment status, as shown in Table 6 and Table 7, respectively. Patients will be 
classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor. Patients who 
are CYP2D6 impaired will have a dose cap in the open-label study, as shown in Table 7.  
Patients and their caregiver will interact weekly with the clinical research staff, either by 
telephone contact (with non-recording live video) or in-clinic visits from week 1 through week 7 
of the titration period, in order to evaluate safety and establish a dose of TEV-50717 that 
optimally reduces dyskinesia (as indicated by a reduction in the CGI-I) and is well tolerated 
(optimal dose). 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. Safety evaluations during the titration period include 
assessment of vital signs, monitoring for adverse events and concomitant medications, 12-lead 
ECGs, identifying patients at risk for suicide, 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.  
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 dose of TEV-50717 should be increased to reach a clinically meaningful reduction in 
dyskinesia, as indicated by a reduction in the CGI-I (see Table 6). The dose of TEV-50717 
should not be increased further if either of the following occurs: 
• the patient experiences a “clinically significant” adverse event (defined as an adverse 
event that is related to TEV-50717 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 day 1. Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. 
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 TEV-50717 should not be increased 
further, but the patient should continue on that dose for the remainder of the titration period. If a 
patient experiences a “clinically significant” adverse event attributable to TEV-50717, 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.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
45 
Dose adjustments should be made based on all available information, including the patient and 
caregiver reports of adverse events and dyskinesia reduction, the clinical assessment of safety 
and efficacy by the investigator, and the information from rating scales. 
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. 
Maintenance period (46 weeks): At the end of the titration period (week 7), the patient’s initial 
dose for the maintenance period (up to week 53) will be established. Dose adjustments of 
TEV-50717 (upward or downward) may be made during the maintenance period, if necessary, 
based on efficacy, safety, and/or tolerability considerations but not more often than every 5 days 
and only in increments of 6 mg up to the maximum allowed dose (Table 6 and Table 7). As 
during titration, dose adjustments should be made based on all available information. Dose 
reductions of TEV-50717 or suspensions of patients for adverse events or tolerability findings 
are allowed.  
During the maintenance period, in-person (in-clinic) study visits will be scheduled at weeks 14, 
27, 40, and 53 for assessments of safety and efficacy, and telephone contacts (with non-recording 
live video) will be scheduled for weeks 21, 33, and 46 in order to assess adverse events and 
dyskinesia. At week 53/early termination (ET), patients will undergo a complete evaluation, 
including vital signs and weight, physical and neurological examination, height measurement, 
12-lead ECG, safety laboratory testing, urine drug screen, and beta-human chorionic 
gonadotropin (β-HCG) test, when applicable, as well as the MD-CRS parts I and II, CaGI-I, 
CGI-I, CGI-S, PEDI-CAT, UHDRS-TMS, UHDRS-TMC, UHDRS-TMD, COPM, children’s 
C-SSRS assessments, ESRS (subscales I and II), CBCL, and ESS. 
Washout and follow-up period: All patients should continue their usual treatment regimen up to 
week 53 visit (ie, the last dose can be administered until visit completion, if applicable). No 
dosing will be given after the week 53 visit. All patients will discontinue TEV-50717 at the 
week 53 visit and will return 1 week later (week 54) for evaluation of safety. Patients will have a 
follow-up telephone contact (no live video streaming) for safety evaluation 1 week after the end 
of the washout period (2 weeks after their last dose of TEV-50717) (week 55). 
Study procedures and assessments with their time points are presented for screening and/or day 1 
in Table 4 and for the titration, maintenance, and follow-up periods in Table 5. The study 
schematic diagram is presented in Figure 1. A flow chart for patient screening and day 1 visit 
assessments is presented in Figure 2.   
For coronavirus disease 2019 (COVID-19) updates, refer to Appendix M. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
46 
Figure 1: 
Overall Study Schematic Diagram  
≥ 40 kg
30 kg to < 40 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (24) 
mg
30 (24) 
mg
36 (24) 
mg
42 (24) 
mg
Stable max maintenance dose 42 (24) mg/day
17 kg to < 30 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (18) 
mg
30 (18) 
mg
Stable max 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 max maintenance dose 48 (36) mg/day
18 (18) 
mg
12 kg to < 17 kg
6 (6)
mg
12 (12) 
mg
18 (12) 
mg
24 (12) 
mg
Stable max maintenance dose 24 (12) mg/day
Titration Period
Dose adjustments should be made on all available information, including 
the patient and caregiver reports of adverse events and dyskinesia 
reduction, and the clinical assessment of safety and efficacy by the 
investigator
Maintenance Period
Wash out
Follow Up
 
 
 
 
  
 
 
 
 
 
 
 
   
  
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
Week 
3
Baseline
Day 
1
Week 
7
Week  
14
Day 
2
Day
 
Week 
33
Week 
27
Week 
1
Week 
2
Week 
4
Week 
5
Week 
6
Week 
21
Week 
40
Week 
46
Week 
54
Week 
55
Week 
53/ ET
Week 
53
In-clinic visit
Telephone call
Telephone contact 
with non-recording 
live video
 
AE=adverse event; CGI-I=Clinical Global Impression of Improvement; CYP2D6=cytochrome P450 2D6; D=day; ET=early termination; max=maximum; 
Wk=week. 
Note: If a patient is CYP2D6-impaired, the dose administered is indicated in parentheses. The dose of TEV-50717 should be increased 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. The maintenance period starts at week 7; however, study procedures and assessments are conducted between weeks 14 and 53/ET. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
47 
Figure 2: 
Flow Chart for Patient Screening and Day 1 Visit Assessments  
 
a Defined as any clinically significant change since the W15 visit of Study TV50717-CNS-30080 in health, concomitant medications, clinical assessments, 
laboratories, ECGs, or non-medical interventions. 
ECG=electrocardiogram; W15=week 15. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
48 
3.2. 
Planned Number of Patients and Regions  
Approximately 45 subjects who have completed parent Study TV50717-CNS-30080 are planned 
for enrollment into this study. 
This study is planned to be conducted in approximately 35 investigational centers in North 
America, Europe, and Asia.  
3.3. 
Justification for Study Design and Selection of Population  
Currently, there is no approved treatment available for DCP. DCP is a hyperkinetic motor 
impairment due to a non-progressive disturbance of brain function that occurs in the developing 
fetal or infant brain, generally before the age of 2 years. DCP has a major debilitating impact on 
the ability of the child with CP to further develop motor skills. 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 at 
the time when they enrolled in the parent study [Study TV50717-CNS-30080]), ie, 6 through 
20 years of age when they enroll in TV50717-CNS-30081 study, with DCP with predominant 
choreiform movement disorder, who have had non-progressive CP symptoms since infancy 
(≤2 years of age), and have completed Study TV50717-CNS-30080. The diagnosis of DCP is 
based on the Surveillance of Cerebral Palsy in Europe criteria (Cans 2000). “Predominant” in 
this instance indicates that the choreiform movement disorder is the main cause of impairment or 
distress.  
Study TV50717-CNS-30081 uses the same versions of scales as in the parent study, to maintain 
consistency of evaluations between these studies. As such, Study TV50717-CNS-30081 includes 
some scales that are designated for patients up to 18 years old, although potentially some patients 
who entered the parent study at age 18 will now be over 18 years old in this extension study. 
Consequently, the open-label study design was chosen for this Phase 3 study to determine 
whether long-term treatment with TEV-50717 results in favorable safety, tolerability, and 
efficacy findings in children and adolescents with DCP. 
3.4. 
Stopping Rules for the Study  
During the conduct of the study, serious adverse events will be reviewed (Section 7.1.5), as they 
are reported from the investigational centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor may 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). 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
49 
3.5. 
Schedule of Study Procedures and Assessments  
Study procedures and assessments with their time points are presented for screening and/or day 1 
in Table 4 and for the titration, maintenance, and follow-up periods in Table 5. During a visit, 
study procedures and assessments should be performed in the order specified in the study 
manual. 
Detailed by-visit information is provided in the sections following the table. Detailed 
descriptions of each assessment are provided in Section 6 (efficacy assessments) and Section 7 
(safety assessments). Study procedures and assessments by visit are listed in Appendix C. 
For COVID-19 updates, refer to Appendix M. 
Table 4: 
Study Procedures and Assessments: Screening and/or Day 1  
 
Day 1 
Between 1 and 
<2 weeks after 
Study TV50717-
CNS-30080 
week 15 visita 
Day 1  
Between 2 and 
≤4 weeks after Study 
TV50717-CNS-30080 
week 15 visit with no 
clinically significant 
changesb 
Day 1 
Between 2 and ≤4 weeks 
after Study TV50717-
CNS-30080 week 15 visit and 
with clinically significant 
changesb 
Study day 
Day 1/BL 
Day 1/BL 
Screening 
Day 1/BL 
(within 31 
days from 
screening) 
In-clinic visit  
X 
X 
X 
X 
Informed consent/assentc 
X 
X 
X 
 
Eligibility criteria 
X 
X 
X 
X 
Medical history and psychiatric 
history 
X 
X 
X 
 
Demographics 
[X] 
X 
X 
 
Vital signs and weightd,e 
[X]f 
Xe 
Xe 
Xe 
Physical examination 
[X] 
X 
X 
X 
Neurological examination 
[X] 
X 
X 
X 
Height 
[X] 
X 
X 
 
12-lead ECGg 
X 
X 
X 
 
Chemistry/hematology/urinalysis 
[X]h 
[X]h 
X 
 
Urine drug screen 
[X]h 
[X]h 
X 
 
β-HCG test 
Xi 
Xj 
Xk 
Xj 
MD-CRS part I (centrally read) 
X 
X 
 
X 
MD-CRS part II (centrally read) 
X 
X 
 
X 
MD-CRS part I (physician rated, 
with video recording)l 
X 
X 
 
X 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
50 
 
Day 1 
Between 1 and 
<2 weeks after 
Study TV50717-
CNS-30080 
week 15 visita 
Day 1  
Between 2 and 
≤4 weeks after Study 
TV50717-CNS-30080 
week 15 visit with no 
clinically significant 
changesb 
Day 1 
Between 2 and ≤4 weeks 
after Study TV50717-
CNS-30080 week 15 visit and 
with clinically significant 
changesb 
Study day 
Day 1/BL 
Day 1/BL 
Screening 
Day 1/BL 
(within 31 
days from 
screening) 
MD-CRS part II (physician rated, 
with video recording)l 
X 
X 
 
X 
CGI-S (global, physician rated) 
X 
X 
 
X 
PEDI-CAT (ADL, caregiver 
completed, content-balanced 
version) 
X 
X 
 
X 
UHDRS-TMC (centrally read) 
X 
X 
 
X 
UHDRS-TMD (centrally read) 
X 
X 
 
X 
UHDRS-TMS (physician rated) 
X 
X 
 
X 
UHDRS-TMC (physician rated) 
X 
X 
 
X 
UHDRS-TMD (physician rated) 
X 
X 
 
X 
COPM (physician rated) 
X 
X 
 
X 
C-SSRS (children’s 
baseline/screening)m 
Xn 
Xn 
Xn 
Xn 
C-SSRS (children’s since last 
visit)m 
X 
X 
X 
X 
ESRS (subscales I and II) 
X 
X 
 
X 
CBCL 
Xo 
Xo 
Xo 
Xp 
ESS 
X 
X 
X 
X 
Assess adverse events 
X 
X 
X 
X 
Concomitant medicationsq 
X 
X 
X 
X 
Dispense TEV-50717r 
X 
X 
 
X 
Contact IWRS 
X 
X 
 
X 
a Assessments indicated in brackets by “[X]” are representative of data carried over from week 15/16 of Study 
TV50717-CNS-30080, whichever is more current. Any scales/questionnaires administered at the week 16 visit for 
Study TV50717-CNS-30080 do not need to be repeated if the day 1 visit of Study TV50717-CNS-30081 is the 
same day as the week 16 visit Study TV50717-CNS-30080. 
b Defined as clinically significant change since the week 15 visit of Study TV50717-CNS-30080 in health, 
concomitant medications, clinical assessments, laboratories, ECGs, or non-medical interventions, in the judgment 
of the investigator. 
c Informed consent/assent, as appropriate, based on the patient’s age, will be obtained from the patient/parent/legally 
acceptable representative and caregiver (as applicable) at baseline/day 1 or screening visit (whichever comes first), 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
51 
and before any study procedures are performed. The informed consent/assent process can begin within 4 weeks 
before possible participation in the open-label study to allow patients adequate time to engage and ask questions. 
d 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). 
e Weight must be measured with shoes and outerwear off. Before pulse and BP are measured, the patient must be in 
a supine or semi-erect/seated position and resting for at least 3 minutes (the same position and arm/leg should be 
used each time vital signs are measured for a given patient). 
f Orthostatic blood pressure and orthostatic pulse rate will be measured at day 1. Weight measurements will be 
carried over from the week 16 visit of Study TV50717-CNS-30080. All other vital sign assessments (respiratory 
rate and body temperature) will be carried over from the week 16 visit of Study TV50717-CNS-30080, if the day 1 
visit in Study TV50717-CNS-30081 is on the same day as the week 16 visit of Study TV50717-CNS-30080. 
Otherwise, these vital sign assessments will be performed at day 1. 
g All ECGs will be performed after at least a 5-minute rest in a supine or semi-supine position. 
h These data will be taken from the week 15 visit of Study TV50717-CNS-30080, unless more current data from the 
week 16 visit are available. 
i For females who are postmenarchal or ≥12 years of age. If the day 1 visit in Study TV50717-CNS-30081 is on the 
same day as the week 16 visit of Study TV50717-CNS-30080, the results of β-HCG tests in urine will be carried 
over from the week 16 visit.  Otherwise, the β HCG tests in urine will be administered at day 1. 
j For females who are postmenarchal or ≥12 years of age, a β-HCG test in urine will be administered. A patient with 
a positive β-HCG test in urine cannot be enrolled until a β-HCG test in serum has been performed and is negative. 
k For females who are postmenarchal or ≥12 years of age, a β-HCG test in serum will be administered. 
l MD-CRS parts I and II assessments are done locally at the investigational center by the investigator, video 
recorded. In certain instances, based on the experience of the rater, certain non-physicians may be approved to rate 
the MD-CRS. 
m Children 13 years of age and under must be interviewed in conjunction with the caregiver. For children over 
13 years of age, caregiver involvement is strongly encouraged. Questions should be directed to the child, but the 
caregiver should be encouraged to add relevant information. The children’s C-SSRS questionnaire will only be 
presented to patients aged ≥12 years. 
n If the patient turned 12 years old during or after Study TV50717-CNS-30080, but before screening or day 1 visit 
of Study TV50717-CNS-30081, whichever comes first, the C-SSRS baseline/screening scale is administered. If 
the patient turns 12 years old during the study, C-SSRS baseline/screening will be completed as the initial 
assessment and the C-SSRS Since Last Visit will be completed as per Table 5. 
o A full CBCL assessment (Competence Scale [Parts I to VII] and a Syndrome Scale [behavioral items]) will be 
performed. 
p Only the CBCL Syndrome Scale (behavioral items) will be performed. 
q Patients and/or caregivers will be instructed during the course of the study to notify the investigator if any new 
medication is prescribed or if there is any change in current medications, including over-the-counter medications. 
Any prescribed medication should be reviewed with the investigator. 
r TEV-50717 will be dispensed once all procedures and eligibility-related assessments are completed and patient 
eligibility is confirmed. 
ADL=activities of daily living; β-HCG=beta-human chorionic gonadotropin; BL=baseline visit; BP=blood pressure; 
CBCL=Child Behavior Checklist (for ages 6 to 18 years); CGI-S=Clinical Global Impression of Severity; 
COPM=Canadian Occupational Performance Measure; 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); IWRS=Interactive Web Response Systems; MD-CRS=Movement 
Disorder-Childhood Rating Scale; PEDI-CAT=Pediatric Evaluation Disability Inventory-Computer Adapted Test; 
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; W15=week 15; W16=week 16. 
Note: 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-30081 Open-RECLAIM-DCP: Order of 
scales administration/completion document). The investigator should review the scales in a timely manner for any 
potential reporting of adverse events and document this review accordingly. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
52 
Table 5: 
Study Procedures and Assessments: Titration, Maintenance, and Follow-up Periods  
 
Titration 
Maintenancea  
Follow-up 
U 
Study weekb  
1 
 
2 
3 
4 
5 
6 
7 
14 
21 
27 
33 
40 
46 
53/ 
ETc 
54 
55d 
 
Study day 
7 
14 
21 
28 
35 
42 
49 
98 
147 
189 
231 
280 
322 
371 
378 
385 
 
Visit window (days) 
+1 
day 
from 
Day 
1/BL  
±1 
day 
from 
Day 
1/BL 
±3 days from Day 1/BL and  
≥5 days from last dose change 
±7 days from Day 1/BL and  
≥5 days from last dose change 
±2 
days 
from 
week 
53 
±2 
days 
from 
week 
54 
 
In-clinic visit 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Telephone contacte  
X 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
Xf 
Evaluate/adjust TEV-50717g  
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
X 
X 
X 
X 
 
 
 
X 
Vital signs and weighti  
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Physical examination 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Xf 
Neurological examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Xf 
Height 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
12-Lead ECGj  
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
Chemistry/hematology/urinalysis 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
Urine drug screen 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Xf 
β-HCG testk  
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
MD-CRS part I (centrally read)l   
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
MD-CRS part II (centrally read) l 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
MD-CRS part I (physician rated with 
video recording) m  
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
MD-CRS part II (physician rated with 
video recording)m 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CaGI-I (global, caregiver rated) n  
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
CGI-I (global, physician rated) o  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
53 
 
Titration 
Maintenancea  
Follow-up 
U 
Study weekb  
1 
 
2 
3 
4 
5 
6 
7 
14 
21 
27 
33 
40 
46 
53/ 
ETc 
54 
55d 
 
Study day 
7 
14 
21 
28 
35 
42 
49 
98 
147 
189 
231 
280 
322 
371 
378 
385 
 
Visit window (days) 
+1 
day 
from 
Day 
1/BL  
±1 
day 
from 
Day 
1/BL 
±3 days from Day 1/BL and  
≥5 days from last dose change 
±7 days from Day 1/BL and  
≥5 days from last dose change 
±2 
days 
from 
week 
53 
±2 
days 
from 
week 
54 
 
CGI-S (global, physician rated)o 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
PEDI-CAT (ADL, caregiver 
completed, content-balanced version) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
UHDRS-TMC (centrally read)l 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
UHDRS-TMD (centrally read)l 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
UHDRS-TMS (physician rated) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
UHDRS-TMC (physician rated) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
UHDRS-TMD (physician rated) 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
COPM (physician rated) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
C-SSRS (children’s since last visit)o 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
ESRS (subscales I and II) 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
CBCLp 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
ESS 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Xf 
Dispense TEV-50717q 
 
 
Xr 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Xf 
Collect TEV-50717 
 
 
Xr 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
Xf 
Assess TEV-50717 accountability/ 
compliance/supplys 
X 
X 
Xr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xf 
Assess adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample collection for 
TEV-50717 concentrationt 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
54 
 
Titration 
Maintenancea  
Follow-up 
U 
Study weekb  
1 
 
2 
3 
4 
5 
6 
7 
14 
21 
27 
33 
40 
46 
53/ 
ETc 
54 
55d 
 
Study day 
7 
14 
21 
28 
35 
42 
49 
98 
147 
189 
231 
280 
322 
371 
378 
385 
 
Visit window (days) 
+1 
day 
from 
Day 
1/BL  
±1 
day 
from 
Day 
1/BL 
±3 days from Day 1/BL and  
≥5 days from last dose change 
±7 days from Day 1/BL and  
≥5 days from last dose change 
±2 
days 
from 
week 
53 
±2 
days 
from 
week 
54 
 
Concomitant medicationsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact IWRS 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
a The maintenance period starts at week 8; however, study procedures and assessments are conducted between weeks 14 and 53/ET. 
b Assessment to occur at the end of study week, unless stated otherwise. 
c For patients who withdraw prematurely, an ET visit should be conducted as soon as possible after the last dose of TEV-50717. All patients who discontinue 
early will have a follow-up telephone contact for safety evaluation 2 weeks after their last dose of TEV-50717; evaluations will be as described for the week 55 
visit.  
d This visit is a telephone contact for safety evaluation. 
e Telephone contacts at weeks 1, 2, 4, 5, 6, 21, 33, and 46 will be conducted with non-recording live video. Telephone contact at week 55 is a phone contact only 
(ie, no live video streaming). 
f Assessment to be completed at investigator’s discretion. 
g Dose increases may not occur more frequently than every 5 days, except for patients ≥40 kg. For patients ≥40 kg, the first dose increase should be performed in 
an interval less than 5 days, only once, on day 3. 
h Patients will continue to receive their maintenance dose from week 8 to week 53. Dose reductions or suspensions for adverse events are allowed. 
i 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/leg should be used each time vital signs are measured for a given patient). 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) and should be measured at W14 and 
W53/ET. 
j All ECGs will be performed after at least 5-minute rest in a supine or semi-supine position. 
k For females who are postmenarchal or ≥12 years of age, a urine pregnancy test will be administered at weeks 14, 27, 40, and 54/follow-up visit while a serum 
pregnancy test will be administered at week 53/ET, and if clinically indicated. 
l Central reading is based on the video recordings, and is done in a blinded manner 
m MD-CRS parts I and II assessments are done locally at the investigational center by the investigator, video recorded. In certain instances, based on the 
experience of the rater, certain non-physicians may be approved to rate the MD-CRS.   
n CaGI-I is to be assessed before all other investigator-rated scales during visits where CaGI-I is collected. 
o Children 13 years of age and under must be interviewed in conjunction with the caregiver. For children over 13 years of age, caregiver involvement is strongly 
encouraged. Questions should be directed to the child, but the caregiver should be encouraged to add relevant information. The children’s C-SSRS 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
55 
questionnaire will only be presented to patients aged ≥12 years. Children who turn 12 years old during the study will be administered C-SSRS 
(baseline/screening) as initial assessment during the study. 
p A full CBCL assessment (Competence Scale [Parts I to VII] and a Syndrome Scale [behavioral items]) will be performed at week 53/ET. The Syndrome Scale 
part of the CBCL assessment will be performed at weeks 3, 7, 14, 27, 40, 53/ET visit, and 54/follow-up visits. 
q 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. 
r During the week 3 visit, the investigator (or designee) will make sure the patient receives the evening dose to complete the week 3 dosing for that day. Refer to 
the pharmacy manual for further details. 
s 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. 
t Patients experiencing an adverse event leading to discontinuation of TEV-50717, or experiencing any other adverse event, should have a single blood sample 
collected for the measurement of TEV-50717, α-HTBZ and β HTBZ concentrations, if possible. This should be done (at the discretion of the investigator) as 
soon as possible after the onset of the ongoing adverse event and within 48 hours after the last dose intake in the case of TEV 50717 discontinuation. To permit 
the assessment of a potential relationship of the adverse event and plasma concentration, an estimate of the date and time of the last dose intake of study drug 
should be recorded along with the date and time of the sample collection. If the estimate of the dose intake cannot be established within a 2-hour window, then 
a blood sample should not be obtained. 
u Patients and/or caregivers will be instructed during the course of the study to notify the investigator if any new medication is prescribed, or if there is any 
change in current medication, including over-the-counter medications. Any prescribed medication should be reviewed with the investigator. 
ADL=activities of daily living; β-HCG=beta human chorionic gonadotropin; BL=baseline visit; BP=blood pressure; CaGI-I=Caregiver Global Impression of 
Improvement; CBCL=Child Behavior Checklist (for ages 6 to 18 years); CGI-I=Clinical Global Impression of Improvement; CGI-S=Clinical Global Impression 
of Severity; COPM=Canadian Occupational Performance Measure; 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); ET=early termination visit; 
HTBZ= dihydrotetrabenazine (active metabolite); IWRS=Interactive Web Response Systems; MD-CRS=Movement Disorder-Childhood Rating Scale; PEDI-
CAT=Pediatric Evaluation Disability Inventory-Computer Adapted Test; 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. 
Note: 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-30081 Open-RECLAIM-DCP: Order of scales administration/completion document). The investigator should review the scales in a timely 
manner for any potential reporting of adverse events and document this review accordingly. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
56 
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, 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. 
4.1. 
Patient Inclusion Criteria  
Patients who meet the criteria below are eligible to be included in the study. 
a. Patient has completed week 16 of Study TV50717-CNS-30080. 
b. Patient weighs at least 12 kg (26 lbs) on day 1 of this study. 
c. Patient is able to swallow TEV-50717 tablet whole. 
d. Patient and caregiver are willing to adhere to TEV-50717 regimen and comply with 
all study procedures. 
e. Patient is in good general health, as indicated by medical and psychiatric history and 
physical and neurological examination. 
f. 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. 
g. For a patient who is a minor, the parent(s)/legally acceptable representative(s) 
provides written informed consent, and the patient provides assent (in accordance 
with local regulations). Adult patients provide written informed consent (in 
accordance with local regulations), and the legally acceptable representative will sign, 
if needed. 
In this study, eligible patients with dyskinetic cerebral palsy 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. 
h. A caregiver provides written informed consent after being assigned the role by an 
adult patient or if this role is delegated by the parent/legally acceptable representative 
of a patient who is a minor. 
i. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative β-HCG test on day 1 or are sterile. Definitions of sterile, 
premenarchal, and postmenarchal are given in Appendix F. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
57 
j. 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 day 1) and for 30 days after last dose of 
TEV-50717. 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: 
a. Patient has clinically significant depression at screening or day 1 of this study. 
− Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose 
for at least 6 weeks before screening or day 1 (whichever comes first) and 
anticipated to remain stable (dose and frequency) within the study duration. 
b. Patient has a history of suicidal intent or related behaviors based on medical or 
psychiatric history or the C-SSRS at screening visit, if performed, or at the day 1 
visit, as applicable according to the patient’s age: 
– intent to act on suicidal ideation with a specific plan, irrespective of level of 
ambivalence, at the time of suicidal thought 
– suicidal preparatory acts or behavior 
c. Patient has a history of a previous actual, interrupted, or aborted suicide attempt 
based on medical or psychiatric history or the C-SSRS at screening visit, if 
performed, or at the day 1 visit, as applicable according to the patient’s age. 
d. Patient has a first-degree relative who has completed suicide. 
e. Patient has received any of the following concomitant medications within the 
specified exclusionary windows from screening or day 1 (whichever comes first) of 
this study: 
– within 30 days: tetrabenazine or valbenazine  
– within 21 days: reserpine 
– within 14 days: levodopa, dopamine agonists, and monoamine oxidase inhibitors   
f. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic 
stimulation, or transcranial direct current stimulation for treatment of abnormal 
movements or CP since the week 15 visit of Study TV50717-CNS-30080, or the 
patient is not in a stable clinical condition.   
g. Patient had a surgical procedure since the week 15 visit of Study TV50717-
CNS-30080 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. 
h. Patient has a severe mental disability or an unstable or serious medical illness (eg, 
epilepsy) that, in the opinion of the investigator, could jeopardize or would 
compromise the patient’s ability to participate in this study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
58 
i. Patient has a QT interval (QTc) corrected for heart rate using Fridericia’s formula 
(QTcF) value >450 msec on 12-lead ECG at screening or day 1 (whichever comes 
first) of this study. 
j. Patients with a history of torsade de pointes, congenital long QT syndrome, 
bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure. 
k. Patient has evidence of hepatic impairment, as indicated by the following: 
– aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× the 
upper limit of the normal range (ULN) at the week 15 or week 16 visit of 
Study TV50717-CNS-30080 or screening of this study, as applicable 
– alkaline phosphatase (ALP) or total bilirubin (Tbil) >2×ULN at the week 15 or 
week 16 visit of Study TV50717-CNS-30080 or screening of this study, as 
applicable 
− 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 AST, ALT, ALP, and Tbil 
parameters that do not meet the above laboratory criteria for exclusion based on 
hepatic impairment must be approved for enrollment by the medical monitor. 
l. Patient has evidence of clinically significant renal impairment, indicated by a serum 
creatinine >1.5×ULN at the week 15 or week 16 visit of Study TV50717-CNS-30080 
or screening of this study, as applicable. 
m. Patient has a known allergy to any of the components of TEV-50717. 
n. Patient has participated in an investigational drug or device study other than 
Study TV50717-CNS-30080 and received IMP/intervention within 30 days or 5 drug 
half-lives of day 1 of this study, whichever is longer. 
o. Patient is pregnant or breastfeeding. 
p. Patient has a history of or acknowledges alcohol or substance abuse. 
q. Patient has a positive urine drug screen test result since the week 15 or week 16 visit 
of Study TV50717-CNS-30080 or screening (as applicable) of this study (with 
exception of medications listed in Table 11 of Appendix H or a justified medical 
explanation). Any request to include a patient with a positive urine drug screen test 
result should be discussed with, and approved by, the medical monitor.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
59 
4.3. 
Withdrawal Criteria and Procedures for the Patient  
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the IMP at any time. The investigator also has 
the right to withdraw a patient from the IMP in the event of intercurrent illness, adverse events, 
pregnancy (see Section 7.3), or change in concomitant treatment (see Appendix H); patient 
engages in alcohol or other substance abuse; patient or parent(s)/legally acceptable representative 
withdraws consent or requests discontinuation from the IMP; the sponsor requests withdrawal of 
the patient or other reasons concerning the health or well-being of the patient; or in the event of 
lack of cooperation.  
If a patient experiences signs of suicidal ideation or behavior (Section 7.10), the investigator 
should consult with the medical monitor to determine whether the patient should continue in the 
study. If a patient reports any suicidal behavior that is an actual attempt as assessed in the 
children’s C-SSRS, the patient will be evaluated immediately by the investigator, referred for 
psychiatric evaluation, and terminated from the study. 
Patients are expected to participate in this study for its entire duration and perform the scheduled 
visits and procedures.  
Patients will be discontinued from the study for the following situations: 
• Laboratory evidence of diminished hepatic function, defined as an AST or ALT 
>2.5×ULN and ALP or total bilirubin >2×ULN 
• Patient develops neuroleptic malignant syndrome  
If a post-treatment QTcF value >500 msec or change from screening or day 1 >60 msec is found, 
the investigator should repeat the ECG assessment twice and then compare the last pre-treatment 
QTcF value to the average of the 3 post-treatment QTcF values. TEV-50717 must be stopped for 
any confirmed post-treatment QTcF average value >500 msec or average increase from 
screening or day 1 >60 msec. In addition, a patient may be withdrawn from the study as 
described in Section 3.4, Section 3.5, and Appendix C. 
Should a patient decide to withdraw after administration of TEV-50717, or should the 
investigator decide to withdraw the patient, all efforts will be made to complete and report all 
observations up to the time of withdrawal. A complete final evaluation at the time of the 
patient’s withdrawal should be made and an explanation given as to why the patient is 
withdrawing or being withdrawn from TEV-50717. 
For patients who withdraw prematurely, an ET visit should be conducted as soon as possible 
after the last dose of TEV-50717. All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after their ET visit; evaluations will be as 
described for the week 55 visit. 
Patients experiencing an adverse event leading to discontinuation of TEV-50717, or experiencing 
any other adverse event, should have a single blood sample collected for the measurement of 
TEV-50717, α-HTBZ and β-HTBZ concentrations, if possible. This should be done (at the 
discretion of the investigator) as soon as possible after the onset of the ongoing adverse event 
and within 48 hours after the last dose intake in the case of TEV-50717 discontinuation. To 
permit the assessment of a potential relationship of the adverse event and plasma concentration, 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
60 
an estimate of the date and time of the last dose intake of study drug should be recorded along 
with the date and time of the sample collection. If the estimate of the dose intake cannot be 
established within a 2 hour window, then a blood sample should not be obtained. 
The reason for and date of withdrawal from TEV-50717 and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed to the 
case report form (CRF). If a patient withdraws consent, every attempt will be made to determine 
the reason. If the reason for withdrawal is an adverse event or a clinically significant abnormal 
laboratory test result, monitoring will be continued at the discretion of the investigator (eg, until 
the event has resolved or stabilized, until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to TEV-50717 or study procedure is 
made). The specific event or test result must be recorded on the source documentation and 
transcribed to the CRF. 
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. 
For COVID-19 updates, refer to Appendix M. 
4.4. 
Replacement of Patients  
A patient who is enrolled but does not complete the treatment period (from day 1 to week 53/ET) 
will not be replaced. 
4.5. 
Rescreening  
A patient who is screened but not enrolled (eg, because inclusion criteria were not met, exclusion 
criteria were 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 ICF will need to be re-signed. 
4.6. 
Screening Failure  
Screening failures are defined as participants who consent to participate in the clinical study but 
are subsequently not enrolled in the study. Minimal information includes, but is not limited to, 
demography, screening failure details, eligibility criteria, and any serious adverse events. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
61 
5. 
TREATMENTS  
5.1. 
Investigational Medicinal Products Used in the Study  
IMP is defined as the test IMP. There is no reference IMP or placebo 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. TEV-50717 is 
coated with a 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-, and 12-mg, or other commercially available, dose strengths, by bottle and 
labeled according to applicable regulatory guidelines. Each bottle pack (60-count tablets 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 8, the IB for TEV-50717, and the Prescribing 
Information for TEV-50717. 
5.1.1.1. 
Starting Dose and Dose Levels  
TEV-50717 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 day 1 are shown in Table 6. The maximum daily dose is determined by body weight at 
day 1 and CYP2D6 impairment status (see Table 7). Patients will be classified as CYP2D6 
impaired if they are receiving a strong CYP2D6 inhibitor.  
TEV-50717 oral tablets are 6, 9, and 12 mg, or other commercially available, dose strengths. 
Each dose strength will have a marking corresponding to the dose strength on the label. TEV-
50717 will be supplied as 60-count tablets per bottle. Each dose strength will be a colored tablet 
with a marking of “SD” and the corresponding strength. 
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.  
If a patient experiences a “clinically significant” adverse event that is attributed to TEV-50717, 
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 initial dose will be 
established for the maintenance period. Dose adjustments of TEV-50717 (upward or downward) 
may be made during the maintenance period, if necessary, based on efficacy, safety, and/or 
tolerability considerations but not more often than every 5 days and only in increments of 6 mg 
up to the maximum allowed dose (Table 6 and Table 7). As during titration, dose adjustments 
should be made based on all available information. The dose of TEV-50717 may be reduced or 
suspended if a patient experiences an adverse event or tolerability finding during the 
maintenance period and the investigator believes a dose reduction or suspension is warranted. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
62 
TEV-50717 will be administered as follows: 
• TEV-50717 cannot be crushed or split but should be swallowed whole; the 
TEV-50717 tablets should 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 and titration will be based on body weight at the day 1 visit and CYP2D6 
impairment status, as shown in Table 6 and Table 7, respectively. 
• The starting dose is 6 mg in all patients. This dose will be administered in the 
morning on days 2 and 3, followed by evening administration starting on day 3 for the 
remainder of the 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. 
• Dose increases may not occur more frequently than every 5 days, except for patients 
≥40 kg. For patients ≥40 kg, 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 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 TEV-50717 should be adjusted according to 
Table 6 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 a telephone or in-clinic visit. 
For COVID-19 updates, refer to Appendix M. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
63 
Table 6: 
Maximum Daily Dose of TEV-50717 by Week and Weight Category on Day 1 
for Titration at Study Initiation  
 
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 mg 
18 mg 
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 a 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 5 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, 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 7). 
CYP2D6=cytochrome P450 2D6. 
 
Table 7: 
Maximum Daily Dose of TEV-50717 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. 
Note: Patients will be classified as CYP2D6 impaired if they are receiving a strong CYP2D6 inhibitor. Strong 
CYP2D6 inhibitors include paroxetine, fluoxetine, and bupropion. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
64 
Table 8: 
Investigational Medicinal Products Used in the Study  
IMP Name 
TEV-50717 Test IMP 
Trade name and INN, if applicable, 
or company-assigned number 
TEV-50717 (SD-809, AUSTEDO®, deutetrabenazine) 
Formulation 
Modified release solid oral dosage form (tablet with film coating) 
Unit dose strength(s)/Dosage level(s) 
TEV-50717 tablets are 6, 9, and 12 mg, or other commercially available, 
dose strengths, all of which are identical in size and shape. Each strength 
will be a colored tablet with a marking of “SD” and the corresponding 
strength. Test IMP will be supplied in 60-count tablets per bottle. 
Route of Administration 
Oral 
Packaging 
Test 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 
Wiley Post Way 
Salt Lake City, UT 84116 
Storage conditionsa 
Stored at controlled room temperature, 20°C-25°C (68°F-77°F) 
IMP=Investigational Medicinal Product; INN=International Nonproprietary Name. 
a For additional information related to IMP storage conditions, please refer to the Pharmacy Manual. 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs  
For COVID-19 updates, refer to Appendix M. 
5.2.1. 
Storage and Security  
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all TEV-50717 received and any discrepancies are reported and resolved before 
use of TEV-50717. 
TEV-50717 must be stored 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. For additional information related to IMP storage conditions, please refer to the 
Pharmacy Manual. 
5.2.2. 
Labeling  
Supplies of TEV-50717 will be labeled according to the current International Council for 
Harmonisation (ICH) 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 TEV-50717 shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
65 
The investigator is responsible for ensuring that deliveries of TEV-50717 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 TEV-50717 and only authorized staff at the 
investigational center may supply or administer TEV-50717. All TEV-50717 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 TEV-50717 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 TEV-50717 accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A record of IMP accountability (ie, TEV-50717 and other study materials received, used, 
unused, retained, returned, or destroyed) must be prepared and signed by the principal 
investigator or designee, with an account given for any discrepancies. Empty, partially used, and 
unused bottles of TEV-50717 that are not destroyed at the site will be returned to the sponsor or 
designee, as agreed with the sponsor. 
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 parent 
Study TV50717-CNS-30080 in DCP and the ongoing TV50717-CNS-30046 Phase 2/3 and 
TV50717-CNS-30060 Phase 3 studies of TEV-50717 in TS. 
5.4. 
Treatment after the End of the Study  
All patients should continue their usual treatment regimen up to week 53 visit (ie, the last dose 
can be administered until visit completion, if applicable). No dosing will be given after the 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
66 
week 53 visit. All patients will discontinue TEV-50717 at the week 53 visit and will return 
1 week later (week 54) for evaluation of safety. Patients will have a follow-up telephone contact 
(no live video streaming) for safety evaluation 1 week after the end of the washout period 
(2 weeks after their last dose of TEV-50717) (week 55). The end of study is defined as the date 
of the week 55 follow-up telephone contact of the last participant. 
There are no plans to provide further treatment to patients upon completion of the study. An 
extension to the study may be considered on an annual basis. 
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 day 1 may be enrolled into this study, the removal of strong CYP2D6 inhibitors 
during treatment is discouraged, as this would have an effect on exposure to active circulating 
drug. If the removal of a strong CYP2D6 inhibitor is required from a clinical perspective, the 
medical monitor should be contacted so that an appropriate change in TEV-50717 dosage can be 
made. The addition of a strong CYP 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 illicit drugs 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 
TEV-50717, and for 14 days after the last dose. 
5.6. 
Prior and Concomitant Medication or Therapy  
Any prior or concomitant therapy, medication, or procedure a patient receives during 
TEV-50717 administration and up to the end of the study period, including follow-up, will be 
recorded on the CRF Generic or trade name, indication, and dosage will be recorded. The 
sponsor will encode all medication according to the World Health Organization drug dictionary. 
At each clinic visit after screening or day 1 (whichever comes first), the investigator will ask 
patients and/or caregivers whether the patient has taken any new medications (other than TEV-
50717) or has any change in current medications, including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, since the previous visit. Patients and/or caregivers 
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 there is any change in current medications, 
including over-the-counter medications. Any prescribed medication should be reviewed with the 
investigator. Indication, dosage, and start and end dates should be entered on the CRF.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
67 
The medical monitor must be contacted if a patient is receiving (or has to begin or stop receiving 
during the study) a medication that is associated with QTc prolongation or that is a known strong 
CYP inhibitor. Allowed strong CYP inhibitors at day 1 are shown in Appendix H, Table 11. The 
addition of a strong CYP inhibitor is prohibited during the study. 
Prohibited medications that are associated with QTc prolongation are listed in Appendix H, 
Table 12.  
Concomitant medication will be monitored throughout the study.  
5.7. 
Procedures for Monitoring Patient Compliance  
The investigator will be responsible for monitoring patient compliance until completion of the 
IMP administration according to the protocol or discontinuation from the IMP. A check of 
compliance with TEV-50717 intake will be performed during each in-clinic visit and telephone 
contact and will be documented in each patient’s file. TEV-50717 accountability records will be 
completed during each in-clinic visit. 
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 (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 TEV-50717 
will be assessed as required (Section 5.1.1.1). 
5.8. 
Temporary Discontinuation of Investigational Medicinal Product  
Refer to Table 5 for data to be collected at the time of TEV-50717 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 TEV-50717, 
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 initial dose will be 
established for the maintenance period. The dose of TEV-50717 may be reduced or suspended if 
a patient experiences an adverse event or tolerability finding during the maintenance period and 
the investigator believes a dose reduction or suspension is warranted. 
Dose adjustments of TEV-50717 (upward or downward) may be made during the maintenance 
periods, if necessary, based on efficacy, safety, and/or tolerability considerations but not more 
often than every 5 days and only in increments of 6 mg up to the maximum allowed dose 
(Table 6 and Table 7). After the dose modification, the patients will remain at the modified dose 
unless further dose adjustments are warranted, 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. The reason for a dose 
reduction must be clearly documented. If the determination that a patient requires a dose 
modification is made during a telephone contact, an unscheduled clinic visit should be conducted 
as soon as practicable thereafter. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
68 
Suspension of TEV-50717 treatment for up to 1 week, if warranted, is allowed. If a patient’s 
serum potassium or magnesium falls below the lower limit of normal, TEV-50717 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. 
TEV-50717 treatment may only be restarted once serum potassium and/or magnesium levels 
have normalized. 
If the patient restarts TEV-50717 within 7 days of suspension, the full dose of TEV-50717 may 
be resumed without titration at the same dose level or 1 dose lower (last tolerated dose). 
Suspension of TEV-50717 treatment for adverse events must be reviewed with the medical 
monitor before TEV-50717 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 suspension is allowed during the titration period and the maintenance period. Patients who 
restart TEV-50717 treatment will remain at the current dose unless further dose adjustments are 
warranted, and will follow the visit schedule as outlined in the protocol.  
If a dose suspension occurs before a scheduled clinic visit, an unscheduled visit should be 
scheduled as soon as possible. If the determination that a patient requires a dose suspension is 
made during a telephone contact, an unscheduled clinic visit should be conducted as soon as 
practicable thereafter. 
The patients who restart TEV-50717 treatment will follow the visit schedule as outlined in 
Table 5. Patients who withdraw from the study will proceed as described in Section 4.3. 
5.9. 
Randomization and Blinding  
This is an open-label, single-arm study, and there is no blinding. 
5.10. 
Maintenance of Randomization and Blinding  
5.10.1. 
Maintenance of Randomization  
Not applicable. 
5.10.2. 
Blinding and Unblinding  
This is an open-label, single-arm study with no blinding. 
5.10.3. 
Data Monitoring Committee  
There will be an Independent Data Monitoring Committee (IDMC) in this study. Details are 
given in Appendix B. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
69 
During the conduct of this study, an IDMC will review accumulating safety data on a regular 
basis to ensure the continuing safety of the study patients and to review any study conduct issues. 
The conduct and specific details regarding the IDMC sessions are outlined in the IDMC Charter. 
5.11. 
Total Blood Volume  
The total blood volume to be collected for each patient in this study is approximately 77.5 mL. 
Details are provided in Appendix I. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
70 
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 
COPM. 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-30081 
Open-RECLAIM-DCP: Order of scales administration/completion document).  
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. 
Assessments of Efficacy  
6.1.1. 
Movement Disorder-Childhood Rating Scale  
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, 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. 
The MD-CRS part I evaluates the 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 II total score 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). 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
71 
region. The minimum score is 0 (absent) and the maximum score is 28 (marked/prolonged). 
Assessment of MD-CRS part II items will be based solely on chorea in this study.   
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. 
The MD-CRS (with video recording) will be administered at the day 1 visit (Table 4) and at 
week 14, week 27, week 40, week 53/ET, and week 54/follow-up visits (Table 5). 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.  
Video review of MD-CRS parts I and II for chorea at day 1, week 27, week 53/ET, and 
week 54/follow-up visits (Table 4 and Table 5) will be assessed 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 will not be disclosed to the investigational site. 
Central reading details will be provided in a separate charter. 
6.1.2. 
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 5). 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 in this study); 
2=much improved; 
3=minimally improved; 
4=no change from day 1 (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 14, week 27, week 40, week 53/ET, and week 54/follow-up 
visits. 
6.1.3. 
Clinical Global Impression of Improvement Scale  
Each time the patient is seen during the treatment period (ie, from day 1 to week 53/ET, 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 day 1 visit (Busner and Targum 2007). The CGI-S score obtained at the day 1 visit 
(see Section 6.1.4) serves as a good basis for making this assessment. The CGI-I is a clinician-
reported outcome that uses a 7-point Likert scale that allows the clinician to compare the 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
72 
patient’s condition at the visit to the day 1 condition as follows (with anchor points for choosing 
the most appropriate improvement level): 
1=very much improved since the initiation of treatment in this study (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 day 1 (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 in this study (severe exacerbation of 
symptoms and loss of functioning). 
The CGI-I will be administered at the in-clinic visits (week 3, week 7, week 14, week 27, week 
40, week 53/ET, and week 54/follow-up). Patients will also be assessed for CGI-I during 
telephone contacts (with non-recording live video) at the week 1, week 2, week 4, week 5, 
week 6, week 21, week 33, and week 46.  
6.1.4. 
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); 
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 administered at the day 1 visit (Table 4) and administered at week 14, week 27, week 
40, week 53/ET, and week 54/follow-up visits. Input from the caregiver is permitted. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
73 
6.1.5. 
Pediatric Evaluation Disability Inventory-Computer Adapted Test (Activities of 
Daily Living, Caregiver Completed, Content-Balanced Version  
The 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 day 1 
and at the week 27 and week 53/ET visits. 
6.1.6. 
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 UHDRS-TMS comprises 15 items and assesses eye movements, speech, alternating 
hand movements, dystonia, chorea, and gait. The minimum score is 0 (absent) and the maximum 
score is 108 (worst) (Huntington Study Group 1996). 
The UHDRS-TMS is administered at the day 1, week 14, week 27, week 40, and week 53/ET 
visits. 
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). 
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) (Huntington Study Group 1996). 
The UHDRS-TMC (physician rated) score and UHDRS-TMD (physician rated) score will be 
determined from the UHDRS-TMS assessment. The protocol refers to UHDRS-TMC and 
UHDRS-TMD 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-TMC and UHDRS-TMD. 
A central reading of the UHDRS-TMC and UHDRS-TMD will be performed at baseline/day 1 
and at weeks 27, 53/ET, and 54 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. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
74 
6.1.7. 
Canadian Occupational Performance Measure  
The COPM has been designed to assess patient outcomes in the areas of self-care, productivity 
and leisure. Using a semi-structured interview, the COPM is a 5-step process which measures 
individual, patient-identified problem areas in daily function. Two scores, for performance and 
satisfaction with performance, are obtained (Law et al 1990). 
The COPM is administered at day 1 and at the week 27 and week 53/ET visits. 
See Table 5 for a detailed description of assessments and procedures. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
75 
7. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, vital signs measurements, ECG findings, clinical laboratory test results, physical 
examination findings (including body weight and height measurements), neurological 
examination, safety rating scales, medication errors, and use of concomitant medications. 
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 which does not necessarily have to have a causal relationship with 
this treatment. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to 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 
(Note: Abnormal laboratory or diagnostic test results at day 1 that preclude a patient 
from entering the study or receiving study treatment are not considered adverse 
events.) 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
76 
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 TEV-50717.  
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 TEV-50717. For serious adverse events, the serious adverse event form must be completed, 
and the serious adverse event must be reported immediately (Section 7.1.5.3.1). The investigator 
does not need to actively monitor patients for adverse events after the defined period. 
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; until the patient is referred for continued care to a health care 
professional; or until a determination of a cause unrelated to TEV-50717 or study procedure is 
made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding TEV-50717, 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 TEV-50717 and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 
Further details are given in the Safety Monitoring Plan. 
7.1.3. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded as 1 of the following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
77 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product  
The relationship of an adverse event to the IMP (ie, TEV-50717) is characterized as follows: 
Table 9: 
The Relationship of an Adverse Event to the IMP  
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
IMP. 
• 
It does not reappear or worsen when the IMP is 
re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists. 
• 
It follows a known pattern of response to the IMP. 
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 
reported to the sponsor if the investigator becomes aware of them, following the procedures 
described in Section 7.1.5.3.1. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
78 
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 pre-existing condition 
during the patient’s participation in this study. 
• results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions) 
• is a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event. 
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event: 
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3× the upper limit of normal (ULN) 
• Tbil increase of >2×ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP]) 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
7.1.5.2. 
Expectedness  
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
79 
A serious adverse event that is not included in the listing of adverse reactions in the RSI by its 
specificity, severity, outcome, or frequency is considered an unexpected adverse event. 
The sponsor’s Global Patient Safety and Pharmacovigilance (GPSP) personnel will determine 
the expectedness for all serious adverse events. 
For the purpose of suspected unexpected serious adverse reaction (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 TEV-50717, 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 of this protocol); 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 the 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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
80 
• 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 TEV-50717, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file to the LSO/CRO 
for submission to the competent authorities, 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. 
7.1.5.3.2. Sponsor Responsibility  
If a serious unexpected adverse event is believed to be related to the TEV-50717 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 
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). 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
81 
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). 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-30081 Open-RECLAIM-DCP: Order of scales 
administration/completion document).  
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. 
7.2.1. 
Children’s Columbia-Suicide Severity Rating Scale  
The children’s C-SSRS assesses suicidal ideation and behaviors for all patients aged ≥12 years to 
determine suicide risk.  
The children’s C-SSRS Since Last Visit is administered at screening and/or day 1, as applicable 
(Table 4), and at weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up (Table 5). However, if the 
patient turned 12 years old during or after Study TV50717-CNS-30080, but before screening or 
day 1 visit of Study TV50717-CNS-30081, whichever comes first, the C-SSRS 
baseline/screening scale is administered. If the patient turns 12 years old during the study, 
C-SSRS baseline/screening will be completed as the initial assessment and the C-SSRS Since 
Last Visit will be completed as per Table 5. 
Children 13 years of age and under must be interviewed in conjunction with the caregiver. For 
children over 13 years of age, caregiver involvement is strongly encouraged. Questions should 
be directed to the child, but the caregiver 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 day 1, compared to the worst (highest) category during the treatment 
period, will be presented. 
7.2.2. 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
82 
akathisia will be evaluated with subscales I (subjective questionnaire) and II (evaluation for 
parkinsonism/akathisia). The ESRS is administered at the day 1 visit (Table 4) and administered 
at weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up visits (Table 5). 
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 the following: 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. 
Subscale II of the ESRS questionnaire for evaluation of parkinsonism and akathisia includes 
17 items with scores ranging from 0 to 102 to assess the following: tremor (0 to 48), gait and 
posture (0 to 6), postural stability (0 to 6), rigidity (0 to 24), expressive automatic movements 
(0 to 6), bradykinesia (0 to 6), and akathisia (0 to 6). 
7.2.3. 
Child Behavior Checklist (for Ages 6 to 18)  
The CBCL assesses behavioral and emotional status in children ages 6 through 18 years of age as 
reported by the caregiver (Achenbach 2005, Achenbach and Ruffle 2000). The full CBCL has 2 
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 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 Scale [Parts I to VII] and Syndrome Scale [behavioral 
items]) will be completed at the screening or day 1 visit, as applicable (Table 4) and at the 
week 53/ET visit (Table 5). The Syndrome Scale part of the CBCL [behavioral items] will be 
completed at day 1, as applicable (Table 4) and at weeks 3, 7, 14, 27, 40, and 54/follow-up visits 
(Table 5).  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
83 
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. Janssen et al (2017) 
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 the screening and/or day 1 visit, as applicable (Table 4) and 
administered at weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up visits (Table 5). 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 asks respondents to rate, on a 4-point Likert scale (0 to 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 TEV-50717. 
All pregnancies of female patients participating in the study that occur since the week 15 visit of 
Study TV50717-CNS-30080, during Study TV50717-CNS-30081, or within 14 days after the 
end of study are to be reported immediately once the investigator has become aware of the 
pregnancy. The pregnancy should be reported 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). 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
84 
If the pregnancy in the female patient participating in the study does not continue to term, 1 of 
the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event 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 Product  
Any administration of IMP that is not in accordance with the study protocol should be reported 
on the CRF as a deviation in the patient’s source documents, regardless of whether or not an 
adverse event occurs as a result, if it meets the deviation criteria specified in the protocol 
(Appendix D). 
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 (ie, TEV-50717), 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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
85 
• 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 day 1 that preclude a patient from 
entering the study or receiving IMP are not considered adverse events.) 
For COVID-19 updates, refer to Appendix M. 
Table 10: 
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 (INR) 
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, urinalysis) will be 
performed at the time points detailed in Table 4 and Table 5 (ie, screening and weeks 3, 7, 14, 
27, 40, 53/ET, and 54/follow-up visits). Clinical laboratory tests will be performed using the 
central laboratory. Specific laboratory tests to be performed are provided in Table 10. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
86 
7.5.2. 
Other Clinical Laboratory Tests  
7.5.2.1. 
Beta-Human Chorionic Gonadotropin Tests  
For females who are postmenarchal or ≥12 years of age, the following β-HCG tests in urine or 
serum will be performed based on when the patient enrolls in the study:   
• If the patient enrolls between 1 and <2 weeks after the week 15 visit of Study 
TV50717-CNS-30080:   
– 
If the day 1 visit in Study TV50717-CNS-30081 is on the same day as the week 
16 visit of Study TV50717-CNS-30080, the results of β-HCG tests in urine will 
be carried over from the week 16 visit.  
– 
Otherwise, the β-HCG tests in urine will be administered at day 1.   
• If the patient enrolls between 2 and ≤4 weeks after the week 15 visit of Study 
TV50717-CNS-30080 and does not have a clinically significant change, β-HCG tests 
in urine will be administered at day 1.   
• If the patient enrolls between 2 and ≤4 weeks after the week 15 visit of Study 
TV50717-CNS-30080 and has a clinically significant change, β-HCG tests in serum 
will be administered at screening. A β-HCG test in urine will be performed at the 
day 1 visit. 
A patient with a positive β-HCG test in urine cannot be enrolled until a β-HCG test in serum has 
been performed and is negative. 
During the treatment period, β-HCG tests in urine will be performed for females who are 
postmenarchal or ≥12 years of age at weeks 14, 27, 40, and 54/follow-up. β-HCG tests in serum 
will be performed for all female patients who are postmenarchal or ≥12 years of age at 
week 53/ET and if clinically indicated. 
7.5.2.2. 
Urine Drug Screen  
A urine drug screen will be performed at the time points specified in Table 4 and Table 5. 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, an alternative matrix (eg, serum) may be considered acceptable. 
The sponsor’s medical expert must be made aware in advance of, and provide approval for, drug 
screen parameters to which this will apply. 
A positive result for any drugs of abuse or their metabolites or drugs prohibited according to the 
laboratory manual, without medical explanation, will preclude the patient from enrollment or 
continued participation in the study. Some of the drugs or drug classes 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/clinician’s 
recommendation for a specific condition; for example, barbiturates for seizures, amphetamines 
for attention deficit hyperactivity disorder, and opiates or oxycodone for pain, if the dosing has 
been stable for at least 4 weeks before screening or day 1 and if no changes to dose or frequency 
are anticipated during the course of the study. Such cases should be discussed with the medical 
monitor. For patients who are either using these medications or who have a positive drug screen 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
87 
for these substances or derivatives, such cases should be submitted to the medical monitor for 
consideration of participation in this study. If per the investigator’s judgment, however, a patient 
does not meet the criteria for substance use disorder, a positive drug screen 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. 
7.6. 
Vital Signs  
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at the time points detailed in Table 4 and Table 5. 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/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 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. 
For COVID-19 updates, refer to Appendix M. 
7.7. 
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 4 and Table 5.  
Weight must be measured with shoes and outerwear off. 
Any new physical examination finding (ie, since day 1) 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. 
7.8. 
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 4 and Table 5. Any neurological examination finding that is 
judged by the investigator as a potentially clinically significant change (worsening) compared 
with the day 1 value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
88 
7.9. 
Electrocardiography  
A 12-lead ECG will be recorded at the time points detailed in Table 4 and Table 5. All ECGs 
will be performed after at least 5-minute rest in a supine or semi-supine position. The 
investigator should review the ECG at day 1 and at screening (in case a screening visit is 
performed) to determine patient eligibility for the study and subsequent ECGs for the patient’s 
continuation in the study. A qualified physician at a central diagnostic center will be interpreting 
the ECG. 
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 Spaulding (the central diagnostic center) will interpret 
the ECG. 
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories: 
• abnormal and not clinically significant  
• abnormal and clinically significant 
Any ECG finding that is judged by the investigator as clinically significant 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 the 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.   
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
89 
• 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. 
For COVID-19 updates, refer to Appendix M. 
7.10. 
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 
behavior. Consideration should be given to discontinuing TEV-50717 in patients who experience 
signs of suicidal ideation or behavior. 
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. 
Day 1 assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation and 
behavior will be assessed during the study using the children’s C-SSRS described in Section 7.2. 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
90 
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. 
7.11. 
Assessment of Depression  
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 
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, the 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. 
7.12. 
Concomitant Medication or Treatment  
Concomitant therapy or medication usage will be monitored throughout the study according to 
time points detailed in Table 4 and Table 5. Patients and/or caregivers 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 there is any change in current medications, 
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 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 must be submitted to the medical monitor for 
consideration of participation in this study. 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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
91 
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 11. 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 if pre-approved by the medical monitor. 
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 12. 
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. 
Methods and time points of assessing safety data are discussed in Section 3.5. Procedures for 
recording safety data are discussed in Appendix K, and methods of analyses are discussed in 
Section 9.6. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
92 
8. 
ASSESSMENT OF 
PHARMACOKINETICS/PHARMACODYNAMICS AND 
PHARMACOGENETICS  
8.1. 
Pharmacokinetic Assessment  
Pharmacokinetic parameters are not evaluated in this study. 
8.2. 
Pharmacodynamics Assessment  
Pharmacodynamic parameters are not evaluated in this study. 
8.3. 
Assessment of Exploratory Biomarkers  
Biomarkers are not evaluated in this study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
93 
9. 
STATISTICS  
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the Statistical 
Analysis Plan. After finalization of the Statistical Analysis Plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report 
(CSR). 
For COVID-19 updates, refer to Appendix M. 
9.1. 
Sample Size and Power Considerations  
This study is open-label and safety oriented in nature; therefore, no formal hypothesis testing is 
planned. The sample size for this study is not based on statistical considerations; hence, only 
descriptive statistics will be presented. 
Based on the number of patients in the parent study (Study TEV50717-CNS-30080), 
approximately 45 patients who completed the parent study may enroll in this study. 
9.2. 
Analysis Sets  
A single analysis set is defined for this clinical study, the intent-to-treat (ITT) analysis set. 
9.2.1. 
Intent-to-Treat Analysis Set  
The ITT analysis set will include all enrolled patients, regardless of whether or not a patient took 
any TEV-50717. A patient is considered enrolled according to the status reported in the database. 
All analyses will be based on the ITT analysis set. 
9.2.2. 
Additional Analyses Sets  
Additional analysis sets may be defined in the Statistical Analysis Plan. 
9.3. 
Data Handling Conventions  
For all variables, only the observed data from the patients will be used in the statistical analyses.  
9.4. 
Study Population  
The ITT analysis set (Section 9.2) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented for all patients. 
9.4.1. 
Patient Disposition  
Data from patients who are enrolled, patients enrolled but not treated (and the reason), patients in 
the ITT analysis set, patients who complete the study, and patients who withdraw from the study 
will be summarized using descriptive statistics. Data from patients who withdraw from the study 
will also be summarized by reason for withdrawal using descriptive statistics. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
94 
9.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics (day 1), including medical and psychiatric 
history, prior medications and therapies, and ECG findings, will be summarized using 
descriptive statistics and will be analyzed by age group. 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. 
Multiple Comparisons and Multiplicity  
This does not apply to this study. 
9.6. 
Safety Endpoints and Analysis  
The primary objective of this study is to evaluate the safety and tolerability of long-term therapy 
with TEV-50717 in children and adolescents with DCP.  
The safety measures/endpoints are as follows:  
• adverse events 
• vital signs 
• children’s C-SSRS 
• ECG parameters 
• clinical laboratory parameters (hematology, serum chemistry, and urinalysis) 
• ESRS (subscales I and II) 
• CBCL 
• ESS 
Safety analyses will be presented for the ITT analysis set (Section 9.2.1). Patients who did not 
receive any TEV-50717 will be excluded from the summaries and presented in listings only. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) 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 
TEV-50717 (ie, reasonable possibility; see Section 7.1.4) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing 
withdrawal from the study. Patient listings of serious adverse events and adverse events leading 
to withdrawal will be presented. 
Observed values and changes from day 1 in laboratory results and vital signs will be summarized 
descriptively.  
Observed values in ECG parameters will be summarized, and counts and percentages of 
abnormal findings will be presented. Changes from baseline of the parent study in ECG 
parameters will be summarized descriptively. In addition, the number and percentage of patients 
with on-treatment QTcF values >450, >480, or >500 msec and change from day 1 >30 or 
>60 msec will be presented. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
95 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with TEV-50717. 
The frequency and severity of suicidal ideation or behavior according to the children’s C-SSRS 
questionnaire will be presented by visit. A shift table for children’s C-SSRS categories at day 1, 
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. 
Safety assessments and time points are provided in Table 5. 
For continuous variables, descriptive statistics will be provided for actual values and changes 
from day 1 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 CSR. 
9.7. 
Efficacy Analysis  
No formal inferential statistics will be applied to the efficacy endpoints.  
Efficacy Endpoints 
The following efficacy endpoints will be assessed in this study: 
• MD-CRS part I total score (centrally read) 
• MD-CRS part II total score (centrally read) 
• MD-CRS part I total score (physician rated) 
• MD-CRS part II total score (physician rated) 
• MD-CRS Global Index (calculated from MD-CRS parts I and II total scores) 
• CaGI-I (global, caregiver rated) 
• CGI-I (global, physician rated) 
• CGI-S (global, physician rated) 
• PEDI-CAT (activities of daily living, caregiver completed, content-balanced version) 
• UHDRS-TMC (centrally read) 
• UHDRS-TMD (centrally read) 
• UHDRS-TMS (physician rated) 
• UHDRS-TMC (physician rated) 
• UHDRS-TMD (physician rated) 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
96 
• COPM (physician rated) 
Planned Method of Analysis 
The ITT analysis set (see Section 9.2.1) will be used for all efficacy analyses. Summaries will be 
presented for all patients. Descriptive statistics will be used to summarize efficacy measures. 
Descriptive statistics of change-from-day 1 will utilize day 1 from the present open-label study 
(Study TEV-50717-30081). 
Patients who did not receive any TEV-50717 will be excluded from the summaries and presented 
in listings only. For continuous variables, descriptive statistics will be provided for actual values 
and changes from day 1 to each time point. For categorical variables, patient counts and 
percentages will be provided.  
9.8. 
Tolerability Analysis  
Tolerability was not specifically defined. 
9.9. 
Planned Interim Analysis  
There is no planned interim analysis of this study. Intermediate analysis may be performed for 
submission of a New Drug Application (NDA) or other purposes. 
9.10. 
Reporting Deviations from the Statistical Plan  
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
97 
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. 
11. 
COMPLIANCE STATEMENT  
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6, and any applicable national and local laws and regulations (eg, Title 21 
CFR [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 IRC, confidentiality regarding study patients, and requirements for registration of 
the clinical study. 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
98 
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 disease that would have occurred or continued if the patient had not taken part 
in the clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Food and Drug Administration 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. 
14. 
PUBLICATION POLICY  
See Appendix L for information regarding the publication policy. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
99 
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 L. 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 and Statistics for Cerebral Palsy. 2018. 
Available at: https://www.cdc.gov/ncbddd/cp/data.html. 
Center for Disease Control and Prevention (CDC). Causes and Risk Factors of Cerebral Palsy. 
2018. 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. Br J Pharmacol 1979;67(2):309-18. 
Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
100 
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. 
Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, Pollock N. The Canadian 
occupational performance measure: an outcome measure for occupational therapy. Can J Occup 
Ther 1990 Apr;57(2):82-7. 
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 Disordes 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. American Journal of 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. 
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. 
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. 
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. 
Xenazine: Highlights of Prescribing Information. 2017. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021894s013lbl.pdf. Accessed 
16 Jul 2019. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
101 
16. 
SUMMARY OF CHANGES TO PROTOCOL  
16.1. 
Amendment 04 Dated 01 June 2022  
The primary reason for this amendment is 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 4 (Study Procedures and Assessments - Screening and/or Day 1), Table 5 (Study 
Procedures and Assessments: Titration, Maintenance, and Follow-up Periods), and Figure 1 
(Overall Study Schematic Diagram) have been revised to reflect changes described below. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
102 
Protocol text with changes shown 
New wording 
Reason/justification for change 
1. INTRODUCTION 
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). 
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. 
1.2.2. 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  
• 
one terminated Phase 3 long-term safety study in 
patients with TS  
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
103 
Protocol text with changes shown 
New wording 
Reason/justification for change 
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 
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. 
Text added for the recently 
completed TS studies 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
104 
Protocol text with changes shown 
New wording 
Reason/justification for change 
2.1. Primary and Secondary Study Objectives and Endpoints 
See new wording column 
• MD-CRS part I total score (centrally read) 
• MD-CRS part II total score (centrally read) 
 
• UHDRS-TMC (centrally read) 
• UHDRS-TMD (centrally read) 
New secondary endpoints 
3.1. General Study Design and Study Schematic Diagram 
If the patient does not wish to enroll in Study TV50717-
CNS-30081 at that visit, or for any other reason, the patient 
can enroll up to 6 months4 weeks following the week 15 
visit of the TV50717-CNS-30080 study. 
If the patient does not wish to enroll in Study TV50717-
CNS-30081 at that visit, or for any other reason, the patient 
can enroll up to 4 weeks following the week 15 visit of the 
TV50717-CNS-30080 study. 
Change to the time period patients 
can enroll following end of Study 
30080 due to changing situation of 
the COVID-19 pandemic 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 6 months4 weeks 
following the week 15 visit of Study TV50717-CNS-30080. 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 4 weeks following the 
week 15 visit of Study TV50717-CNS-30080. 
Change to the time period patients 
can enroll following end of Study 
30080 due to changing situation of 
the COVID-19 pandemic 
The following text was deleted: 
Day 1: More than 4 weeks and up to 6 months after Study 
TV50717-CNS-30080 week 15 visit: 
The patient will undergo all screening procedures outlined in 
Table 4. Patients who remain eligible for participation in the 
study will be asked to return for day 1 assessments. Study 
drug will be dispensed at day 1 once all procedures and 
investigator related assessments are completed and patient 
eligibility is confirmed. 
For patients who enroll in the study more than 4 weeks and 
up to 6 months after the Study TV50717-CNS-30080 week 
15 visit, the investigator is required to consult with the 
medical monitor regarding eligibility prior to baseline/day 1. 
The patient’s file should include all related correspondence 
with the medical monitor. 
 
Change to the time period patients 
can enroll following end of Study 
30080 due to changing situation of 
the COVID-19 pandemic 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
105 
Protocol text with changes shown 
New wording 
Reason/justification for change 
Patients will receive 6 mg of TEV-50717 on the morning of 
day 2 (Table 6). This dose will be administered in the 
morning on days 2 and 3, followed by evening 
administration starting on day 3 for the remainder of the 
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. 
Patients will receive 6 mg of TEV-50717 (Table 6). This 
dose will be administered in the morning on days 2 and 3, 
followed by evening administration starting on day 3 for the 
remainder of the 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. 
Text revised for consistency with 
other sections of protocol 
Figure 2: Flow Chart for Patient Screening and Day 1 Visit Assessments 
See new wording column 
Figure 2 has been revised to remove the Day 1 option for 
enrollment >4 weeks for consistency with the rest of the 
changes to the protocol 
Change to the time period patients 
can enroll following end of Study 
30080 due to changing situation 
of the COVID-19 pandemic 
3.2. Planned Number of Patients and Regions 
Up to aApproximately 18545 patients (up to a maximum of 
230 patients) who have completed parent Study TV50717-
CNS-30080 are planned for enrollment into this study. 
This study is planned to be conducted in approximately 
7035 investigational centers in North America, and the 
Europe, and Africaan Union. The study is expected to start 
by the end of Q1 2020 and last until Q2 2023. 
Approximately 45 patients who have completed parent 
Study TV50717-CNS-30080 are planned for enrollment into 
this study. 
This study is planned to be conducted in approximately 
35 investigational centers in North America, Europe, and 
Africa. 
Text revised to account for the 
change in sample size and the 
removal of the second interim 
analysis 
Table 4: Study Procedures and Assessments:  Screening and/or Day 1 
See new wording column 
Table 4 has been revised as described below: 
• Remove the Day 1 option for enrollment >4 weeks for 
consistency with the rest of the changes to the protocol 
• Add new secondary endpoints:  MD-CRS parts I and II 
(centrally read), UHDRS-TMC (centrally read), and 
UHDRS-TMD (centrally read)  
 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
106 
Protocol text with changes shown 
New wording 
Reason/justification for change 
Table 5: Study Procedures and Assessments: Titration, Maintenance, and Follow-up Periods 
See new wording column 
Table 4 has been revised as described below: 
• Add new secondary endpoints:  MD-CRS parts I and II 
(centrally read), UHDRS-TMC (centrally read), and 
UHDRS-TMD (centrally read) 
 
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 
f. 
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. 
f. 
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 
If a patient who experiences signs of suicidal ideation or 
behavior (Section 7.10), the investigator should consult with 
the medical monitor to determine whether the patient should 
continue in the study.  If a patient reports any suicidal 
behavior that is an actual attempt as assessed in the 
children’s C SSRS, the patient will be evaluated 
immediately by the investigator, referred for psychiatric 
evaluation, and terminated from the study. 
Added to align with Section 7.10 
Patients experiencing an adverse event leading to 
discontinuation of TEV-50717, or experiencing any other 
adverse event at the discretion of the investigator, should 
have a single blood sample collected as soon as possible 
after the adverse event and within 48 hours for the 
measurement of TEV-50717, α-HTBZ and β-HTBZ 
concentrations, if possible. This should be done (at the 
discretion of the investigator) as soon as possible after the 
onset of the ongoing adverse event and within 48 hours after 
the last dose intake in the case of TEV-50717 
discontinuation.  
Patients experiencing an adverse event leading to 
discontinuation of TEV-50717 or experiencing any other 
adverse event, should have a single blood sample collected 
for the measurement of TEV 50717, α- and β HTBZ 
concentrations, if possible.  This should be done (at the 
discretion of the investigator) as soon as possible after the 
onset of the ongoing adverse event and within 48 hours after 
the last dose intake in the case of TEV-50717 
discontinuation.  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
107 
Protocol text with changes shown 
New wording 
Reason/justification for change 
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 6 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 a telephone or in-clinic visit. 
• 
During the titration period, the dose of IMP should be 
adjusted according to Table 6 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 a telephone or in-clinic visit. 
Revised for clarity 
Table 6: Maximum Daily Dose of IMP During the Titration Period by Week and Weight Category at Baseline 
See new wording column 
Table 6 has been revised as described below: 
• The title was changed from “by Study 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. 
Revised for clarity 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
108 
Protocol text with changes shown 
New wording 
Reason/justification for change 
Table 8: Investigational Medicinal Products Used in the Study 
See new wording column 
The footnote to Table 8 has been revised as described 
below: 
• Reference to the specific section of the pharmacy manual 
has been removed 
Revised for clarity 
5.2.1. Storage and Security 
For additional information related to IMP storage 
conditions, please refer to Section 10 of the Pharmacy 
Manual. 
For additional information related to IMP storage 
conditions, please refer to the Pharmacy Manual. 
Revised for clarity 
A record of IMP accountability (ie, TEV-50717 and other 
study materials received, used, unused, retained, returned, or 
destroyed) must be prepared and signed by the principal 
investigator or designee, with an account given for any 
discrepancies. Empty, partially used, and unused bottles of 
TEV-50717 that are not destroyed at the site will be returned 
to the sponsor or designee, as agreed with the sponsor. 
A record of IMP accountability (ie, TEV-50717 and other 
study materials received, used, unused, retained, returned, 
or destroyed) must be prepared and signed by the principal 
investigator or designee, with an account given for any 
discrepancies. Empty, partially used, and unused bottles of 
TEV-50717 that are not destroyed at the site will be 
returned to the sponsor or designee, as agreed with the 
sponsor. 
Revised for clarity 
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 the IMP. 
The investigator will be responsible for monitoring patient 
compliance until completion of the IMP administration 
according to the protocol or discontinuation from the IMP. 
Revised for clarity 
Based on pill counts at in-clinic visits, poor compliance with 
study drug (ie, <80%) or overdose (ie, >105%) is to be 
recorded as an important deviation and expeditiously 
reported to the medical monitor. 
Based on pill counts at in-clinic visits, poor compliance 
with study drug (ie, <80%) or overdose (ie, >105%) is to be 
recorded as an important deviation and expeditiously 
reported to the medical monitor. 
Revised for clarity 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
109 
Protocol text with changes shown 
New wording 
Reason/justification for change 
6.1.1. Movement Disorder-Childhood Rating Scale 
See new wording column 
Video review of MD-CRS for chorea at day 1, week 27, 
week 53/ET, and week 54/follow-up visits (Table 5) will be 
assessed 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 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 
6.1.3. Clinical Global Impression of Improvement Scale 
Patients will also be assessed for CGI-I during telephone 
contacts (with non-recording live video) at the week 1, week 
2, week 4, week 5, week 6, week 21, week 33, and week 46, 
and week 55/follow up visits. 
Patients will also be assessed for CGI-I during telephone 
contacts (with non-recording live video) at the week 1, 
week 2, week 4, week 5, week 6, week 21, week 33, and 
week 46. 
The endpoint will not be assed at 
the follow-up visits.   
6.1.6. Unified Huntington’s Disease Rating Scale-Total Motor Score 
See new wording column 
The UHDRS-TMC (physician rated) score and UHDRS-
TMD (physician rated) score will be determined from the 
UHDRS-TMS assessment. The protocol refers to UHDRS-
TMC and UHDRS-TMD 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-TMC and UHDRS-TMD. 
A central reading of the UHDRS-TMC will be performed at 
baseline/day 1 and at weeks 27, 53/ET, and 54 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 endpoints 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
110 
Protocol text with changes shown 
New wording 
Reason/justification for change 
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 
7.5.2.1. Beta-Human Chorionic Gonadotropin Tests 
• If the patient enrolls between 2 and ≤4 weeks after the 
week 15 visit of Study TV50717-CNS-30080 and has a 
clinically significant change OR enrolls more than 4 
weeks and up to 6 months after the week 15 visit of Study 
TV50717 CNS 30080, β-HCG tests in serum will be 
administered at screening. A β-HCG test in urine will be 
performed at the day 1 visit. 
• If the patient enrolls between 2 and ≤4 weeks after the 
week 15 visit of Study TV50717-CNS-30080 and has a 
clinically significant change, β-HCG tests in serum will 
be administered at screening. A β-HCG test in urine will 
be performed at the day 1 visit. 
Change to the time period patients 
can enroll following end of Study 
30080 due to changing situation 
of the COVID-19 pandemic 
7.9. 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 Spaulding (the 
central diagnostic center) will interpret the ECG. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
111 
Protocol text with changes shown 
New wording 
Reason/justification for change 
The following paragraph was deleted:   
If a post-treatment QTcF value >500 msec or change from 
screening or day 1 >60 msec is found, the investigator 
should repeat the ECG assessment twice and then compare 
the last pre-treatment QTcF value to the average of the 
3 post-treatment QTcF values. TEV-50717 must be stopped 
for any confirmed post-treatment QTcF average value 
>500 msec or average increase from screening or day 1 >60 
msec. 
 
Clarification 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
112 
Protocol text with changes shown 
New wording 
Reason/justification for change 
9.1. Sample Size and Power Considerations 
Based on the number of patients in the parent study (Study 
TEV50717-CNS-30080), up to approximately 
18545 patients (up to a maximum of 230 patients) who 
completed the parent study may enroll in this study. 
However, it is expected that approximately 15% of patients 
enrolled in the parent study will drop out of that study. This 
sample size is considered sufficient for the exploratory 
nature of the study. 
Based on the number of patients in the parent study (Study 
TEV50717-CNS-30080), to approximately 45 patients who 
completed the parent study may enroll in this study.  
Text revised to account for the 
change in sample size  
9.6. 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. 
The frequency and severity of suicidal ideation or behavior 
according to the children’s C-SSRS questionnaire will be 
presented by visit. 
Clarification 
9.7. Efficacy Analysis 
See new wording column 
• MD-CRS part I total score (centrally read) 
• MD-CRS part II total score (centrally read) 
 
• UHDRS-TMC (centrally read) 
• UHDRS-TMD (centrally read) 
New secondary endpoints 
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. 
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 
 
References deleted to account for 
the change in sample size and the 
removal of the second interim 
analysis as well changes in the 
introduction 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
113 
Protocol text with changes shown 
New wording 
Reason/justification for change 
AUSTEDO® (deutetrabenazine) tablets (US prescribing 
information). Teva Pharmaceuticals USA, Inc; 20172021. 
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 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Row: Sponsor’s Authorized Representative 
Column: 
 
  
Teva Pharmaceutical Industries, 
 
 
Cell: 
 
 
 
Row: Sponsor’s Authorized Representative 
Column:  
 
 
Teva Pharmaceutical Industries 
Cell: 
 
 
Administrative change 
Row:  Sponsor’s Medical Expert/Contact Point designated 
by the Sponsor for Further Information on the Study 
Deleted text:   Tel: 
 
 
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:  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:  Trial Supply Management vendor 
Column:   
Calyx 
4 Canal Street 
Nottingham, United Kingdom, NG1 7EH 
Tel: 
 
Administrative change 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
114 
Protocol text with changes shown 
New wording 
Reason/justification for change 
Row:  Scales and Central Rater for MD CRS Reading 
Column: 
Bracket Global LLC 
785 Arbor Way 
Blue Bell, PA, 19422  
Tel : 
 
Row:  Scales and Central Reading 
Column: 
Signant Health 
785 Arbor Way 
Blue Bell, PA 19422 
Tel: 
 
 
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Screening and Enrollment 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 6 months4 weeks 
following the week 15 visit of Study TV50717-CNS-30080. 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 4 weeks following the 
week 15 visit of Study TV50717-CNS-30080. 
Study procedures and assessments 
have been updated for consistency 
with changes made to the protocol 
body and Tables 4 and 5. 
This justification applies to all 
changes indicated within 
Appendix C. 
2.1 Procedures for Patients Who Enroll Between 1 and <2 Weeks After Study TV50717-CNS-30080 Week 15 Visit 
c. Day 1 Assessments 
−  Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I (physician centrally read, video 
recording)  
−  MD-CRS part II (centrally read) 
−  MD-CRS part I (physician rated, video recording) 
−  MD-CRS part II (physician rated, video recording) 
 
− Unified Huntington’s Disease Rating Scale-Total 
Maximal Chorea (UHDRS-TMC) (centrally read) 
− Unified Huntington’s Disease Rating Scale-Total 
Maximal Dystonia (UHDRS-TMD) (centrally read) 
−  UHDRS-TMC (physician rated) 
−  UHDRS-TMD (physician rated) 
− Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I (centrally read)  
−  MD-CRS part II (centrally read) 
−  MD-CRS part I (physician rated, video recording) 
−  MD-CRS part II (physician rated, video recording) 
 
 
− Unified Huntington’s Disease Rating Scale-Total 
Maximal Chorea (UHDRS-TMC) (centrally read) 
− Unified Huntington’s Disease Rating Scale-Total 
Maximal Dystonia (UHDRS-TMD) (centrally read) 
−  UHDRS-TMC (physician rated) 
−  UHDRS-TMD (physician rated) 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
115 
Protocol text with changes shown 
New wording 
Reason/justification for change 
2.2 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with No Clinically Significant 
Changes Since the Week 15 Visit of Study TV50717-CNS-30080 
b. Day 1 Assessments 
See new wording column 
○  MD-CRS part I (centrally read) 
○  MD-CRS part II (centrally read) 
 
○  UHDRS-TMC (centrally read) 
○  UHDRS-TMD (centrally read) 
 
○  UHDRS-TMC (physician rated) 
○  UHDRS-TMD (physician rated) 
○  UHDRS-TMC (physician rated) 
○  UHDRS-TMD (physician rated) 
 
2.3 Procedures for Patients Who Enroll Between 2 and 
≤4 Weeks After Study TV50717-CNS-30080 Week 15 
Visit with Clinically Significant Changes and for 
Patients Who Enroll More Than 4 Weeks and up to 6 
Months After Study TV50717 CNS 30080 Week 15 
Visit 
2.3 Procedures for Patients Who Enroll Between 2 and 
≤4 Weeks After Study TV50717-CNS-30080 Week 
15 Visit with Clinically Significant Changes 
 
2.3Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with Clinically Significant Changes 
b. Day 1 
See new wording column 
○  MD-CRS part I (centrally read) 
○  MD-CRS part II (centrally read) 
 
○  UHDRS-TMC (centrally read) 
○  UHDRS-TMD (centrally read) 
 
○  UHDRS-TMC (physician rated) 
○  UHDRS-TMD (physician rated) 
○  UHDRS-TMC (physician rated) 
○  UHDRS-TMD (physician rated) 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
116 
Protocol text with changes shown 
New wording 
Reason/justification for change 
3. Procedures During TEV-50717 Treatment 
a. Titration Period (Weeks 1 to 7) 
ii. In-clinic Visits (Weeks 3 and 7) 
• assess drugTEV-50717 accountability/compliance/supply 
(Note: At the week 3 in-clinic visit, accountability will be 
performed on all bottles returned except for patients who 
receive 1 bottle back to complete the week 3 in-clinic 
evening dose. Refer to the pharmacy manual for further 
details.) 
• assess TEV-50717 accountability/compliance/supply 
(Note: At the week 3 in-clinic visit, accountability will be 
performed on all bottles returned except for patients who 
receive 1 bottle back to complete the week 3 in-clinic 
evening dose. Refer to the pharmacy manual for further 
details.) 
 
b. Maintenance Period (Weeks 14 to 53/Early Termination) 
i. In-clinic Visits (Weeks 14, 27, 40, and 53/Early Termination) 
See new wording column 
−  MD-CRS part I (centrally read) at weeks 27 and 53/ET 
−  MD-CRS part II (centrally read) at weeks 27 and 53/ET 
 
−  UHDRS-TMC (physician rated) at weeks 27 and 53/ET 
−  UHDRS-TMD (physician rated) at weeks 27 and 53/ET 
 
−  UHDRS-TMC (physician rated) 
−  UHDRS-TMD (physician rated) 
−  UHDRS-TMC (physician rated) 
−  UHDRS-TMD (physician rated) 
 
ii.Telephone Contacts (Weeks 21, 33, and 46) 
If additional drugTEV-50717 is required, it would be 
ordered from the distributor and provided to the patient at an 
unscheduled visit. 
If additional TEV-50717 is required, it would be ordered 
from the distributor and provided to the patient at an 
unscheduled visit. 
 
4. Procedures After TEV-50717 Treatment (Follow-Up) 
a. In-clinic Visit (Week 54) 
See new wording column 
−  MD-CRS part I (centrally read) 
−  MD-CRS part II (centrally read) 
 
−  UHDRS-TMC (centrally read) 
−  UHDRS-TMD (centrally read) 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
117 
Protocol text with changes shown 
New wording 
Reason/justification for change 
b. Telephone Contact (Week 55) 
The following was deleted: 
• CGI-I (Note: Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For 
children over 13 years of age, caregiver involvement is 
strongly encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to add 
relevant information.) 
 
 
5. Unscheduled Visits 
• assess drugTEV 50717 accountability/compliance/supply  
• 
assess TEV-50717 accountability/compliance/supply  
 
APPENDIX I. TOTAL BLOOD VOLUME 
Patients experiencing an adverse event leading to 
discontinuation of TEV-50717, or experiencing any other 
adverse event at the discretion of the investigator, should 
have a single blood sample collected as soon as possible 
after the adverse event and within 48 hours for the 
measurement of TEV-50717, α-HTBZ and β HTBZ 
concentrations, if possible. This should be done (at the 
discretion of the investigator) as soon as possible after the 
onset of the ongoing adverse event and within 48 hours after 
the last dose intake in the case of TEV 50717 
discontinuation. 
Patients experiencing an adverse event leading to 
discontinuation of TEV-50717 or experiencing any other 
adverse event, should have a single blood sample collected 
for the measurement of TEV 50717, α- and β HTBZ 
concentrations, if possible.  This should be done (at the 
discretion of the investigator) as soon as possible after the 
onset of the ongoing adverse event and within 48 hours after 
the last dose intake in the case of TEV-50717 
discontinuation. 
 
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 (eg, geopolitical 
situation) 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 (eg, geopolitical situation) 
affecting normal per-protocol conduct of the study.   
Text revised due to the ongoing, 
changing nature of the COVID-19 
pandemic 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
118 
Protocol text with changes shown 
New wording 
Reason/justification for change 
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. 
Update 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
119 
16.2. 
Administrative Letter 06 Dated 11 June 2021  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
120 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
121 
16.3. 
Administrative Letter 05 Dated 23 February 2021  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
122 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
123 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
124 
16.4. 
Administrative Letter 04 Dated 14 November 2020  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
125 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
126 
16.5. 
Administrative Letter 03 Dated 14 July 2020  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
127 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
128 
16.6. 
Amendment 03 Dated 23 June 2020  
The primary reason for this amendment is to provide the management of COVID-19 pandemic-
related operational updates as detailed in a new appendix (Appendix M).  
This amendment is considered to be substantial by the sponsor’s authorized representative. These 
substantive changes included the addition of video recording of the MD-CRS assessment. The 
MD-CRS video recording was added to this amendment as the video is a recognized component 
of the MD-CRS.  
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Minor or editorial non-substantial changes (typos, punctuation, etc) 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. 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
129 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
3.1. General Study Design and Study Schematic Diagram 
Site-administered scales include the Movement Disorder-
Childhood Rating Scale (MD-CRS) parts I and II (physician 
rated, with video recording)… 
Site-administered scales include the Movement Disorder-
Childhood Rating Scale (MD-CRS) parts I and II 
(physician rated, with video recording)… 
MD-CRS video recording added as 
recognized part of the assessment.  
• 
vital signs (respiratory rate and body temperature) and 
weight isare performed at week 16 in Study TV50717-
CNS-30080 and height is performed at week 15 in study 
TV50717-CNS-30080; these assessments will serve as 
day 1 baseline values in this study.  
• 
vital signs (respiratory rate and body temperature) are 
performed at week 16 in Study TV50717-CNS-30080. If 
the day 1 visit in Study TV50717-CNS-30081 is on the 
same day as the week 16 visit of Study TV50717-
CNS-30080, these assessments will serve as day 1 
baseline values in this study. Otherwise, these 
assessments will be performed at day 1. 
• weight is performed at week 16 in Study 
TV50717-CNS-30080 and height is performed at week 
15 in study TV50717-CNS-30080; these assessments 
will serve as day 1 baseline values in this study. 
• vital signs (respiratory rate and body temperature) are 
performed at week 16 in Study TV50717-CNS-30080. 
If the day 1 visit in Study TV50717-CNS-30081 is on 
the same day as the week 16 visit of Study 
TV50717-CNS-30080, these assessments will serve as 
day 1 baseline values in this study. Otherwise, these 
assessments will be performed at day 1. 
Clarification 
See New Wording Column 
For corona virus disease 2019 (COVID-19) updates, refer 
to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
3.2. Planned Number of Patients and Regions 
The study is expected to start by the end of Q1 2020 and last 
until Q4 2022Q2 2023. 
The study is expected to start by the end of Q1 2020 and 
last until Q2 2023. 
 
3.3. Justification for Study Design and Selection of Population 
The study population will include pediatric and adolescent 
patients (6 through 18+ years of age at the time when they 
enrolled in the parent study [Study TV50717-CNS-30080]), 
ie, 6 through 20 years of age when they enroll in TV50717-
CNS-30081 study, with DCP with predominant choreiform 
movement disorder, who have had non-progressive CP 
symptoms since infancy (≤2 years of age), and have 
completed Study TV50717-CNS-30080. 
The study population will include pediatric and adolescent 
patients (6 through 18+ years of age at the time when they 
enrolled in the parent study [Study TV50717-CNS-
30080]), ie, 6 through 20 years of age when they enroll in 
TV50717-CNS-30081 study, with DCP with predominant 
choreiform movement disorder, who have had non-
progressive CP symptoms since infancy (≤2 years of age), 
and have completed Study TV50717-CNS-30080. 
Clarification 
3.5. Schedule of Study Procedures and Assessments 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
130 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Table 4 Study Procedures and Assessments: Screening and/or Day 1 
See New Wording Column 
Table 4 has been revised as described below: 
• Video recording added to both MD-CRS Part I and 
Part II 
• CBCL has been added to screening visit  
• Footnotes revised/added to clarify which CBCL 
assessments are completed at day 1 and screening, to 
clarify when vital signs are to be performed, and to add 
the video recording to the MD-CRS assessments 
Revisions were incorporated to 
clarify and align Table 4 with 
Appendix C (Section 2.3), to clarify 
when vital signs will be performed, 
and to add MD-CRS video 
recording as a recognized part of 
the assessment. 
Table 5 Study Procedures and Assessments: Titration, Maintenance, and Follow-up Periods 
See New Wording Column 
Table 5 has been revised as described below: 
• Video recording added to both MD-CRS Part I and 
Part II 
• Footnotes revised/added to add video recording for 
MD-CRS 
MD-CRS video recording added as 
recognized part of the assessment.  
4.3. Withdrawal Criteria and Procedures for the Patient 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
5.1.1.2. Dose Modification and Dose Stratification 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
5.2. Preparation, Handling, Labeling, Storage, and Accountability for IMPs 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
5.11 Total Blood Volume 
The total blood volume to be collected for each patient in this 
study is approximately 7677.5 mL. 
The total blood volume to be collected for each patient in 
this study is approximately 77.5 mL. 
Clarification 
6. ASSESSMENT OF EFFICACY 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
131 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
the addition of Appendix M 
6.1.1. Movement Disorder-Childhood Rating Scale 
The MD-CRS (with video recording) will be administered at 
the day 1 visit (Table 4) and at week 14, week 27, week 40, 
week 53/ET, and week 54/follow-up visits (Table 5).  
The MD-CRS (with video recording) will be administered 
at the day 1 visit (Table 4) and at week 14, week 27, week 
40, week 53/ET, and week 54/follow-up visits (Table 5).  
MD-CRS video recording added as 
recognized part of the assessment.   
7. ASSESSMENT OF SAFETY 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
7.2. Safety Rating Scales 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
7.2.3. Child Behavior Checklist (for Ages 6 to 18) 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at the screening or day 1 visit, as applicable (Table 
4) and at the week 53/ET visit (Table 5). The Syndrome Scale 
part of the CBCL [behavioral items] will be completed at day 
1, as applicable (Table 4) and at weeks 3, 7, 14, 27, 40, and 
54/follow-up visits (Table 5). 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at the screening or day 1 visit, as applicable 
(Table 4) and at the week 53/ET visit (Table 5). The 
Syndrome Scale part of the CBCL [behavioral items] will 
be completed at day 1, as applicable (Table 4) and at 
weeks 3, 7, 14, 27, 40, and 54/follow-up visits (Table 5). 
Revisions were incorporated to 
clarify and align with Appendix C 
7.2.4. Epworth Sleepiness Scale (for Children and Adolescents 
The ESS is administered at the screening and/or day 1 visit, 
as applicable (Table 4) and administered at weeks 3, 7, 14, 
27, 40, 53/ET, and 54/follow-up visits (Table 5).  
The ESS is administered at the screening and/or day 1 
visit, as applicable (Table 4) and administered at weeks 3, 
7, 14, 27, 40, 53/ET, and 54/follow-up visits (Table 5).  
Revisions were incorporated to 
clarify and align with Table 4 
7.5. Clinical Laboratory Tests 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
7.5.1. Serum Chemistry, Hematology, and Urinalysis 
Clinical laboratory tests (serum chemistry, hematology and 
coagulation, urinalysis) will be performed at the time points 
detailed in Table 4 and Table 5 (ie, screening and weeks 3, 7, 
14, 27, 40, 53/ET, and 54/follow-up visits). Clinical 
Clinical laboratory tests (serum chemistry, hematology 
and coagulation, urinalysis) will be performed at the time 
points detailed in Table 4 and Table 5 (ie, screening and 
weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up visits). 
Revisions were incorporated to 
clarify and align with Table 4 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
132 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
laboratory tests will be performed using the central 
laboratory.  Specific laboratory tests to be performed are 
provided in Table 10. 
Clinical laboratory tests will be performed using the 
central laboratory.  Specific laboratory tests to be 
performed are provided in Table 10. 
7.5.2.2. Urine Drug Screen 
Some of the drugs or drug classes listed in this urine drug 
screen may be permitted in certain cases in which the 
particular drug or drug class is being used under a physician’s 
or clinician’s guidance and in compliance with the 
physician’s/clinician’s recommendation for a specific 
condition; for example, phenobarbital (barbiturates) for 
seizures, stimulant medications (including amphetamines, 
methylphenidate, and lisdexamfetamine) for attention deficit 
hyperactivity disorder, and opiates or oxycodone for pain, if 
the dosing has been stable for at least 4 weeks before 
screening or day 1 and if no changes to dose or frequency are 
anticipated during the course of the study. 
Some of the drugs or drug classes listed in this urine drug 
screen may be permitted in certain cases in which the 
particular drug or drug class is being used under a 
physician’s or clinician’s guidance and in compliance with 
the physician’s/clinician’s recommendation for a specific 
condition; for example, phenobarbital (barbiturates) for 
seizures, amphetamines for attention deficit hyperactivity 
disorder, and opiates or oxycodone for pain, if the dosing 
has been stable for at least 4 weeks before screening or 
day 1 and if no changes to dose or frequency are 
anticipated during the course of the study. 
Text clarified to provide examples 
of some drug classes that might be 
prescribed and possibly be 
identified on the urine drug screen; 
some of the mentioned drugs may 
not be identified on urine drug 
screen 
7.6. Vital Signs 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
7.9. Electrocardiography 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
9. Statistics 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section 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 section to cross-reference 
the addition of Appendix M 
Appendix C. Study Procedures And Assessments By Visit 
2. 
Procedures Before TEV-50717 Treatment 
2.1 Procedures for Patients Who Enroll Between 1 and <2 Weeks After Study TV50717-CNS-30080 Week 15 Visit 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
133 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
b. Assessments carried over from Study TV50717-CNS-30080 - Week 15/16 
• 
W16 vital signs (body temperature and respiratory 
rate). If the day 1 visit in Study TV50717-CNS-
30081 is on the same day as the week 16 visit of 
Study TV50717-CNS-30080, these assessments will 
serve as day 1 baseline values in this study. 
Otherwise, these assessments will be performed at 
day 1. 
• 
W16 vital signs (body temperature and 
respiratory rate). If the day 1 visit in Study 
TV50717-CNS-30081 is on the same day as the 
week 16 visit of Study TV50717-CNS-30080, 
these assessments will serve as day 1 baseline 
values in this study. Otherwise, these assessments 
will be performed at day 1. 
Clarification 
c. 
Day 1 Assessments 
• 
administer the following assessments: 
– 
Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
• 
administer the following assessments: 
– 
Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
MD-CRS video recording added as 
recognized part of the assessment. 
2.2 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with No Clinically Significant 
Changes Since the Week 15 Visit of Study TV50717-CNS-30080 
b. Day 1 Assessments 
• 
vital signs (orthostatic pulse, and BP, body 
temperature, and respiratory rate) 
• 
vital signs (orthostatic pulse and BP, body 
temperature, and respiratory rate) 
Clarification 
• 
MD-CRS part I (physician rated, video recording) 
• 
MD-CRS part II (physician rated, video recording) 
• 
MD-CRS part I (physician rated, video 
recording) 
• 
MD-CRS part II (physician rated, video 
recording) 
MD-CRS video recording added as 
recognized part of the assessment. 
2.3. Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with Clinically Significant Changes 
and for Patients Who Enroll More Than 4 Weeks and up to 6 Months After Study TV50717-CNS-30080 Week 15 Visit 
a. 
Screening 
See New Wording Column 
• 
ESS (for children and adolescents)  
Revisions were incorporated to 
clarify and align with Table 4 
b. Day 1 
• 
vital signs (orthostatic pulse, and BP, body 
• 
vital signs (orthostatic pulse and BP, body 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
134 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
temperature, and respiratory rate) 
temperature, and respiratory rate) 
• 
MD-CRS part I (physician rated, video recording) 
• 
MD-CRS part II (physician rated, video recording) 
• 
MD-CRS part I (physician rated, video 
recording) 
• 
MD-CRS part II (physician rated, video 
recording) 
MD-CRS video recording added as 
recognized part of the assessment. 
3. 
Procedures During TEV-50717 Treatment 
i. 
In-clinic Visits (Weeks 14, 27, 40, and 53/Early Termination) 
• 
administer the following assessments: 
– 
MD-CRS part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
• 
administer the following assessments: 
– 
MD-CRS part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
MD-CRS video recording added as 
recognized part of the assessment. 
4. 
Procedures After TEV-50717 Treatment (Follow-Up) 
a. 
In-clinic Visit (Week 54) 
• 
administer the following assessments: 
– 
MD-CRS part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
• 
administer the following assessments: 
– 
MD-CRS part I (physician rated, video 
recording) 
– 
MD-CRS part II (physician rated, video 
recording) 
MD-CRS video recording added as 
recognized part of the assessment. 
Appendix D. Quality Control and Quality Assurance 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
Appendix H. List of Allowed and Prohibited Medications 
See New Wording Column 
For COVID-19 updates, refer to Appendix M. 
Updated section to cross-reference 
the addition of Appendix M 
Appendix I. Total Blood Volume 
Total blood volume to be collected for each patient in this 
study is approximately 7677.5 mL. 
Total blood volume to be collected for each patient in this 
study is approximately 77.5 mL. 
Clarification 
See New Wording Column 
The table has been revised as described below: 
• The total blood volume for each visit has been updated 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
135 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Footnote has been deleted  
Appendix M. Management of Study Activities During COVID-19 
See New Wording Column 
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. 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
136 
16.7. 
Amendment 02 Dated 19 March 2020  
The primary reason for this amendment is to extend the rolling-over period from the parent 
Study TV50717-CNS-30080 to the open-label safety extension Study TV50717-CNS-30081.  
This amendment is considered to be substantial by the sponsor’s authorized representative. These 
substantive changes included revised inclusion and exclusion criteria, changes to the allowed and 
prohibited medications, and updates to the general study design. Table 4 and Figure 2 were 
included to provide further clarification and support the more significant adjustments to the study 
design. Table 5 (Study Procedures and Assessments: Titration, Maintenance, and Follow-up 
Periods) has been revised to reflect agreed changes to the study design. All of the changes in the 
table below reflect what has changed from Amendment 01.  
Other minor or editorial non-substantial 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. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
137 
 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Title page (Other sections affected by these changes: Synopsis) 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road145 Brandywine Parkway 
West ChesterFrazer, Pennsylvania 1938055 
United States of America 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
New sponsor address 
SYNOPSIS (Planned Study Period) 
Q4 2019Q1 2020 to Q4 2022 with a duration of 
approximately 55 weeks 
Q1 2020 to Q4 2022 with a duration of approximately 55 
weeks 
Clarification 
SYNOPSIS (Plans for Treatment or Care after the Patient Has Ended Participation in the Study) 
There is no treatment or care planned for patients after the 
end of the study. There are no plans to provide further 
treatment to patients upon completion of the study. An 
extension to the study may be considered on an annual basis.  
There are no plans to provide further treatment to patients 
upon completion of the study. An extension to the study may 
be considered on an annual basis.  
Clarification of the potential plans 
for patient treatment upon 
completion of the study 
1.1. Introduction 
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.  
Clarification 
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). 
Clarification 
2.1.Primary and Secondary Study Objectives and Endpoints 
See New Wording Column 
• 
UHDRS-TMC (physician rated) 
• 
UHDRS-TMD (physician rated) 
UHDRS-TMC=Unified Huntington’s Disease Rating Scale-
Total Maximal Chorea; UHDRS-TMD=Unified 
Huntington’s Disease Rating Scale-Total Maximal Dystonia. 
The table in this section has been 
revised to add two new secondary 
objectives and to add to the list of 
abbreviations   
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
138 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
3.1.General Study Design and Study Schematic Diagram 
For patients rolling over from Study TV50717-CNS-30080, 
the week 16 visit willmay be the day 1 visit for 
Study TV50717-CNS-30081. If the patient does not wish to 
enroll in Study TV50717-CNS-30081 at that visit, or for any 
other reason, the patient can enroll up to 1 week6 months 
following the week 156 visit of the TV50717-CNS-30080 
study. Any patient who cannot enroll within this timeframe, 
for any justified reason, must be discussed and pre-approved 
by the medical monitor prior to enrolling the patient. The 
end of study TV50717-CNS-30081 is defined as the date of 
the week 55 follow-up telephone contact of the last 
participant. 
For patients rolling over from Study TV50717-CNS-30080, 
the week 16 visit may be the day 1 visit for Study TV50717-
CNS-30081. If the patient does not wish to enroll in 
Study TV50717-CNS-30081 at that visit, or for any other 
reason, the patient can enroll up to 6 months following the 
week 15 visit of the TV50717-CNS-30080 study. Any 
patient who cannot enroll within this timeframe, for any 
justified reason, must be discussed and pre-approved by the 
medical monitor prior to enrolling the patient. The end of 
study TV50717-CNS-30081 is defined as the date of the 
week 55 follow-up telephone contact of the last participant. 
Clarification on timing of 
enrollment and informed 
consent/assent process 
Informed consent/assent, as appropriate, based on the child’s 
patient’s age and condition, will be obtained from the 
patient/parent(s)/legally acceptable representative and 
caregiver (as applicable) at baseline/day 1 or screening visit 
(whichever comes first), and before any study procedure is 
performed. Informed consent/assent should be obtained  at 
day 1 of Study TV50717 CNS 30081; however, process can 
begin within 4 weeks before possible participation in the 
open label study to allow patients adequate time to engage 
and ask questions. Informed consent/assent the informed 
consent/assent process can begin within 4 weeks before 
possible participation in the open label study to allow 
patients adequate time to engage and ask questions. 
Informed consent/assent, as appropriate, based on the 
patient’s age and condition, will be obtained from the 
patient/parent(s)/legally acceptable representative and 
caregiver (as applicable) at baseline/day 1 or screening visit 
(whichever comes first), and before any study procedure is 
performed. Informed consent/assent process can begin 
within 4 weeks before possible participation in the open 
label study to allow patients adequate time to engage and ask 
questions.  
Clarification on timing of 
enrollment and informed 
consent/assent process 
For patients who are minors, the caregiver is typically a 
parent or legal guardianlegally acceptable representative. In 
some countries, an adult (such as grandparent or nurse) 
canmay be appointed by the parent or legal guardian legally 
acceptable representative (as per local regulations and laws) 
and would take over this responsibility as caregiver. The 
parent or legal guardian legally acceptable representative 
only has to sign the parent/legal guardianlegally acceptable 
representative informed consent form (ICF) and not the 
caregiver ICF. 
For patients who are minors, the caregiver is typically a 
parent or legally acceptable representative. In some 
countries, an adult (such as grandparent or nurse) may be 
appointed by the parent or legally acceptable representative 
(as per local regulations and laws) and would take over this 
responsibility as caregiver. The parent or legally acceptable 
representative only has to sign the parent/legally acceptable 
representative informed consent form (ICF) and not the 
caregiver ICF. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
139 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
For adult patients, a caregiver must be appointed by the 
patient;. The caregiverthis can be the parent or other adult as 
appropriate and according to local laws and regulations. 
For adult patients, a caregiver must be appointed by the 
patient. The caregiver can be the parent or other adult as 
appropriate and according to local laws and regulations. 
Clarification 
For patients who are minors, certain responsibilities in the 
protocol can only be completed by the parent/ legal 
guardianlegally acceptable representative, 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 the child’s health, or where “parent/legal guardianlegally 
acceptable representative” is specifically indicated in the 
protocol. 
For patients who are minors, certain responsibilities in the 
protocol can only be completed by the parent/legally 
acceptable representative, 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 the child’s 
health, or where “parent/legally acceptable representative” is 
specifically indicated in the protocol. 
Clarification 
… 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), Canadian Occupational Performance 
Measure (COPM)… 
… 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), Canadian Occupational Performance 
Measure (COPM)… 
Revised to add two new secondary 
objectives 
See New Wording Column 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 6 months following the 
week 15 visit of Study TV50717-CNS-30080. The time 
when the patient enrolls (baseline/day 1) in this study will 
determine the assessments that will need to be performed at 
the initial visit for the study (Figure 2).   
Clarification 
Day 1: Between 1 and <2 weeks after Study TV50717-
CNS-30080 week 15 visit: 
Screening: Screening evaluations for this open label study 
will be performed as part of the baseline visit. To reduce 
patient burden and not collect duplicate information, after 
obtaining appropriate informed consent/assent, relevant data 
collected in Study TV50717-CNS-30080 will be used to 
provide corresponding data in this open-label study 
baseline/day 1 visit. Any adverse event that started after the 
end of the parent study and is recorded after informed 
consent/assent for this open label study will be captured 
within this study baselinevisit.   
Day 1: Between 1 and <2 weeks after Study TV50717-
CNS-30080 week 15 visit: 
To reduce patient burden and not collect duplicate 
information, after obtaining appropriate informed 
consent/assent, relevant data collected in Study TV50717-
CNS-30080 will be used to provide corresponding data in 
this open-label study baseline/day 1 visit.  
Day 1 assessments for Study TV50717-CNS-30081 that are 
identical to Study TV50717-CNS-30080 week 15/week 16 
visit assessments, whichever is most current, do not need to 
be repeated, except for orthostatic pulse rate and blood 
pressure, electrocardiogram (ECG), beta-human chorionic 
Clarification of the timing of 
enrollment and subsequent 
assessments required/carried over 
from the parent study based on the 
window of time when the patient 
rolled into the open-label 
extension study 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
140 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Day 1 visit: For all patients, the week 16 visit from Study 
TV50717 CNS 30080 may be the day 1 visit for Study 
TV50717 CNS 30081. Day 1 assessments for Study 
TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/week 16 visit assessments, whichever 
is most current, do not need to be repeated, except for 
orthostatic pulse rate and blood pressure, electrocardiogram 
(ECG), beta-human chorionic gonadotropin (β-HCG) tests in 
urine, the site-administered scales, and the patient/caregiver-
completed questionnaires, which need to be repeated at 
day 1.  
Any scales/questionnaires administered at the week 16 visit 
for Study TV50717-CNS-30080 do not need to be repeated, 
if the day 1 visit of Study TV50717-CNS-30081 is the same 
day as the week 16 visit Study TV50717-CNS-30080. 
gonadotropin (β-HCG) tests in urine, the site-administered 
scales, and the patient/caregiver-completed questionnaires, 
which need to be repeated at day 1.  
Any scales/questionnaires administered at the week 16 visit 
for Study TV50717-CNS-30080 do not need to be repeated, 
if the day 1 visit of Study TV50717-CNS-30081 is the same 
day as the week 16 visit Study TV50717-CNS-30080. 
• Urine drug screen is performed at week 16 in study 
TV50717-CNS-30080 and will serve as day 1 baseline 
values in this study. 
• If the day 1 visit in Study TV50717-CNS-30081 is on the 
same day as the week 16 visit of Study TV50717-CNS-
30080, the results of β-HCG tests in urine will be carried 
over from the week 16 visit.  Otherwise, the β HCG tests in 
urine will be administered at day 1. 
• vital signs (respiratory rate and body temperature) and 
weight are performed at week 16 in Study TV50717-
CNS-30080 and height is performed at week 15 in study 
TV50717-CNS-30080; these findingsassessments will 
serve as day 1 baseline values in this study.  
• physical and neurological examinations are performed at 
week 15 (and week 16, if applicable) in Study TV50717-
CNS-30080. The findings from the last assessment taken 
will serve as day 1 baseline values in this study. 
• ECG is to be performed on day 1 of Study 
TV50717-CNS-30081 and will serve as day 1 baseline 
values in this study.  
• medical and psychiatric history are to be assessed on day 1 
• Urine drug screen is performed at week 16 in study 
TV50717-CNS-30080 and will serve as day 1 baseline 
values in this study. 
• If the day 1 visit in Study TV50717-CNS-30081 is on the 
same day as the week 16 visit of Study TV50717-CNS-
30080, the results of β-HCG tests in urine will be carried 
over from the week 16 visit.  Otherwise, the β HCG tests 
in urine will be administered at day 1. 
• vital signs (respiratory rate and body temperature) and 
weight are performed at week 16 in Study TV50717-CNS-
30080 and height is performed at week 15 in study 
TV50717-CNS-30080; these assessments will serve as day 
1 baseline values in this study.  
• physical and neurological examinations are performed at 
week 15 (and week 16, if applicable) in Study TV50717-
CNS-30080. The findings from the last assessment taken 
will serve as day 1 baseline values in this study. 
• ECG is to be performed on day 1 of Study TV50717-
CNS-30081 and will serve as day 1 baseline values in this 
study.  
• medical and psychiatric history are to be assessed on 
Clarification of the timing of 
enrollment and subsequent 
assessments required/carried over 
from the parent study based on the 
window of time when the patient 
rolled into the open-label 
extension study 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
141 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
of Study TV50717-CNS- 30081 and will serve as day 1 
baseline values in this study. 
• COPM (an assessment included only in Study TV50717-
CNS-30081) will also be performed at day 1.   
day 1 of Study TV50717-CNS- 30081 and will serve as 
day 1 baseline values in this study. 
• COPM (an assessment included only in Study TV50717-
CNS-30081) will also be performed at day 1.   
See New Wording Column 
Day 1: Between 2 and ≤4 weeks after Study TV50717-
CNS-30080 week 15 visit: 
If, in the judgment of the investigator, the patient has not 
had any clinically significant change since the week 15 visit 
of Study TV50717-CNS-30080 in health, concomitant 
medications, clinical assessments, laboratories, ECGs, or 
non-medical interventions, the patient will undergo all day 1 
assessments outlined in Table 4, except hematology, 
chemistry, and urinalysis laboratories and urine drug screen, 
which can be carried over from Study TV50717-CNS-30080 
week 15 or week 16 visit, whichever is more current. 
If, in the judgment of the investigator, the patient has had a 
clinically significant change since the week 15 visit of Study 
TV50717-CNS-30080 in health, concomitant medications, 
clinical assessments, laboratories, ECGs, or non-medical 
interventions, the patient will undergo all screening 
procedures outlined in Table 4. Patients who remain eligible 
for participation in the study will be asked to return for day 1 
assessments.   
Study drug will be dispensed at day 1 once all procedures 
and investigator related assessments are completed and 
patient eligibility is confirmed. 
For patients who enroll in the study between 2 and ≤4 weeks 
after the Study TV50717-CNS-30080 week 15 visit, the 
investigator is required to consult with the medical monitor 
regarding eligibility prior to baseline/day 1. The patient’s 
file should include all related correspondence with the 
medical monitor. 
Clarification of the timing of 
enrollment and subsequent 
assessments required/carried over 
from the parent study based on the 
window of time when the patient 
rolled into the open-label 
extension study 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
142 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
See New Wording Column 
Day 1: More than 4 weeks and up to 6 months after 
Study TV50717-CNS-30080 week 15 visit: 
The patient will undergo all screening procedures outlined in 
Table 4. Patients who remain eligible for participation in the 
study will be asked to return for day 1 assessments. Study 
drug will be dispensed at day 1 once all procedures and 
investigator related assessments are completed and patient 
eligibility is confirmed. 
For patients who enroll in the study more than 4 weeks and 
up to 6 months after the Study TV50717-CNS-30080 week 
15 visit, the investigator is required to consult with the 
medical monitor regarding eligibility prior to baseline/day 1. 
The patient’s file should include all related correspondence 
with the medical monitor. 
Clarification of the timing of 
enrollment and subsequent 
assessments required/carried over 
from the parent study based on the 
window of time when the patient 
rolled into the open-label 
extension study 
The dose of the TEV-50717 should be increased on a weekly 
basis to reach a clinically meaningful reduction in 
dyskinesia, as indicated by a reduction in the CGI-I (see 
Table 6). … 
• the maximum allowable dose is reached based on the 
patient’s weight and CYP2D6 impairment status at day 1. 
Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. 
The dose of TEV-50717 should be increased to reach a 
clinically meaningful reduction in dyskinesia, as indicated 
by a reduction in the CGI-I (see Table 6). … 
• the maximum allowable dose is reached based on the 
patient’s weight and CYP2D6 impairment status at day 1. 
Patients will be classified as CYP2D6 impaired if they are 
receiving a strong CYP2D6 inhibitor. 
Clarification 
Maintenance period (46 weeks): At the end of the titration 
period (week 7), the patient’s initial dose for the 
maintenance period (week 8up to week 53) will be 
established.  Dose adjustments of TEV 50717 (upward or 
downward) may be made during the maintenance period, if 
necessary, based on efficacy, safety, and/or tolerability 
considerations but not more often than every 5  days and 
only in increments of 6 mg. up to the maximum allowed 
dose (Table 6 and Table 7). 
Maintenance period (46 weeks): At the end of the titration 
period (week 7), the patient’s initial dose for the 
maintenance period (up to week 53) will be established. 
Dose adjustments of TEV 50717 (upward or downward) 
may be made during the maintenance period, if necessary, 
based on efficacy, safety, and/or tolerability considerations 
but not more often than every 5  days and only in increments 
of 6 mg. up to the maximum allowed dose (Table 6 and 
Table 7). 
Revised to include the two newly 
added secondary objectives 
… UHDRS-TMS, UHDRS-TMC, UHDRS-TMD, COPM… 
… UHDRS-TMS, UHDRS-TMC, UHDRS-TMD, COPM… 
 
Study procedures and assessments with their time points are 
shown presented for screening and/or day 1 in Table 4 and 
for the titration, maintenance, and follow-up periods in Table 
Study procedures and assessments with their time points are 
presented for screening and/or day 1 in Table 4 and for the 
titration, maintenance, and follow-up periods in Table 5. The 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
143 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
5. The study schematic diagram is presented in Figure 1. A 
flow chart for patient screening and day 1 visit assessments 
is presented in Figure 2. 
study schematic diagram is presented in Figure 1. A flow 
chart for patient screening and day 1 visit assessments is 
presented in Figure 2. 
See New Wording Column 
New Figure 2 (Flow Chart for Patient Screening and Day 1 
Visit Assessments) has been added 
New figure included for 
clarification around patient 
rollover expectations 
3.2.Planned Number of Patients and Regions 
The study is expected to start by the end of Q4 2019Q1 2020 
and last until Q4 2022. 
The study is expected to start by the end of Q1 2020 and last 
until Q4 2022. 
Clarification to the expected start 
date of the study 
3.3. Justification for Study Design and Selection of Population 
The study population will include pediatric and adolescent 
patients (6 through 18 years of age) at the time when they 
enrolled in the parent study [Study TV50717-CNS-30080]) 
with DCP with predominant choreiform movement 
disorder… 
Study TV50717-CNS-30081 uses the same versions of 
scales as in the parent study, to maintain consistency of 
evaluations between these studies. As such, Study TV50717-
CNS-30081 includes some scales that are designated for 
patients up to 18 years old, although potentially some 
patients who entered the parent study at age 18 will now be 
over 18 years old in this extension study. 
The study population will include pediatric and adolescent 
patients (6 through 18 years of age at the time when they 
enrolled in the parent study [Study TV50717-CNS-30080]) 
with DCP with predominant choreiform movement 
disorder.... 
Study TV50717-CNS-30081 uses the same versions of 
scales as in the parent study, to maintain consistency of 
evaluations between these studies. As such, Study TV50717-
CNS-30081 includes some scales that are designated for 
patients up to 18 years old, although potentially some 
patients who entered the parent study at age 18 will now be 
over 18 years old in this extension study. 
Clarification 
3.5. Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are 
presented for screening and day 1 in Table 4 and for the 
titration, maintenance, and follow-up periods in Table 5. 
Study procedures and assessments with their time points are 
presented for screening and day 1 in Table 4 and for the 
titration, maintenance, and follow-up periods in Table 5. 
Clarification to align with updates 
to the schedule of assessments 
tables 
See New Wording Column 
Table 4 (Study Procedures and Assessments:  Screening 
and/or Day 1) has been added 
Table 4 added to provide 
clarification of assessments 
carried over or required upon 
entry to the open-label extension 
study, based on length of time 
between completion of parent 
study and rollover into this study 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
144 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Table 5: Study Procedures and Assessments: Titration, Maintenance, and Follow-up Periods 
See New Wording Column 
Table 5 has been revised as described below: 
• Baseline visit, any related baseline-only procedures, and 
any related footnotes have been removed 
• UHDRS-TMC and UHDRS-TMD have been added 
• Contact IWRS has been added for in clinic visits and 
unscheduled visits 
• Table footnotes have been adjusted to align with updated 
study design expectations 
• List abbreviations has been updated 
• A general note was included to recommend/indicate that 
the same order of administration/completion of the scales 
be kept per patient throughout the study (as best as 
possible) and to advise on timely review of scales for any 
potential adverse events that require reporting 
Revisions were incorporated to 
clarify and align Table 5 and its 
corresponding footnotes against 
the updates included throughout 
the study design and body of the 
protocol 
fc …Patients experiencing an adverse event leading to 
discontinuation or any other adverse event at the 
discretion of the investigator of TEV-50717 should have 
aA blood sample collected as soon as possible after the 
adverse event and within 48 hours for the measurement of 
TEV-50717, α- and β-HTBZ concentrations should be 
collected, if possible, from each patient experiencing a 
serious adverse event or an adverse event leading to 
discontinuation of TEV 50717in at any time during the 
study. To permit the assessment of potential relationship 
of the adverse event and plasma concentration, an 
estimate of the date and time of the last dose intake of 
study drug should be recorded along with the date and 
time of the sample collection. If the estimate of the dose 
intake cannot be established within a 2 hour window, then 
a blood sample should not be obtained. 
c …Patients experiencing an adverse event leading to 
discontinuation or any other adverse event at the 
discretion of the investigator of TEV-50717 should have 
a blood sample collected as soon as possible after the 
adverse event and within 48 hours for the measurement of 
TEV-50717, α- and β-HTBZ concentrations, if possible. 
To permit the assessment of potential relationship of the 
adverse event and plasma concentration, an estimate of 
the date and time of the last dose intake of study drug 
should be recorded along with the date and time of the 
sample collection. If the estimate of the dose intake 
cannot be established within a 2 hour window, then a 
blood sample should not be obtained. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
145 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
ki 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/leg should be 
used each time vital signs are measured for a given 
patient). 
i 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/leg should be 
used each time vital signs are measured for a given 
patient). 
Clarification 
g With the exception of patients weighing ≥40 kg (see 
footnote “c” in Table 6), dose increases may not occur 
more frequently than every 5 days. 
g With the exception of patients weighing ≥40 kg (see 
footnote “c” in Table 6), dose increases may not occur 
more frequently than every 5 days. 
Clarification 
li 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) and should be measured at 
day 1W14 and W53/ET. 
i 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) and should be measured at 
W14 and W53/ET. 
Clarification 
rn. … Children who turn 12 years old during the study will 
be administered C-SSRS (baseline/screening) as initial 
assessment during the study. 
n. … Children who turn 12 years old during the study will 
be administered C-SSRS (baseline/screening) as initial 
assessment during the study. 
 
See New wording column 
p 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. 
 
See New wording column 
s Patients experiencing an adverse event leading to 
discontinuation of TEV-50717 or experiencing any other 
adverse event, at the discretion of the investigator, should 
have a single blood sample collected as soon as possible 
after the adverse event and within 48 hours for the 
measurement of TEV-50717, α- and β-HTBZ 
concentrations, if possible. To permit the assessment of 
potential relationship of the adverse event and plasma 
concentration, an estimate of the date and time of the last 
dose intake of study drug should be recorded along with 
the date and time of the sample collection. If the estimate 
of the dose intake cannot be established within a 2 hour 
window, then a blood sample should not be obtained. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
146 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
See New wording column 
q During the week 3 visit, the investigator (or designee) 
will make sure the patient receives the evening dose to 
complete the week 3 dosing for that day. Refer to the 
pharmacy manual for further details 
Footnote added to provide 
additional guidance to the 
investigator 
tr 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. 
r 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. 
Clarification provided around  
verification of study drug 
compliance 
ut Patients and/or caregivers will be instructed during the 
course of the study to notify the investigator if any new 
medication is prescribed, or if there is any change in 
current medication, including over-the-counter 
medications. Any prescribed medication should be 
reviewed with the investigator. 
t Patients and/or caregivers will be instructed during the 
course of the study to notify the investigator if any new 
medication is prescribed, or if there is any change in 
current medication, including over-the-counter 
medications. Any prescribed medication should be 
reviewed with the investigator. 
Clarification 
Note: 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-30081 Open-RECLAIM-DCP: Order of 
scales administration/completion document). The 
investigator should review the scales in a timely manner for 
any potential reporting of adverse events and document this 
review accordingly. 
Note: 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-30081 Open-RECLAIM-DCP: Order of 
scales administration/completion document). The 
investigator should review the scales in a timely manner for 
any potential reporting of adverse events and document this 
review accordingly. 
Table note included to provide 
additional guidance to the 
investigator surrounding the order 
of administration and review of 
scales 
4.1. Patient Inclusion Criteria 
Inclusion Criteria: Patients who have completed Study 
TV50717 CNS 30080 have already met meet the criteria 
below are eligible to be included in the study. 
a. 
Patient has completed week 16 of the parent Study 
TV50717-CNS-30080 
Inclusion Criteria: Patients who meet the criteria below are 
eligible to be included in the study. 
a. 
Patient has completed week 16 of Study TV50717-
CNS-30080 
Clarification 
g. For a patient who is a minor, the parent(s)/legal 
guardianlegally acceptable representative(s) provides 
written informed consent, and the patient provides assent 
(in accordance with local regulations). Adult patients 
provide written informed consent (in accordance with 
local regulations) and the legally acceptable 
g. For a patient who is a minor, the parent(s)/legally 
acceptable representative(s) provides written informed 
consent, and the patient provides assent (in accordance 
with local regulations). Adult patients provide written 
informed consent (in accordance with local regulations) 
and the legally acceptable representative will sign, if 
Text added to provide additional 
guidance in consideration of 
exclusion crtieria “i” 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
147 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
representative will sign, if needed provide their own 
written informed consent. 
In this study, eligible patients with dyskinetic cerebral 
palsy 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 
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 requirement to obtain the relevant consent/assent.   
needed. 
In this study, eligible patients with dyskinetic cerebral 
palsy 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 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 requirement to obtain the relevant 
consent/assent.   
h. A caregiver provides written informed consent after 
being assigned the role by an adult patient or if this role 
is delegated by the parent/legal guardianlegally 
acceptable representative of a patient who is a minor. 
h. A caregiver provides written informed consent after 
being assigned the role by an adult patient or if this role 
is delegated by the parent/legally acceptable 
representative of a patient who is a minor. 
Clarification 
4.2. Patient Exclusion Criteria 
a. 
Patient has clinically significant depression at 
screening or day 1 of this study. 
Note: Patients receiving antidepressant therapy may be 
enrolled if on a stable dose for at least 6 weeks before 
screening or day 1 (whichever comes first) and 
anticipated to remain stable (dose and frequency) within 
the study duration. 
b. Patient has clinically significant depression at 
screening or day 1 of this study. 
Note: Patients receiving antidepressant therapy may be 
enrolled if on a stable dose for at least 6 weeks before 
screening or day 1 (whichever comes first) and 
anticipated to remain stable (dose and frequency) within 
the study duration. 
Exclusion criteria were revised to 
provide more clear guidelines for 
patient exclusion. Specific 
stipulations and concomitant 
medications were clarified 
b. Patient has a history of suicidal intent or related 
behaviors based on medical or psychiatric history or the 
C-SSRS at screening visit, if performed, or at the day 1 
visit, as applicable according to the patient’s age: 
– 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 
b. Patient has a history of suicidal intent or related 
behaviors based on medical or psychiatric history or the 
C-SSRS at screening visit, if performed, or at the day 1 
visit, as applicable according to the patient’s age: 
– intent to act on suicidal ideation with a specific plan, 
irrespective of level of ambivalence, at the time of 
suicidal thought 
– suicidal preparatory acts or behavior 
Clarification 
c. Patient has a history of a previous actual, interrupted, or 
aborted suicide attempt based on medical or psychiatric 
history or the C-SSRS at screening visit, if performed, or 
at the day 1 visit, as applicable according to the patient’s 
c. Patient has a history of a previous actual, interrupted, or 
aborted suicide attempt based on medical or psychiatric 
history or the C-SSRS at screening visit, if performed, or 
at the day 1 visit, as applicable according to the patient’s 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
148 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
age. 
age. 
e. Patient who is currently receiving or who 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. 
“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 
Prior exclusion criteria “e” has been removed 
 
  
Upon further consideration of 
exlusion criteria “e”, it was 
decided to remove the criteria 
surrounding BoNT and provide 
clarification in Appendix H. 
fe. Patient has received any of the following concomitant 
medications for dystonia and chorea within the specified 
exclusionary windows offrom screening or day 1 
(whichever comes first) of this study: 
 within 3 months: depot neuroleptics 
− within 30 days: tetrabenazine or valbenazine  
− within 21 days: reserpine 
− within 14 days: neuroleptics (oral), typical and 
atypical antipsychotics, metoclopramide, levodopa, 
dopamine agonists, and monoamine oxidase 
inhibitors 
e. Patient has received any of the following concomitant 
medications within the specified exclusionary windows 
from screening or day 1 (whichever comes first) of this 
study: 
− within 30 days: tetrabenazine or valbenazine  
− within 21 days: reserpine 
− within 14 days: levodopa, dopamine agonists, and 
monoamine oxidase inhibitors 
Clarification of the concomitant 
medication types and criteria for 
patient exclusion 
gf. Patient has received treatment with stem cells, deep brain 
stimulation, transmagnetic stimulation, or transcranial 
direct current stimulation for treatment of abnormal 
movements or CP since the week 15 visit of Study 
TV50717-CNS-30080, or the patient is not in a stable 
clinical condition.   
f. Patient has received treatment with stem cells, deep brain 
stimulation, transmagnetic stimulation, or transcranial 
direct current stimulation for treatment of abnormal 
movements or CP since the week 15 visit of Study 
TV50717-CNS-30080, or the patient is not in a stable 
clinical condition.   
Clarification 
hg. Patient had as recent surgical procedure since the week 
15 visit of Study TV50717-CNS-30080 or is anticipated 
to have a surgical procedure during the study that, in the 
g. Patient had a surgical procedure since the week 15 visit 
of Study TV50717-CNS-30080 or is anticipated to have a 
surgical procedure during the study that, in the opinion of 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
149 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
opinion of the investigator, makes the patient unsuitable 
for the study. 
the investigator, makes the patient unsuitable for the 
study. 
ji. Patient has a QT interval corrected for heart rate (QTc) 
using Fridericia’s formula (QTcF) value >450 msec on 
12-lead ECG at screening or day 1 (whichever comes 
first) of this study. 
i. Patient has a QT interval corrected for heart rate (QTc) 
using Fridericia’s formula (QTcF) value >450 msec on 
12-lead ECG at screening or day 1 (whichever comes 
first) of this study . 
Clarification 
lk. Patient has evidence of hepatic impairment, as indicated 
by the following: 
– aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2.5× the upper limit of the 
normal range (ULN) at day 1the week 15 or week 16 
visit of Study TV50717-CNS-30080 or screening of 
this study, as applicable 
– alkaline phosphatase (ALP) or total bilirubin (Tbil) 
>2×ULN at day 1 the week 15 or week 16 visit of 
Study TV50717-CNS-30080 or screening of this 
study, as applicable 
Note: Patients with abnormalities in 2 or more of 
AST, ALT, ALP, and Tbil the following clinical 
laboratory parameters that do not meet the above 
laboratory criteria for exclusion based on hepatic 
impairment must be approved for enrollment by the 
medical monitor: AST, ALT, ALP, and Tbil. 
k. Patient has evidence of hepatic impairment, as indicated 
by the following: 
– aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2.5× the upper limit of the 
normal range (ULN) at the week 15 or week 16 visit 
of Study TV50717-CNS-30080 or screening of this 
study, as applicable 
– alkaline phosphatase (ALP) or total bilirubin (Tbil) 
>2×ULN at the week 15 or week 16 visit of Study 
TV50717-CNS-30080 or screening of this study, as 
applicable 
Note: Patients with abnormalities in 2 or more of 
AST, ALT, ALP, and Tbil parameters that do not 
meet the above laboratory criteria for exclusion based 
on hepatic impairment must be approved for 
enrollment by the medical monitor. 
Clarification 
ml. Patient has evidence of clinically significant renal 
impairment, indicated by a serum creatinine >1.5×ULN 
at day 1the week 15 or week 16 visit of Study TV50717-
CNS-30080 or screening of this study, as applicable 
l. Patient has evidence of clinically significant renal 
impairment, indicated by a serum creatinine >1.5×ULN 
at the week 15 or week 16 visit of Study TV50717-CNS-
30080 or screening of this study, as applicable 
Clarification 
qp. Patient has a history of or acknowledges alcohol or 
substance abuse, as defined in the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition 
(DSM V™). 
p. Patient has a history of or acknowledges alcohol or 
substance abuse. 
Clarification 
rq. Patient has a positive urine drug screen test result since 
the week 15 or week 16 visit of Study TV50717-CNS-
30080 or at screening (as applicable) of this study (with 
exception of medications listed in Table 10Table 11 of 
q. Patient has a positive urine drug screen test result since 
the week 15 or week 16 visit of Study TV50717-CNS-
30080 or at screening (as applicable) of this study (with 
exception of medications listed in Table 11 of Appendix 
Clarification provided with 
regards to urine drug screen 
exclusion criteria ‘r” 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
150 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Appendix H or a justified medical explanation). Any 
request to include a patient with a positive urine drug 
screen test result should be discussed with, and approved 
by, the medical monitor. or is unable to refrain from 
substance abuse throughout the study. 
H or a justified medical explanation). Any request to 
include a patient with a positive urine drug screen test 
result should be discussed with, and approved by, the 
medical monitor.  
4.3. 
Withdrawal Criteria and Procedures for the Patient (Other sections affected by these changes: 7.9) 
The investigator also has the right to withdraw a patient from 
the IMP in the event of intercurrent illness, adverse events, 
pregnancy (see Section 7.3), or change in concomitant 
treatment (see Appendix H); patient engages in alcohol or 
other substance abuse; patient or parent(s)/legally acceptable 
representative withdraws consent or requests discontinuation 
from the IMP; the sponsor requests withdrawal of the patient 
or other reasons concerning the health or well being of the 
patient; or other reasons concerning the health or well being 
of the patient, or in the event of lack of cooperation. 
If a post-day 1treatment QTcF value >500 msec or change 
from screening or day 1 >60 msec is found, the investigator 
should repeat the ECG assessment twice and then compare 
the last pre treatment QTcF value (baseline) to the average of 
the 3 post day 1treatment QTcF values. TEV 50717 must be 
stopped for any confirmed post- day 1treatment QTcF 
average value >500 msec or average increase from screening 
or day 1 >60 msec. 
Patients experiencing an adverse event leading to 
discontinuation or any other adverse event at the discretion 
of the investigator of TEV-50717 should have a single blood 
sample collected as soon as possible after the adverse event 
and within 48 hours for the measurement of TEV-50717, α-
HTBZ and β-HTBZ concentrations, if possible. To permit the 
assessment of potential relationship of the adverse event and 
plasma concentration, an estimate of the date and time of the 
last dose intake of study drug should be recorded along with 
the date and time of the sample collection. If the estimate of 
the dose intake cannot be established within a 2 hour 
window, then a blood sample should not be obtained. 
The investigator also has the right to withdraw a patient 
from the IMP in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.3), or change in 
concomitant treatment (see Appendix H); patient engages in 
alcohol or other substance abuse; patient or parent(s)/legally 
acceptable representative withdraws consent or requests 
discontinuation from the IMP; the sponsor requests 
withdrawal of the patient or other reasons concerning the 
health or well being of the patient; or other reasons 
concerning the health or well being of the patient, or in the 
event of lack of cooperation. 
If a post-treatment QTcF value >500 msec or change from 
screening or day 1 >60 msec is found, the investigator 
should repeat the ECG assessment twice and then compare 
the last pre treatment QTcF value to the average of the 3 
post treatment QTcF values. TEV 50717 must be stopped for 
any confirmed post-treatment QTcF average value 
>500 msec or average increase from screening or day 1 
>60 msec. 
Patients experiencing an adverse event leading to 
discontinuation or any other adverse event at the discretion 
of the investigator of TEV-50717 should have a single blood 
sample collected as soon as possible after the adverse event 
and within 48 hours for the measurement of TEV-50717, α-
HTBZ and β-HTBZ concentrations, if possible. To permit the 
assessment of potential relationship of the adverse event and 
plasma concentration, an estimate of the date and time of the 
last dose intake of study drug should be recorded along with 
the date and time of the sample collection. If the estimate of 
the dose intake cannot be established within a 2 hour 
window, then a blood sample should not be obtained. 
Criteria for patient withdrawal 
was clarified and elaborated upon 
Additional guidance provided on 
how to handle blood samples for 
patients experiencing an adverse 
event leading to discontinuation 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
151 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
4.5 Rescreening 
See New wording column 
A patient who is screened but not enrolled (eg, because 
inclusion criteria were not met,  exclusion criteria were 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. 
Section added to provide 
clarification around rescreening 
procedures 
5.1.1.2.Dose Modification and Dose Stratification 
Dose adjustments of TEV 50717 (upward or downward) may 
be made during the maintenance period, if necessary, based 
on efficacy, safety, and/or tolerability considerations but not 
more often than every 5 days and only in increments of 6 mg 
up to the maximum allowed dose (Table 6 and Table 7). 
Dose adjustments of TEV 50717 (upward or downward) 
may be made during the maintenance period, if necessary, 
based on efficacy, safety, and/or tolerability considerations 
but not more often than every 5 days and only in increments 
of 6 mg up to the maximum allowed dose (Table 6 and 
Table 7). 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
152 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
TEV-50717 will be administered as follows: 
• TEV-50717 cannot be crushed or split but should be 
swallowed whole; the TEV 50717 tablets should 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 and titration will be based on body weight at the 
day 1 visit and CYP2D6 impairment status, as shown in 
Table 5Table 6 and Table 6Table 7, respectively. 
• After week 1, dDose increases may not occur more 
frequently than every 5 days, except for patients ≥40 kg. 
For patients ≥40 kg, 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 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. 
• During the titration period, the dose of TEV-50717 
should be adjusted weekly according to Table 5Table 6 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. 
 
Footnote “a” was added to Table 6: 
a 
Dose increases may not occur more frequently than every 
5 days, except for patients ≥40 kg. For patients ≥40 kg, 
the first dose increase may be performed in an interval 
less than 5 days, only once, on day 3. 
TEV-50717 will be administered as follows: 
• TEV-50717 cannot be crushed or split but should be 
swallowed whole; the TEV 50717 tablets should 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 and titration will be based on body weight at the 
day 1 visit and CYP2D6 impairment status, as shown in 
Table 6 and Table 7, respectively. 
• Dose increases may not occur more frequently than every 
5 days, except for patients ≥40 kg. For patients ≥40 kg, 
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 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. 
• During the titration period, the dose of TEV-50717 
should be adjusted according to Table 6 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. 
 
Footnote “a” was added to Table 6: 
a Dose increases may not occur more frequently than every 
5 days, except for patients ≥40 kg. For patients ≥40 kg, 
the first dose increase may be performed in an interval 
less than 5 days, only once, on day 3. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
153 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Table 8: Investigational Medicinal Products Used in the Study 
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F), protected from light and moisture 
Stored at controlled room temperature, 20°C-25°C 
(68°F-77°F) 
Study storage stipulations were 
clarified 
5.2.1. 
Storage and Security 
TEV-50717 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. 
TEV-50717 must be stored 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. 
Study drug storage stipulations 
were clarified 
5.5. Restrictions 
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.  
 
Clarification 
5.6. Prior and Concomitant Medication or Therapy 
At each clinic visit after screening or day 1 (whichever 
comes first), the investigator will ask patients and/or 
caregivers whether the patient has taken any new 
medications (other than TEV-50717) or has any change in 
current medications, including… 
At each clinic visit after screening or day 1 (whichever 
comes first), the investigator will ask patients and/or 
caregivers whether the patient has taken any new 
medications (other than TEV-50717) or has any change in 
current medications, including 
Clarification 
Patients and/or caregivers 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 there is any change in current medications, 
including over-the-counter medications. 
Patients and/or caregivers 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 there is any change in current medications, 
including over-the-counter medications. 
Clarification 
Prohibited medications that are associated with QTc 
prolongation are listed in Appendix H, Table 1112. 
Prohibited antipsychotic drugs are listed in Appendix H, 
Table 12. 
Prohibited medications that are associated with QTc 
prolongation are listed in Appendix H, Table 12.  
Prohibited antipsychotic drugs 
table has been deleted 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
154 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
5.7. Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient 
compliance. A check of compliance with TEV-50717 intake 
will be performed during each in-clinic visit and telephone 
contact after TEV 50717 has been dispensed and will be 
documented in each patient’s file.; and TEV-50717 
accountability records will be completed during each in-
clinic visit. 
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. Poor compliance with study 
drug (ie, <80%) or overdose (ie, >105%) is to be recorded as 
an important deviation and expeditely reported to the 
medical monitor. 
The investigator will be responsible for monitoring patient 
compliance. A check of compliance with TEV-50717 intake 
will be performed during each in-clinic visit and telephone 
contact and will be documented in each patient’s file. TEV-
50717 accountability records will be completed during each 
in-clinic visit. 
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. Poor compliance with study 
drug (ie, <80%) or overdose (ie, >105%) is to be recorded as 
an important deviation and expeditely reported to the 
medical monitor. 
Clarification 
5.8. Temporary Discontinuation of Investigational Medicinal Product 
Dose adjustments of TEV 50717 (upward or downward) may 
be made during the titration and maintenance periods, if 
necessary, based on efficacy, safety, and/or tolerability 
considerations but not more often than every 5 days and only 
in increments of 6 mg up to the maximum allowed dose 
(Table 6 and Table 7). After the dose modification, the 
patients will remain at the modified dose throughout that 
period unless further dose adjustments are warranted, and 
will otherwise follow the visit schedule as outlined in the 
protocol. 
Dose adjustments of TEV 50717 (upward or downward) 
may be made during the maintenance periods, if necessary, 
based on efficacy, safety, and/or tolerability considerations 
but not more often than every 5 days and only in increments 
of 6 mg up to the maximum allowed dose (Table 6 and 
Table 7). After the dose modification, the patients will 
remain at the modified dose unless further dose adjustments 
are warranted, and will follow the visit schedule as outlined 
in the protocol. 
Clarification 
Suspension of TEV-50717 treatment for up to 1 week, if 
warranted, is allowed. If a patient’s serum potassium or 
magnesium falls below the lower limit of normal, TEV-
50717 must should be suspended. 
Suspension of TEV-50717 treatment for up to 1 week, if 
warranted, is allowed. If a patient’s serum potassium or 
magnesium falls below the lower limit of normal, 
TEV-50717 should be suspended. 
Clarification 
Patients who restart TEV-50717 treatment will remain at the 
current dose unless further dose adjustments are warranted, 
and will otherwise follow the visit schedule as outlined in the 
protocol. 
Patients who restart TEV-50717 treatment will remain at the 
current dose unless further dose adjustments are warranted, 
and will follow the visit schedule as outlined in the protocol. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
155 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
5.11. 
Total Blood Volume 
The total blood volume to be collected for each patient in 
this study is approximately 7672 mL. 
The total blood volume to be collected for each patient in 
this study is approximately 76 mL. 
Update to align with slightly 
increased blood draws as indicated 
in Appendix I 
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 COPM. 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-30081 Open-RECLAIM-DCP: Order of 
scales administration/completion document).  
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 and any trends observed 
throughout the study. 
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 COPM. 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-30081 Open-RECLAIM-DCP: Order 
of scales administration/ completion document).  
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 and any trends observed 
throughout the study. 
Clarification to provide 
recommendation to the sites 
regarding the order that each scale 
is administered 
6.1.1. 
Movement Disorder-Childhood Rating Scale 
The MD-CRS will be either carried over from the week 16 
visit of Study TV50717 CNS 30080 W16 and administered 
by the investigational center physician at the day 1 visit 
(Table 4) and at week 14, week 27, week 40, week 53/ET, 
and week 54/follow-up visits. 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. 
The MD-CRS will be administered at the day 1 visit (Table 
4) and at week 14, week 27, week 40, week 53/ET, and 
week 54/follow-up visits (Table 5). 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. 
Clarifications provided on carry 
over and administration of the 
MD-CRS 
6.1.2. 
Caregiver Global Impression of Improvement Scale 
The CaGI-I is to be assessed completed before all other 
investigator rated scales during visits where CaGI-I is 
collected (Table 4Table 5). 
The CaGI-I is to be completed before all other investigator 
rated scales during visits where CaGI-I is collected 
(Table 5). 
Clarification 
6.1.4. 
Clinical Global Impression of Severity 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
156 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
The CGI-S is carried over from Study TV50717 CNS 30080 
W16 administered at the day 1 visit (Table 4) and …   
The CGI-S is administered at the day 1 visit (Table 4) and 
…   
Clarification 
6.1.6. 
Unified Huntington’s Disease Rating Scale-Total Motor Score 
See New wording column 
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). 
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) (Huntington 
Study Group 1996). 
Revised to include the definitions 
of the UHDRS-TMC and the 
UHDRS-TMD 
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 
for this study to the end of the follow up period. 
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. 
 
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). 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-30081 Open-RECLAIM-DCP: Order of scales 
administration/completion document).  
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 and any trends observed 
throughout the study. 
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-30081 Open-RECLAIM-DCP: Order of 
scales administration/completion document).  
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 and any trends observed 
throughout the study. 
Text added to clarify that there is a 
recommended order of 
administration of scales that 
should be followed throughout the 
study’s duration 
7.2.1. 
Children’s Columbia-Suicide Severity Rating Scale 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
157 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
The children’s C-SSRS Since Last Visit is administered at 
screening and/or day 1, as applicable (Table 4), and at the 
weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up (Table 5). 
However, if the patient turned 12 years old during or after 
Study TV50717-CNS-30080, but before screening or day 1 
visit of Study TV50717-CNS-30081, whichever comes first, 
the C-SSRS baseline/screening scale is administered. If the 
patient turns 12 years old during the study, C-SSRS 
baseline/screening will be completed as the initial 
assessment and the C-SSRS Since Last Visit will be 
completed as per Table 5. 
The children’s C-SSRS Since Last Visit is administered at 
screening and/or day 1, as applicable (Table 4), and at weeks 
3, 7, 14, 27, 40, 53/ET, and 54/follow up (Table 5). 
However, if the patient turned 12 years old during or after 
Study TV50717-CNS-30080, but before screening or day 1 
visit of Study TV50717-CNS-30081, whichever comes first, 
the C-SSRS baseline/screening scale is administered. If the 
patient turns 12 years old during the study, C-SSRS 
baseline/screening will be completed as the initial 
assessment and the C-SSRS Since Last Visit will be 
completed as per Table 5. 
Clarification on C-SSRS 
administration and carry over 
expectations 
A shift table for children’s C SSRS categories at day 1 
(carried over from study TV50717 CNS  30080 W16), 
compared to the worst (highest) category during the 
treatment period, will be presented. 
A shift table for children’s C SSRS categories at day 1, 
compared to the worst (highest) category during the 
treatment period, will be presented. 
 
7.2.2. 
Extrapyramidal Symptom Rating Scale 
The ESRS is carried over from study TV50717 CNS 30080 
W16 and administered at the day 1 visit (Table 4) and at the 
weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up visits (Table 
5). 
The ESRS is administered at the day 1 visit (Table 4) and 
administered at weeks 3, 7, 14, 27, 40, 53/ET, and 
54/follow-up visits (Table 5). 
Clarification on ESRS 
administration and carry over 
expectations 
7.2.3. 
Child Behavior Checklist (for Ages 6 to 18) 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at the day 1 visit (Table 4) and at the week 53/ET 
visit (Table 5). The Competence part [Parts I to VII] will be 
carried over from study TV50717 CNS 30080 W15. The 
Syndrome Scale part of the CBCL [behavioral items] will be 
carried over from study TV50717 CNS 30080 W16 and 
completed at weeks 3, 7, 14, 27, 40, and 54/follow-up visits 
(Table 5). 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at the day 1 visit (Table 4) and at the week 53/ET 
visit (Table 5). The Syndrome Scale part of the CBCL 
[behavioral items] will be completed at weeks 3, 7, 14, 27, 
40, and 54/follow-up visits (Table 5). 
Text added to include and clarify 
expectations surrounding the 
administration of the CBCL 
7.2.4. 
Epworth Sleepiness Scale (for Children and Adolescents) 
The ESS is carried over from study TV50717 CNS 30080 
W16 and administered at the day 1 visit (Table 4) and at the 
weeks 3, 7, 14, 27, 40, 53/ET, and 54/follow-up visits (Table 
The ESS is administered at the day 1 visit (Table 4) and 
administered at weeks 3, 7, 14, 27, 40, 53/ET, and 
54/follow-up visits (Table 5). 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
158 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
5). 
7.3. Pregnancy 
All pregnancies of female patients participating in the study 
that occur since the week 15 visit of Study TV50717-
CNS-30080, during the sStudy TV50717-CNS-30081, or 
within 14 days after the end of study are to be reported 
immediately once the investigator has become aware of the 
pregnancy. The pregnancy should be reported to… 
All pregnancies of female patients participating in the study 
that occur since the week 15 visit of Study TV50717-
CNS-30080, during Study TV50717-CNS-30081, or within 
14 days after the end of study are to be reported immediately 
once the investigator has become aware of the pregnancy. 
The pregnancy should be reported to… 
Clarification of pregnancy 
reporting process and timing 
7.5.2.1. Beta-Human Chorionic Gonadotropin Tests 
See New wording column 
For females who are postmenarchal or ≥12 years of age, the 
following β-HCG tests in urine or serum will be performed 
based on when the patient enrolls in the study:   
• 
If the patient enrolls between 1 and <2 weeks after 
the week 15 visit of Study TV50717-CNS-30080:   
– If the day 1 visit in Study TV50717-CNS-30081 
is on the same day as the week 16 visit of Study 
TV50717-CNS-30080, the results of β-HCG tests 
in urine will be carried over from the week 16 
visit.   
– Otherwise, the β HCG tests in urine will be 
administered at day 1.   
• 
If the patient enrolls between 2 and ≤4 weeks after 
the week 15 visit of Study TV50717-CNS-30080 and 
does not have a clinically significant change, β-HCG 
tests in urine will be administered at day 1.   
• 
If the patient enrolls between 2 and ≤4 weeks after 
the week 15 visit of Study TV50717-CNS-30080 and 
has a clinically significant change OR enrolls more 
than 4 weeks and up to 6 months after the week 15 
visit of Study TV50717-CNS-30080, β-HCG tests in 
serum will be administered at screening. A β-HCG 
test in urine will be performed at the day 1 visit. 
A patient with a positive β-HCG test in urine cannot be 
enrolled until a β-HCG test in serum has been performed 
Text added to provide clarification 
around the assessment and timing 
of administration of β-HCG tests. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
159 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
and is negative. 
During the treatment period, β-HCG tests in urine will be 
performed for females who are postmenarchal or ≥12 years 
of age at day 1 and at weeks 14, 27, 40, and 54/follow-up. 
During the treatment period, β-HCG tests in urine will be 
performed for females who are postmenarchal or ≥12 years 
of age at weeks 14, 27, 40, and 54/follow-up. 
Clarification 
7.5.2.2. Urine Drug Screen 
…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/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, if 
the dosing has been stable for at least 4 weeks before 
screening or day 1 and if no changes to dose or frequency are 
anticipated during the course of the study. Such cases should 
be discussed with the medical monitor. For patients who are 
either using these medications or who have a positive drug 
screen for these substances or derivatives, such cases should 
be submitted to the medical monitor for consideration of 
participation in this study. If per the investigator’s judgment, 
however, a patient does not meet the criteria for substance 
use disorder, a positive drug screen 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. 
…will preclude the patient from 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/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, if 
the dosing has been stable for at least 4 weeks before 
screening or day 1 and if no changes to dose or frequency 
are anticipated during the course of the study. Such cases 
should be discussed with the medical monitor. For patients 
who are either using these medications or who have a 
positive drug screen for these substances or derivatives, such 
cases should be submitted to the medical monitor for 
consideration of participation in this study. If per the 
investigator’s judgment, however, a patient does not meet 
the criteria for substance use disorder, a positive drug screen 
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. 
Clarification on the possible 
exceptions that may be considered 
upon conducting the urine drug 
screen 
7.6. 
Vital Signs 
(The same position and arm/leg should be used each time 
vital signs are measured for a given patient.) 
(The same position and arm/leg should be used each time 
vital signs are measured for a given patient.) 
Clarification 
7.9. 
Electrocardiography 
A 12 lead ECG will be recorded at the time points detailed in 
Table 4 and Table 5. All ECGs will be performed after at 
A 12 lead ECG will be recorded at the time points detailed 
in Table 4 and Table 5. All ECGs will be performed after at 
Text added to provide additional 
guidance to the investigator with 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
160 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
least 5-minute rest in a supine or semi-supine position. The 
investigator should review the ECG at day 1 and at screening 
(in case a screening visit is performed) to determine patient 
eligibility for the study and subsequent ECGs for patient’s 
continuation in the study.  
least 5-minute rest in a supine or semi-supine position. The 
investigator should review the ECG at day 1 and at 
screening (in case a screening visit is performed) to 
determine patient eligibility for the study and subsequent 
ECGs for patient’s continuation in the study.  
regards to patient eligibility.  
If a post-day 1treatment QTcF value >500 msec or change 
from screening or day 1 >60 msec is found, the investigator 
should repeat the ECG assessment twice and then compare 
the last pre treatment QTcF value (baseline) to the average of 
the 3 post day 1treatment QTcF values. TEV 50717 must be 
stopped for any confirmed post-day 1treatment QTcF 
average value >500 msec or average increase from screening 
or day 1 >60 msec. 
If a post-treatment QTcF value >500 msec or change from 
screening or day 1 >60 msec is found, the investigator 
should repeat the ECG assessment twice and then compare 
the last pre treatment QTcF value to the average of the 3 
post treatment QTcF values. TEV-50717 must be stopped 
for any confirmed post-treatment QTcF average value >500 
msec or average increase from screening or day 1 >60 msec. 
Clarification 
7.12. Concomitant Medication or Treatment 
Patients and/or caregivers 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 there is any change in current medications, 
including over the counter medications.  
Patients and/or caregivers 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 has any change in current medications, 
including over the counter medications.  
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 
…under the guidance, supervision, or prescription of a 
clinician and anticipated to remain stable (dose and 
frequency) within the study duration. 
…under the guidance, supervision, or prescription of a 
clinician and anticipated to remain stable (dose and 
frequency) within the study duration. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
161 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
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 must 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. 
Medications that are allowed, provided that conditions 
outlined in the table are met, are shown in Appendix H, 
Table 11. 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 if pre-approved by the medical monitor.. 
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 must be submitted 
to the medical monitor for consideration of participation in 
this study.  
Medications that are allowed, provided that conditions 
outlined in the table are met, are shown in Appendix H, 
Table 11. 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 if pre-approved by the medical monitor. 
Prohibited medications that are associated with QTc 
prolongation are listed in Appendix H, Table 12, while 
prohibited antipsychotic drugs are listed in Appendix H, 
Table 13. 
Prohibited medications that are associated with QTc 
prolongation are listed in Appendix H, Table 12. 
Table 13 was deleted 
9.7. 
Efficacy Analysis 
See New wording column 
• 
UHDRS-TMC (physician rated) 
• 
UHDRS-TMD (physician rated) 
Text added to include the two 
newly added secondary objectives 
15. 
REFERENCES 
See New wording column 
National Institute of Neurological Disordes 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 
New reference added in the 
Introduction 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
162 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
See New wording column 
Bioanalytic Laboratory 
 
 
Watson Pharma Pvt, Ltd. 
Seawoods Grand Central Tower 2, 
Level-11, Wing-E, Plot N0 R-1, 
Sector 40, Nerul, Navi Mumbai-400706 
India  
Tel. No. 
 
 
Administrative change 
See New wording column 
Scales Raters Training And Qualification 
Bracket Global LLC 
785 Arbor Way 
Blue Bell, PA, 19422  
Tel : 
 
Administrative change 
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. 
Procedures for Screening and Enrollment  
Informed consent/assent, depending on the child’spatient’s 
age and condition, as appropriate, will be obtained from the 
patient/parent(s)/legally acceptable representative and 
caregiver (as applicable) at baseline/day 1 or screening visit 
(whichever comes first), and before any study procedures are 
performed. Informed consent/assent should be obtained at 
day 1 of Study TV50717 CNS 30081 ; however, the 
informed consent/assent process can begin within 4 weeks 
before possible participation in the open label study to allow 
patients adequate time to engage and ask questions.  
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 6 months following the 
week 15 visit of Study TV50717-CNS-30080. The time 
when the patient enrolls (baseline/day 1) in this study will 
determine the assessments that will need to be performed at 
the initial visit for the study (Figure 2). 
Informed consent/assent, depending on the patient’s age and 
condition will be obtained from the patient/parent(s)/legally 
acceptable representative and caregiver (as applicable) at 
baseline/day 1 or screening visit (whichever comes first), 
and before any study procedures are performed. Informed 
consent/assent process can begin within 4 weeks before 
possible participation in the open label study to allow 
patients adequate time to engage and ask questions. 
Patients can either enroll in the study at the week 16 visit of 
Study TV50717-CNS-30080 or up to 6 months following the 
week 15 visit of Study TV50717-CNS-30080. The time 
when the patient enrolls (baseline/day 1) in this study will 
determine the assessments that will need to be performed at 
the initial visit for the study (Figure 2). 
Study procedures and assessments 
have been updated for consistency 
with changes made to the protocol 
body, Table 4, and Table 5. 
 
This justification applies to all 
changes indicated within 
Appendix C. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
163 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
2. 
Procedures Before TEV-50717 Treatment  
2.1 Procedures for Patients Who Enroll Between 1 and <2 Weeks After Study TV50717-CNS-30080 Week 15 Visit 
For all patients, the week 16 visit from Study TV50717
CNS 30080 may be the day 1 visit for Study TV50717
CNS 30081. Day 1 assessments for Study TV50717 CNS
30081 that are identical to Study TV50717 CNS 30080 
baseline/week 15/16 visit assessments, whichever is most 
current, will serve as day 1 baseline values in this study 
and do not need to be repeated, except for orthostatic 
pulse rate, blood pressure (BP), Pediatric Evaluation 
Disability Inventory Computer Adapted Test (PEDI 
CAT), and Unified Huntington’s Disease Rating Scale
Total Motor Score (UHDRS TMS) which need to be 
repeated at day 1. 
a. AssessmentsData carried over from Study TV50717-
CNS-30080 - BaselineScreening 
• Medical history and psychiatric history 
• Demographics 
b. Assessments carried over from Study TV50717-
CNS-30080 - Week 15/16 
• Week 16 (W16) vital signs (pulse, BP, body 
temperature, and respiratory rate) 
• W16 urine pregnancy (beta human chorionic 
gonadotropin [β HCG]) test (required for all females 
who are postmenarchal or ≥12 years of age) 
… 
• administer the following assessments: 
 W16 Movement Disorder Childhood Rating Scale 
(MD CRS) part I  
 W16 MD CRS part II 
 W16 Clinical Global Impression of Severity 
(CGI S)  
 W16 Columbia Suicide Severity Rating Scale (C
SSRS) …. 
a. Data carried over from Study TV50717-CNS-30080 
- Screening 
• Demographics 
b. Assessments carried over from Study TV50717-
CNS-30080 - Week 15/16 
• Week 16 (W16) vital signs (body temperature, and 
respiratory rate) 
… 
c. Day 1 Assessments  
• medical history and psychiatric history 
• urine pregnancy (beta-human chorionic 
gonadotropin [β-HCG]) test (required for all females 
who are postmenarchal or ≥12 years of age) 
• administer the following assessments: 
– Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I  
– MD-CRS part II 
– Clinical Global Impression of Severity (CGI-S)  
– Pediatric Evaluation Disability Inventory-
Computer Adapted Test (PEDI-CAT) 
– Child Behavior Checklist (CBCL) (for ages 6-18) 
(Competence Scale [Parts I to VII] and Syndrome 
Scale [behavioral items]) 
− 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) 
– Canadian Occupational Performance Measure 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
164 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
 W16 Extrapyramidal Symptom Rating Scale 
(ESRS) subscales I and II 
 Child Behavior Checklist (for ages 6 18) (CBCL) 
(full assessment [Competence and Syndrome 
Scales]) (Competence part [Parts I to VII] week 
15 and Syndrome Scale [behavioral items] week 
16 data from Study TV50717 CNS 30080 will be 
used) 
 W16 Epworth Sleepiness Scale (ESS) (for 
children and adolescents)  
c. Day 1 Assessments  
• medical history and psychiatric history 
• administer the following assessments: 
– Movement Disorder-Childhood Rating Scale 
(MD-CRS) part I  
– MD-CRS part II 
– Clinical Global Impression of Severity (CGI-S)  
– Pediatric Evaluation Disability Inventory-
Computer Adapted Test (PEDI CAT) 
– Child Behavior Checklist (CBCL) (for ages 6-18) 
(Competence Scale [Parts I to VII] and Syndrome 
Scale [behavioral items]) 
− 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) 
– Canadian Occupational Performance Measure 
(COPM) 
– Columbia-Suicide Severity Rating Scale (C-
SSRS) Since Last Visit (Note: Children 13 years 
of age and under must be interviewed in 
conjunction with the caregiver. For children over 
13 years of age, caregiver involvement is strongly 
(COPM) 
– Columbia-Suicide Severity Rating Scale (C-
SSRS) Since Last Visit (Note: Children 13 years 
of age and under must be interviewed in 
conjunction with the caregiver. For children over 
13 years of age, caregiver involvement is strongly 
encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to 
add relevant information. The children’s C-SSRS 
questionnaire will only be presented to patients 
aged ≥12 years.). If the patient turned 12 years 
old during or after Study TV50717-CNS-30080, 
but before screening or day 1 visit (whichever 
comes first) of Study TV50717-CNS-30081, the 
C-SSRS baseline/screening scale will be 
completed. 
– Extrapyramidal Symptom Rating Scale (ESRS) 
subscales I and II 
– Epworth Sleepiness Scale (ESS) (for children and 
adolescents)  
• inquire about adverse events 
• review concomitant medications 
• dispense TEV-50717 
• contact Interactive Web Response Systems (IWRS) 
Any scales/questionnaires administered at the week 16 visit 
for Study TV50717-CNS-30080 do not need to be repeated 
if the day 1 visit of Study TV50717-CNS-30081 is the same 
day as the week 16 visit Study TV50717-CNS-30080. 
If all inclusion/exclusion criteria have been reviewed and are 
met, and the patient is eligible for treatment, he/she will be 
dispensed with study drug. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
165 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to 
add relevant information. The children’s C-SSRS 
questionnaire will only be presented to patients 
aged ≥12 years.). If the patient turned 12 years old 
during or after Study TV50717-CNS-30080, but 
before screening or day 1 visit (whichever comes 
first) of Study TV50717-CNS-30081, the C-SSRS 
baseline/screening scale will be completed. 
– Extrapyramidal Symptom Rating Scale (ESRS) 
subscales I and II 
– Epworth Sleepiness Scale (ESS) (for children and 
adolescents)  
• inquire about adverse events 
• review concomitant medications 
• dispense TEV-50717 
• contact Interactive Web Response Systems (IWRS) 
Any scales/questionnaires administered at the week 16 visit 
for Study TV50717-CNS-30080 do not need to be repeated 
if the day 1 visit of Study TV50717-CNS-30081 is the same 
day as the week 16 visit Study TV50717-CNS-30080. 
If all inclusion/exclusion criteria have been reviewed and are 
met, and the patient is eligible for treatment, he/she will be 
dispensed with study drug. 
2. 
Procedures Before TEV-50717 Treatment (Day 1) 
2.2 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with no clinically significant changes 
since the week 15 visit of Study TV50717-CNS-30080 
See New wording column 
Patients who enroll in the study between 2 and ≤4 weeks 
after the Study TV50717-CNS-30080 week 15 visit with no 
clinically significant changes since the week 15 visit of 
Study TV50717-CNS-30080 will undergo the following 
assessments: 
a. Assessments carried over from Study TV50717-CNS-
30080 - Week 15/16 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
166 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
• 
W15 or W16 (whichever is the most current) 
chemistry, hematology, urinalysis 
• 
W16 urine drug screen 
b. Day 1 Assessments  
• obtain informed consent/assent  
• 
review of eligibility criteria 
• 
medical history and psychiatric history 
• 
demographics 
• 
vital signs (pulse, BP, body temperature, and 
respiratory rate) 
• 
weight 
• 
physical examination 
• 
neurological examination 
• 
height 
• 
12-lead ECG (after at least 5-minute rest in a supine 
or semi-supine position) 
• 
urine pregnancy (β-HCG) test (required for all 
females who are postmenarchal or ≥12 years of age) 
• 
MD-CRS part I  
• 
MD-CRS part II 
• 
CGI-S 
• 
PEDI-CAT 
• 
UHDRS-TMS 
• 
UHDRS-TMC 
• 
UHDRS-TMD 
• 
COPM 
• 
C-SSRS Since Last Visit (Note: Children 13 years of 
age and under must be interviewed in conjunction 
with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver should be encouraged to add relevant 
information. The children’s C-SSRS questionnaire 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
167 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
will only be presented to patients aged ≥12 years.) If 
the patient turned 12 years old during Study or after 
Study TV50717-CNS-30080, but before screening or 
day 1 visit (whichever comes first) of Study 
TV50717-CNS-30081, the C-SSRS 
baseline/screening scale will be completed. 
• 
ESRS subscales I and II 
• 
CBCL (for ages 6 to 18) (full assessment 
Competence Scale [Parts I to VII] and Syndrome 
Scale [behavioral items])  
• 
ESS (for children and adolescents)  
• 
inquire about adverse events 
• 
review concomitant medications 
• 
dispense TEV-50717 
• 
contact IWRS 
If all inclusion/exclusion criteria have been reviewed and are 
met, and the patient is eligible for treatment, he/she will be 
dispensed with study drug. 
For patients who enroll in the study Between 2 and 
≤4 Weeks after the Study TV50717-CNS‑30080 week 15 
visit, the investigator is required to consult with the medical 
monitor regarding eligibility prior to baseline/day 1. The 
patient’s file should include all related correspondence with 
the medical monitor. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
168 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
2. 
Procedures Before TEV-50717 Treatment (Day 1) 
2.3 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-CNS-30080 Week 15 Visit with Clinically Significant Changes 
and for Patients Who Enroll More Than 4 Weeks and up to 6 Months After Study TV50717-CNS-30080 Week 15 Visit 
See New wording column 
The patient will undergo all screening procedures. Patients 
who remain eligible for participation in the study will be 
asked to return for day 1 assessments.   
a. Screening 
• 
obtain informed consent/assent  
• 
review of eligibility criteria 
• 
medical history and psychiatric history 
• 
demographics 
• 
vital signs (pulse, BP, body temperature, and 
respiratory rate) 
• 
weight 
• 
physical examination 
• 
neurological examination 
• 
height 
• 
12-lead ECG (after at least 5-minute rest in a supine 
or semi-supine position) 
• 
chemistry, hematology, urinalysis 
• 
urine drug screen 
• 
serum pregnancy (β-HCG) test (required for all 
females who are postmenarchal or ≥12 years of age) 
• 
C-SSRS Since Last Visit (Note: Children 13 years of 
age and under must be interviewed in conjunction 
with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver should be encouraged to add relevant 
information. The children’s C-SSRS questionnaire 
will only be presented to patients aged ≥12 years.)  If 
the patient turned 12 years old during or after Study 
TV50717-CNS-30080, but before screening or day 1 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
169 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
visit (whichever comes first) of Study TV50717-
CNS-30081, the C-SSRS baseline/screening scale 
will be completed. 
• 
CBCL (for ages 6 to 18) (full assessment 
Competence Scale [Parts I to VII] and Syndrome 
Scale [behavioral items])  
• 
inquire about adverse events 
• 
review concomitant medications 
• 
contact IWRS 
b. Day 1 
• 
review of eligibility criteria 
• 
vital signs (pulse, BP, body temperature, and 
respiratory rate) 
• 
weight 
• 
physical examination 
• 
neurological examination 
• 
urine pregnancy (β-HCG) test (required for all 
females who are postmenarchal or ≥12 years of age) 
• 
MD-CRS part I  
• 
MD-CRS part II 
• 
CGI-S 
• 
PEDI-CAT 
• 
UHDRS-TMS 
• 
UHDRS-TMC 
• 
UHDRS-TMD 
• 
COPM 
• 
C-SSRS Since Last Visit (Note: Children 13 years of 
age and under must be interviewed in conjunction 
with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. 
Questions should be directed to the child, but the 
caregiver should be encouraged to add relevant 
information. The children’s C-SSRS questionnaire 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
170 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
will only be presented to patients aged ≥12 years.) If 
the patient turned 12 years old between screening and 
day 1, the C-SSRS baseline/screening scale will be 
completed. 
• 
ESRS subscales I and II 
• 
CBCL (for ages 6-18) Syndrome Scale (behavioral 
items)  
• 
ESS (for children and adolescents)  
• 
inquire about adverse events 
• 
review concomitant medications 
• 
dispense TEV-50717 
• 
contact IWRS 
If all inclusion/exclusion criteria have been reviewed and are 
met, and the patient is eligible for treatment, he/she will be 
dispensed with study drug. 
For patients who enroll in the study more than 2 weeks and 
up to 6 months after the Study TV50717-CNS‑30080 week 
15 visit, the investigator is required to consult with the 
medical monitor regarding eligibility prior to baseline/day 1. 
The patient’s file should include all related correspondence 
with the medical monitor. 
3. 
Procedures During TEV-50717 Treatment 
a. 
Titration Period (Weeks 1 to 7) 
ii. In-clinic Visits (Weeks 3 and 7) 
• dispense/collect TEV-50717 (During the week 3 visit, 
the investigator (or designee) will make sure the patient 
receives the evening dose to complete the week3 
dosing for that day. Refer to the pharmacy manual for 
further details). 
• collect used and unused TEV-50717 bottles (Note: At 
the week 3 in-clinic visit, accountability will be 
performed on all bottles returned except for patients 
who receive 1 bottle back to complete the week 3 in-
clinic evening dose. Refer to the pharmacy manual for 
• dispense/collect TEV-50717 (During the week 3 visit, the 
investigator (or designee) will make sure the patient 
receives the evening dose to complete the week3 dosing 
for that day. Refer to the pharmacy manual for further 
details). 
• collect used and unused TEV-50717 bottles (Note: At the 
week 3 in-clinic visit, accountability will be performed on 
all bottles returned except for patients who receive 1 
bottle back to complete the week 3 in-clinic evening dose. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
171 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
further details.) 
• assess drug accountability/compliance/supply (Note: At 
the week 3 in-clinic visit, accountability will be 
performed on all bottles returned except for patients 
who receive 1 bottle back to complete the week 3 in-
clinic evening dose. Refer to the pharmacy manual for 
further details.) 
• contact IWRS 
Refer to the pharmacy manual for further details.) 
• 
assess drug accountability/compliance/supply (Note: At 
the week 3 in-clinic visit, accountability will be 
performed on all bottles returned except for patients 
who receive 1 bottle back to complete the week 3 in-
clinic evening dose. Refer to the pharmacy manual for 
further details.) 
• 
contact IWRS 
b. Maintenance Period (Weeks 14 to 53/Early Termination) 
i. 
In-clinic Visits (Weeks 14, 27, 40, and 53/Early Termination) 
See New wording column 
– 
UHDRS-TMC 
– 
UHDRS-TMD 
− 
contact IWRS 
 
4. 
Procedures After TEV-50717 Treatment (Follow-Up) 
b. Telephone Contact (Week 55) 
Patients who participate in the study in compliance with the 
protocol for at least 534 weeks of treatment will be 
considered to have completed the studytreatment. See 
Section 5.4 for the definition of the end of study. 
Patients who participate in the study in compliance with the 
protocol for at least 53 weeks of treatment will be 
considered to have completed the treatment. See Section 5.4 
for the definition of the end of study. 
 
5. 
Unscheduled Visits 
The following procedures/assessments will be performed at 
all in-clinic unscheduled visits: 
• 
contact IWRS 
The following procedures/assessments will be performed at 
all in-clinic unscheduled visits: 
• 
contact IWRS 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
172 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
APPENDIX H. LIST OF ALLOWED AND PROHIBITED MEDICATIONS 
Table 11: Allowed Medications 
See New wording column 
Table 11 has been revised as described below: 
• 
Added text to include dose was “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 11 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 12: 
Prohibited Antipsychotic Drugs 
Table deleted 
 
Table 12 deleted 
APPENDIX I. 
TOTAL BLOOD VOLUME 
Total blood volume to be collected for each patient in this 
study is approximately 7276 mL. 
 
See New wording column 
Total blood volume to be collected for each patient in this 
study is approximately 76 mL. 
 
The Total Blood Volumes tables has been revised as 
described below: 
• 
Added screening as part of the baseline column 
• 
Added collection of blood for β-HCG at baseline 
(day 1) 
• 
Added collection of blood for TEV-50717 
concentration at Week 53/ET and unscheduled 
timepoints 
• 
Updated list of abbreviations 
Total blood volume/draw amount 
has been updated to 76 mL. 
Total blood volume table has been 
revised to account for an 
additional ~4 mL of blood as per 
the changes implemented in this 
amendment 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
173 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
c Serum β-HCG to be taken onlyperformed at screening for 
patients who enroll between 2 and ≤4 weeks after Study 
TV50717-CNS-30080 week 15 visit and had a clinically 
significant change and for patients who enroll >4 weeks 
and up to 6 months after Study TV50717-CNS-30080 
week 15 visit and at week 53 for all patients. 
c Serum β-HCG to be performed at screening for patients 
who enroll between 2 and ≤4 weeks after Study 
TV50717-CNS-30080 week 15 visit and had a clinically 
significant change and for patients who enroll >4 weeks 
and up to 6 months after Study TV50717-CNS-30080 
week 15 visit and at week 53 for all patients. 
Footnote revised for clarity 
See New wording column 
d Patients experiencing an adverse event leading to 
discontinuation or any other adverse event at the 
discretion of the investigator of TEV-50717 should have 
a single blood sample collected as soon as possible after 
the adverse event and within 48 hours for the 
measurement of TEV-50717, and α- and β-HTBZ 
concentrations, if possible. To permit the assessment of 
potential relationship of the adverse event and plasma 
concentration, an estimate of the date and time of the last 
dose intake of study drug should be recorded along with 
the date and time of the sample collection. If the estimate 
of the dose intake cannot be established within a 2 hour 
window, then a blood sample should not be obtained. 
Footnote added for alignment with 
changes made to protocol body. 
Additional guidance provided to 
the investigator regarding how to 
handle patients who experience 
adverse events leading to 
discontinuation 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
174 
16.8. 
Amendment 01 Dated 02 October 2019  
The primary reason for this amendment is to provide clarification for the day 1 procedures in 
Study TV50717-CNS-30081 relative to the same assessments performed at weeks 15 and 16 in 
the parent Study TV50717-CNS-30080. 
This amendment is considered to be substantial by the sponsor’s authorized representative. These 
substantive changes included revised inclusion and exclusion criteria and new criteria for early 
withdrawal of study treatment. 
Other minor or editorial non-substantial 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. 
All of the changes in the first table below reflect what has changed from the original protocol. 
All of the changes in the second table below reflect what has changed from the Letter of 
Clarification 01 (Section 16.10). 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
175 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Title Page (Other sections affected by these changes: Investigator Agreement, Synopsis) 
EUDRACT Number: NA2019-001807-19 
EudraCT Number: 2019-001807-19 
 
Synopsis and Throughout the protocol 
parent/caregiver 
caregiver 
 
caregiver/adult  
caregiver 
 
caregiver/parent 
caregiver 
 
Synopsis [Planned Study Period] 
Q42 2019 to Q41 2022  
Q4 2019 to Q4 2022  
Clarification 
Synopsis [General Study Design] (Other sections affected by these changes: Brief Summary of Study Design for the Trial Registry(s) and 3.1) 
If the patient does not wish to enroll in Study TV50717-
CNS-30081 at that visit or for any other reason, the patient 
can enroll up to 1 week following the week 16 visit.  
If the patient does not wish to enroll in Study 
TV50717-CNS-30081 at that visit or for any other reason, 
the patient can enroll up to 1 week following the week 16 
visit.  
Clarification 
This study will include children and adolescents between 
6 and 18 years of age at the time when they enrolled in the 
parent study (Study TV50717-CNS-30080). 
This study will include children and adolescents between 
6 and 18 years of age at the time when they enrolled in the 
parent study (Study TV50717-CNS-30080). 
Clarification 
Synopsis [General Study Design] (Other sections affected by 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 responsible as caregiver. The parent or legal 
guardian only has to sign the parent/legal guardian 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 responsible as caregiver. The parent or legal 
guardian only has to sign the parent/legal guardian ICF and 
not the caregiver ICF. 
For adult patients, a caregiver must be appointed by the 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
176 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
patient; this can be the parent 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 the child’s health, or where “parent/legal 
guardian” is specifically indicated in the protocol. 
patient; this can be the parent 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 the child’s health, or where 
“parent/legal guardian” is specifically indicated in the 
protocol. 
Synopsis [Brief Summary of Study Design for the Trial Registry(s)] 
For pPatients can rolling over from Study TV50717-
CNS-30080, on the same days as the week 16 visit, or within 
1 week from the week 16 visit, and that will be the day 1 
visit for Study TV50717-CNS-30081. If the patient does not 
wish to participate in Study TV50717 CNS 30081 at that 
visit, the patient can enroll up to 1 week following the 
week 16 visit. The end of study is defined as the date of the 
week 55 follow-up telephone contact of the last participant. 
Patients can roll over from Study TV50717-CNS-30080 on 
the same day as the week 16 visit or within 1 week from the 
week 16 visit, and that will be their day 1 visit for 
Study TV50717-CNS-30081. The end of study is defined as 
the date of the week 55 follow-up telephone contact of the 
last participant. 
Clarification 
Synopsis [Brief Summary of Study Design for the Trial Registry(s)] (Other sections affected by these changes: 3.2) 
The study is expected to start by the end of Q42 2019 and to 
last until early Q4 2022. 
The study is expected to start by the end of Q4 2019 and to 
last until Q4 2022. 
Clarification 
Synopsis [Investigational Medicinal Products] (Other sections affected by these changes: 1.1.1, 5.1.1, 5.1.1.1, and Table 8) 
TEV-50717 oral tablets (test IMP) are available in 
commercially available the following dose strengths: 6, 9, 
and 12 mg dose strengths. 15, and 18 mg. Each dose strength 
will have a marking of SD 6, SD 9, SD 12, SD 15, and SD 
18 corresponding to the dose strength on the label. It is 
possible that all dose strengths may not be used during the 
study. TEV-50717 will be supplied as 20  or 60-count white 
tablets per dose strength per bottle. Each dose strength will 
be a colored tablet with a marking of “SD” and the 
corresponding strength. 
TEV-50717 oral tablets (test IMP) are 6, 9, and 12 mg dose 
strengths. Each dose strength will have a marking 
corresponding to the dose strength on the label. TEV-50717 
will supplied in 60-count tablets per bottle. Each dose 
strength will be a colored tablet with a marking of “SD” 
and the corresponding strength. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
177 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Synopsis [Duration of Patient Participation and Maximal Exposure to IMP] 
Any patient that turns 18 years of age reaches the age of 
legal competence to give informed consent during the course 
of Study TV50717-CNS-30081 will need to be re-consented 
as an adult. When the patient is a minor advancing to the 
next age range (new assent available and patient is still 
considered a minor by local law), the patient may need to 
sign on new assent appropriate for that age in order to 
continue participation in the study (in accordance to local 
laws and regulations). 
Any patient that reaches the age of legal competence to 
give informed consent during the course of 
Study TV50717-CNS-30081 will need to be re-consented 
as an adult. When the patient is a minor advancing to the 
next age range (new assent available and patient is still 
considered a minor by local law), the patient may need to 
sign on new assent appropriate for that age in order to 
continue participation in the study (in accordance to local 
laws and regulations). 
Clarification 
Synopsis [Inclusion Criteria] (Other sections affected by these changes: 4.1) 
a. 
Patient is of an eligible age from has completed parent 
Study TV50717-CNS-30080. 
g. Patient and caregiver/parent provide written informed 
consent/assent, depending on the child’s age, as 
appropriate, according to local regulations.For a patient 
who is a minor, the parent(s)/legal guardian(s) provides 
written informed consent, and the patient provides 
assent (in accordance with local regulations). Adult 
patients (in accordance with local regulations) provide 
their own written informed consent. 
h. A caregiver will provide written informed consent after 
being assigned the role by an adult patient o, if this role 
is delegated by the parent/legal guardian of a patient 
who is a minor. 
a. Patient has completed parent Study TV50717-
CNS-30080. 
g. For a patient who is a minor, the parent(s)/legal 
guardian(s) provides written informed consent, and the 
patient provides assent (in accordance with local 
regulations). Adult patients (in accordance with local 
regulations) provide their own written informed consent. 
h. A caregiver will 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. 
Clarification 
Synopsis [Exclusion Criteria] (Other sections affected by these changes: 4.2) 
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. 
ae. 
Patient has clinically significant depression at day 1 of 
c. 
a. 
Patient has clinically significant depression at day 
1 of this study. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
178 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
this study. 
d. ei. Patient who is currently receiving or who 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.  
 
“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. 
e. 
e. 
Patient who is currently receiving or who 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.   
 
“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. 
Clarification 
vr. Patient has a positive urine drug screen test result (with 
exception of medications listed in Table 10 of Appendix 
H) or is unable to refrain from substance abuse 
throughout the study. 
r. 
Patient has a positive urine drug screen test result (with 
exception of medications listed in Table 10 of 
Appendix H) or is unable to refrain from substance 
abuse throughout the study. 
 
1.1.1. Background for TEV-50717 (Other sections affected by these changes: Table 7) 
TEV-50717 tablets are available in the following dose 
strengths: 6, 9, and 12, 15, and 18 mg, or other commercially 
available dose strengths, all of which are identical in size, 
and shape, and color (white). Each strength will be a colored 
tablet with a marking of “SD” and the corresponding 
strength. It is possible that all dose strengths may not be used 
during the study. The investigational medicinal product 
(IMP) will be supplied in 20  or 60-count tablets per dose 
strength per bottle. 
TEV-50717 tablets are 6, 9, and 12 mg, or other 
commercially available dose strengths, all of which are 
identical in size and shape. Each strength will be a colored 
tablet with a marking of “SD” and the corresponding 
strength. The investigational medicinal product (IMP) will 
be supplied in 60-count tablets per bottle. 
Clarification 
1.2.1.2. Nonclinical Pharmacokinetics and Drug Metabolism 
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 20175).  
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 2017).  
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
179 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
1.2.2.1. Clinical Pharmacology Studies 
SevenNine Phase 1 clinical pharmacology studies were 
conducted in healthy adult volunteers.  
Nine Phase 1 clinical pharmacology studies were conducted 
in healthy adult volunteers.  
Clarification 
1.2.2. Clinical Studies 
The clinical development plan for TEV-50717 to date 
includes the following: 
• 
seven nine completed Phase 1 studies in healthy 
adult volunteers 
• 
two ongoing Phase 1 studies in healthy adult 
volunteers 
The clinical development plan for TEV-50717 to date 
includes the following: 
• 
nine completed Phase 1 studies in healthy adult 
volunteers 
 
Clarification 
Figure 1: Overall Study Schematic Diagram 
 
≥ 40 kg
30 kg to  40 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (24) 
mg
30 (24) 
mg
36 (24) 
mg
42 (24) 
mg
Stable max maintenance dose 42 (24) mg/day
17 kg to < 30 kg
6 (6)
mg
12 (12) 
mg
18 (18) 
mg
24 (18) 
mg
30 (18) 
mg
Stable max ma ntenance 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 max maintenance dose 48 (36) mg/day
18 (18) 
mg
12 kg to < 17 kg
6 (6)
mg
12 (12) 
mg
18 (12) 
mg
24 (12) 
mg
Stable max maintenance dose 24 (12) mg/day
Titration Period
Dose adjustments should be made on a l ava lable nfo mat on, nclud ng 
the pat ent and ca eg ve
epo ts of adve se events and dysk nes a 
educt on, and the cl n cal assessment of safety and eff cacy by the 
nvest gato
Maintenance Period
Wash out
Follow Up
AE=adve se event  CGI-I=Cl n cal Global Imp ess on of Imp ovement  CYP2D6=cytoch ome P450 2D6  D=day  ET=ea ly te m nat on  max=max mum
Wk=week.
Note  If a pat ent s CYP2D6- mpa ed, the dose adm n ste ed s nd cated n pa entheses. The dose of TEV-50717 should be nc eased on a weekly bas s unt l
any of the follow ng events occu  cl n ca ly mean ngful educt on n dysk nes a ( e, CGI-I) as dete m ned by the nvest gato , cl n cally s gn f cant AE, o  the
max mum allowable dose s eached. The ma ntenance pe od sta ts at week 7  howeve , study p ocedu es and assessments a e conducted between weeks 14
and 53/ET.
Week 
3
Basel ne
Day 
1
Week 
7
Week  
14
Day 
2
Day
 
Week 
33
Week 
27
Week 
1
Week 
2
Week 
4
Week 
5
Week 
6
Week 
21
Week 
40
Week 
46
Week 
54
Week 
55
Week 
53/ ET
Week 
53
In-cl nic visit
Telephone call
Telephone contact 
w th non-record ng 
live video
 
Clarification 
In the titration box: Dose adjustments should be made on all 
available information, including the patient and 
caregiver/adult reports of adverse events and dyskinesia 
reduction, and the clinical assessment of safety and efficacy 
by the investigator 
In the footnote: The maintenance period starts at week 87 
In the titration box: Dose adjustments should be made on 
all available information, including the patient and 
caregiver reports of adverse events and dyskinesia 
reduction, and the clinical assessment of safety and efficacy 
by the investigator 
In the footnote: The maintenance period starts at week 87 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
180 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Table 4 Study Procedures and Assessments 
Row: Visit window (days) 
Column: BL 
0 days 
Row: Visit window (days) 
Column: BL 
 
Clarification 
Row:  Informed consent/assent and/or co consent for 
patients 14 years of age and older 
Row: Informed consent/assent  
Row: Evaluate/adjust TEV-50717 
Column: Week 53/ET 
X 
Row: Evaluate/adjust TEV-50717 
Column: Week 53/ET 
 
Row: Vital signs and weight 
Column: BL 
[Xl] 
Row: Vital signs and weight 
Column: BL 
[Xl] 
Row: Urine drug screen 
Column: BL 
[X] 
Row: Urine drug screen 
Column: BL 
[X] 
Row: β-HCG test 
Column: BL 
[X] 
Row: β-HCG test 
Column: BL 
[X] 
Row: MD-CRS part I (physician rated) 
Column: BL 
[X] 
Row: MD-CRS part I (physician rated) 
Column: BL 
[X] 
Row: MD-CRS part II (physician rated) 
Column: BL 
[X] 
Row: MD-CRS part II (physician rated) 
Column: BL 
[X] 
Row: CGI-S (global, physician rated) 
Column: BL 
[X] 
Row: CGI-S (global, physician rated) 
Column: BL 
[X] 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
181 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Row: C-SSRS (children’s since last visit) 
Column: BL 
[X] 
Row: C-SSRS (children’s since last visit) 
Column: BL 
[X] 
Row: ESRS (subscales I and II) 
Column: BL 
[X] 
Row: ESRS (subscales I and II) 
Column: BL 
[X] 
Row: CBCL 
Column: BL 
[X] 
Row: CBCL 
Column: BL 
[X] 
Row: ESS 
Column: BL 
[X] 
Row: ESS 
Column: BL 
[X] 
Row: Assess TEV-50717 accountability/compliance/ supplyt 
Column: 1 
 
Row: Assess TEV-50717 accountability/compliance/ 
supplyt 
Column: 1 
Row: Concomitant medicationst 
Column: 1 
Concomitant medicationset  
Row: Concomitant medicationst  
Column: 1 
Row: Concomitant medicationsf 
a Assessments indicated in brackets by “[X]” are 
representative of data carried over from baseline or week 
15/16 of parent Study TV50717-CNS-30080, whichever is 
the most current. Screening evaluations for this open-label 
study will be performed as part of the baseline visit. 
a Assessments indicated in brackets by “[X]” are 
representative of data carried over from baseline or week 
15/16 of parent Study TV50717-CNS-30080, whichever 
is the most current. Screening evaluations for this open-
label study will be performed as part of the baseline visit. 
Clarification 
d For all patients, the week 16 visit from Study TV50717-
CNS-30080 may be the day 1 visit for Study TV50717-
CNS-30081. If the patient does not wish to enroll in 
Study TV50717-CNS-30081 at the week 16 visit of parent 
Study TV50717-CNS-30080 or for any other reason, the 
patient can enroll up to 1 week following the week 16 
visit. Day 1 assessments in Study TV50717-CNS-30081 
that are identical to Study TV50717-CNS-30080 
d For all patients, the week 16 visit from Study TV50717-
CNS-30080 may be the day 1 visit for Study TV50717-
CNS-30081. If the patient does not wish to enroll in 
Study TV50717-CNS-30081 at the week 16 visit of 
parent Study TV50717-CNS-30080 or for any other 
reason, the patient can enroll up to 1 week following the 
week 16 visit. Day 1 assessments in Study TV50717-
CNS-30081 that are identical to Study TV50717-
To clarify some of the day 1 
procedures in Study TV50717-
CNS-30081 relative to the same 
assessments performed at weeks 
15 and 16 in the parent Study 
TV50717-CNS-30080 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
182 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
baseline/week 15/16 visit assessments, whichever is the 
most current, do not need to be repeated, except for 
orthostatic pulse rate, BP, PEDI-CAT, and UHDRS-TMS, 
which need to be repeated at Day 1. 
CNS-30080 week 15/16 visit assessments, whichever is 
the most current, do not need to be repeated, except for 
orthostatic pulse rate and blood pressure, which need to 
be repeated at Day 1. 
e For patients who withdraw prematurely, an ET visit should 
be conducted as soon as possible after the last dose of 
TEV-50717. All patients who discontinue early will have a 
follow-up telephone contact for safety evaluation 2 weeks 
after their last dose of TEV-50717; evaluations will be as 
described for the week 53 55 visit. 
e For patients who withdraw prematurely, an ET visit 
should be conducted as soon as possible after the last 
dose of TEV-50717. All patients who discontinue early 
will have a follow-up telephone contact for safety 
evaluation 2 weeks after their last dose of TEV-50717; 
evaluations will be as described for the week 55 visit. 
Clarification 
l 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) and should be measured at day 1. 
l 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) and should be measured at 
day 1. 
 
o For females who are postmenarchal or ≥12 years of age, a 
urine pregnancy test will be administered at day 1 and at 
weeks 14, 27,and 40, and 54 while a serum pregnancy test 
will be administered at week 53, and if clinically 
indicated. 
o For females who are postmenarchal or ≥12 years of age, a 
urine pregnancy test will be administered at day 1 and at 
weeks 14, 27, 40, and 54 while a serum pregnancy test 
will be administered at week 53, and if clinically 
indicated. 
Clarification 
t Study drug accountability will be assessed during clinical 
visits only. 
t Study drug accountability will be assessed during clinical 
visits only. 
Clarification 
Section 3.3. Justification for Study Design and Selection of Population 
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), and have completed Study TV50717-CNS-30080. The 
diagnosis of DCP is based on the Surveillance of Cerebral 
Palsy in Europe criteria (Cans 2000).  “Predominant” in this 
instance indicates that the choreiform movement disorder is 
the main cause of impairment or distress.  
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), and have completed Study TV50717-CNS-30080. The 
diagnosis of DCP is based on the Surveillance of Cerebral 
Palsy in Europe criteria (Cans 2000). “Predominant” in this 
instance indicates that the choreiform movement disorder is 
the main cause of impairment or distress.  
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
183 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Section 4.3. Withdrawal Criteria and Procedures for the Patient 
Patients are to be discontinued from the study for the 
following situations: 
• 
Laboratory evidence of diminished hepatic function, 
defined as an AST or ALT >2.5×ULN and ALP or 
total bilirubin >2×ULN 
• 
Patient develops neuroleptic malignant syndrome. 
Patients are to be discontinued from the study for the 
following situations: 
• 
Laboratory evidence of diminished hepatic function, 
defined as an AST or ALT >2.5×ULN and ALP or 
total bilirubin >2×ULN 
• 
Patient develops neuroleptic malignant syndrome.  
Added per MHRA request 
All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after their 
ET visit; evaluations will be as described for the week 5455 
visit. 
All patients who discontinue early will have a follow-up 
telephone contact for safety evaluation 2 weeks after their 
ET visit; evaluations will be as described for the week 55 
visit. 
Clarification 
Section 5.1.1. Test Investigational Medicinal Product 
TEV 50717 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-, 
and 12- 15 , and 18-mg tablets, or other commercially 
available dose strengths, by bottle and labeled according to 
applicable regulatory guidelines. It is possible that all dose 
strengths may not be used during the study. Each bottle pack 
(20  or 60-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. 
TEV 50717 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-, 
and 12-mg tablets, or other commercially available dose 
strengths, by bottle and labeled according to applicable 
regulatory guidelines. Each bottle pack (60-count tablets 
per dose strength) will contain a sufficient supply of drug 
until the next specified visit/telephone contact, plus overage 
to account for potential delays in study visits. 
Clarification 
Table 7: Investigational Medicinal Products Used in the Study 
Row: Dosing instructionsPackaging 
Column: 1 
Row: Packaging 
Column: 1 
Typographical error correction 
Row: PackagingManufacturer 
Column: 1 
Row: Manufacturer 
Column: 1 
Row: ManufacturerStorage conditions 
Column: 1 
Row: Storage conditions 
Column: 1 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
184 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Row: Manufacturer 
Anesta, LLC 
Wiley Post Way 
Salt Lake City, UT 84116 
Column: 2   
Row: Manufacturer 
Anesta, LLC 
Wiley Post Way 
Salt Lake City, UT 84116 
Column: 2   
New contractor 
Section 5.4. Treatment after the End of the Study 
There are no plans to provide further treatment to patients 
upon completion of the study. An extension to the study may 
be considered on an annual basis.   
There are no plans to provide further treatment to patients 
upon completion of the study. An extension to the study 
may be considered on an annual basis.   
Clarification 
Section 5.6. Prior and Concomitant Medication or Therapy 
At each clinic visit after day 1, the investigator will ask 
patients and/or parent(s)/caregiver whether they or the 
patient, respectively, hasve taken any medications (other 
than TEV-50717), including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, since the 
previous visit.  
At each clinic visit after day 1, the investigator will ask 
patients and/or caregiver whether the patient has taken any 
medications (other than TEV-50717), including over-the-
counter medications, vitamins, or herbal or nutritional 
supplements, since the previous visit.  
Clarification 
Table 9: Clinical Laboratory Tests 
Row: Magnesium 
Column: 1 
Row: Magnesium 
Column: 1 
Typographical error correction 
Section 5.8. Temporary Discontinuation of Investigational Medicinal Product 
Suspension of TEV-50717 treatment for up to 1 week, if 
warranted, is allowed. If a patient’s serum potassium or 
magnesium falls below the lower limit of normal, TEV-
50717 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 mustshould be contacted to discuss the 
suspension and possible resumption of the IMPdetermine the 
Suspension of TEV-50717 treatment for up to 1 week, if 
warranted, is allowed. If a patient’s serum potassium or 
magnesium falls below the lower limit of normal, TEV-
50717 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. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
185 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
appropriate investigation and treatment. TEV-50717 
treatment may only be restarted once serum potassium 
and/or magnesium levels have normalized. 
TEV-50717 treatment may only be restarted once serum 
potassium and/or magnesium levels have normalized. 
Section 6.1.1. Movement Disorder-Childhood Rating Scale 
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). 
Assessment of MD-CRS part II items will be based solely on 
chorea in this study.  
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). Assessment of MD-CRS part II items 
will be based solely on chorea in this study.  
Clarification 
The MD-CRS will be carried over from study TV50717-
CNS-30080 W16 and administered by the investigational 
center physician at day 1, week 14, week 27, week 40, 
week 53/ET, and week 54/follow-up visits. 
The MD-CRS will be carried over from study TV50717-
CNS-30080 W16 and administered by the investigational 
center physician at week 14, week 27, week 40, 
week 53/ET, and week 54/follow-up visits. 
Clarification 
Section 6.1.4. Clinical Global Impression of Severity 
The CGI-S carried over from study TV50717 CNS 30080 
W16 and administered at the day 1 visit (Table 4) and 
administered at week 14, week 27, week 40, week 53/ET, 
and week 54/follow up visits. 
The CGI-S administered at the day 1 visit (Table 4) and 
administered at week 14, week 27, week 40, week 53/ET, 
and week 54/follow up visits. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
186 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Section 7.2.1. Children’s Columbia-Suicide Severity Rating Scale 
The children’s C-SSRS assesses suicidal ideation and 
behaviors for all patients aged ≥12years to determine suicide 
risk. The children’s C-SSRS Since Last Visit is carried over 
from study TV50717-CNS-30080 W16 and administered at 
day 1, and at the weeks 3, 7, 14, 27, 40, 53/ET, and 
54/follow-up. Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For children 
over 13 years of age, caregiver involvement is strongly 
encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant 
information.  
The children’s C-SSRS assesses suicidal ideation and 
behaviors for all patients aged ≥12years to determine 
suicide risk. The children’s C-SSRS Since Last Visit is 
carried over from study TV50717-CNS-30080 W16 and 
administered at the weeks 3, 7, 14, 27, 40, 53/ET, and 
54/follow-up. Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For children 
over 13 years of age, caregiver involvement is strongly 
encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant 
information.  
Clarification 
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 day 1 (carried over from 
study TV50717-CNS-30080 W16), compared to the worst 
(highest) category during the treatment period, will be 
presented. 
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 day 1 (carried over from 
study TV50717-CNS-30080 W16), compared to the worst 
(highest) category during the treatment period, will be 
presented. 
Clarification 
Section 7.2.2. Extrapyramidal Symptom Rating Scale 
The ESRS is carried over from study TV50717-CNS-30080 
W16 and administered at day 1, and at the weeks 3, 7, 14, 
27, 40, 53/ET, and 54/follow-up visits. 
The ESRS is carried over from study TV50717-CNS-30080 
W16 and administered at the weeks 3, 7, 14, 27, 40, 53/ET, 
and 54/follow-up visits. 
Clarification 
Section 7.2.3. Child Behavior Checklist (for Ages 6 to 18) 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at day 1, and at the week 53/ET visit. The 
Competence part [Parts I to VII] will be carried over from 
study TV50717-CNS-30080 W15. The Syndrome Scale part 
of the CBCL [behavioral items] will be carried over from 
study TV50717-CNS-30080 W16 and completed at day 1, 
and at weeks 3, 7, 14, 27, 40, 53/ET visit, and 54/follow-up 
visits. 
The full CBCL assessment (Competence Scale [Parts I to 
VII] and Syndrome Scale [behavioral items]) will be 
completed at the week 53/ET visit. The Competence part 
[Parts I to VII] will be carried over from study TV50717-
CNS-30080 W15. The Syndrome Scale part of the CBCL 
[behavioral items] will be carried over from study 
TV50717-CNS-30080 W16 and completed at weeks 3, 7, 
14, 27, 40, and 54/follow-up visits. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
187 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Section 7.2.4. Epworth Sleepiness Scale (for Children and Adolescents) 
The ESS is carried over from study TV50717-CNS-30080 
W16 and administered at day 1, and at the weeks 3, 7, 14, 
27, 40, 53/ET, and 54/follow-up visits.  
The ESS is carried over from study TV50717-CNS-30080 
W16 and administered at the weeks 3, 7, 14, 27, 40, 53/ET, 
and 54/follow-up visits.  
Clarification 
Section 7.5.2.1. Beta-Human Chorionic Gonadotropin Tests 
β-HCG tests in urine will be performed for females who are 
postmenarchal or ≥12 years of age at day 1 and at weeks 14, 
27, and 40, and 54. β-HCG tests in serum will be performed 
for all female patients who are postmenarchal or ≥12 years 
of age aged 12 years or older of childbearing potential at 
week 53/ET and if clinically indicated. 
β-HCG tests in urine will be performed for females who are 
postmenarchal or ≥12 years of age at day 1 and at 
weeks 14, 27, 40, and 54. β-HCG tests in serum will be 
performed for all female patients who are postmenarchal or 
≥12 years of age at week 53/ET and if clinically indicated. 
Corrected an omission and 
clarification 
Section 7.10. Assessment of Suicidality 
Families and cCaregivers 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. 
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. 
Clarification 
Section 7.11. Assessment of Depression 
Families and cCaregivers 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.  
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.  
Clarification 
Section 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.  
Patients may be included in this study if they are using 
cannabis or formulations or derivatives of cannabis in 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
188 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
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. 
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. 
Section 15. References 
Xenazine: Highlights of Prescribing Information. 20175. 
Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/20175/
021894s0130lbl.pdf. Accessed 27 Oct 2015. 
Xenazine: Highlights of Prescribing Information. 2017. 
Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/
021894s013lbl.pdf. Accessed 16 Jul 2019. 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
189 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Appendix A 
Sponsor’s Authorized Representative: 
 
Teva Pharmaceutical Industries, 
 
 
 
Cell: 
 
 
Sponsor’s Authorized Representative: 
 
Teva Pharmaceutical Industries, 
 
 
Cell: 
 
 
Change in Sponsor’s 
representative 
Appendix C, 2. Procedures Before TEV-50717 Treatment (Day 1) 
− 
Extrapyramidal Symptom Rating Scale (ESRS) 
subscales I and II (week 16 data from Study TV50717-
CNS-30080 will be used) 
− 
Child Behavior Checklist (for ages 6-18) (CBCL) (full 
assessment [Competence and Syndrome Scales]) 
(Competence part [Parts I to VII] week 15 and 
Syndrome Scale [behavioral items] week 16 data from 
Study TV50717-CNS-30080 will be used) 
− 
Epworth Sleepiness Scale (ESS) (for children and 
adolescents) (week 16 data from Study TV50717-
CNS-30080 will be used) 
− 
Extrapyramidal Symptom Rating Scale (ESRS) 
subscales I and II (week 16 data from Study TV50717-
CNS-30080 will be used) 
− 
Child Behavior Checklist (for ages 6-18) (CBCL) (full 
assessment [Competence and Syndrome Scales]) 
(Competence part [Parts I to VII] week 15 and 
Syndrome Scale [behavioral items] week 16 data from 
Study TV50717-CNS-30080 will be used) 
− 
Epworth Sleepiness Scale (ESS) (for children and 
adolescents) (week 16 data from Study TV50717-
CNS-30080 will be used) 
Clarification 
Appendix C 
c. Day 1 Assessments  
The following procedures will be performed at the day 1 
visit: 
• obtain informed consent/assent (or co consent for 
patients 14 years of age and older where applicable) 
• review of eligibility criteria (required for all patients) 
• measure vital signs (pulse, blood pressure [BP], body 
temperature, and respiratory rate); orthostatic BP and 
pulse should be measured after standing for at least 3 
minutes (for patients who are able to stand) 
• measure weight (Note: Weight must be measured with 
c. Day 1 Assessments  
• obtain informed consent/assent 
• review of eligibility criteria 
• orthostatic BP and pulse should be measured after 
standing for at least 3 minutes (for patients who are 
able to stand) 
• perform 12-lead ECG (after at least 5-minute rest in a 
supine or semi-supine position 
• administer the following assessments: 
- Pediatric Evaluation Disability Inventory-Computer 
Adapted Test (PEDI CAT) 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
190 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
shoes and outerwear off.) 
• perform 12-lead ECG (after at least 5-minute rest in a 
supine or semi-supine position [required for all 
patients]) 
• perform urine drug screen 
• perform a urine pregnancy (beta human chorionic 
gonadotropin [β HCG]) test (required for all females 
who are postmenarchal or ≥12 years of age) 
• administer the following assessments: 
 Movement Disorder Childhood Rating Scale (MD
CRS) part I (week 16 data from Study TV50717
CNS 30080 will be used) 
 MD CRS part II (week 16 data from Study TV50717
CNS 30080 will be used) 
 Clinical Global Impression of Severity (CGI S) (week 
16 data from Study TV50717 CNS 30080 will be 
used) 
- Pediatric Evaluation Disability Inventory-Computer 
Adapted Test (PEDI CAT) 
- Unified Huntington’s Disease Rating Scale-Total 
Maximal Chorea Motor Score (UHDRS TMS) 
- Canadian Occupational Performance Measure 
(COPM) 
 Columbia Suicide Severity Rating Scale (C SSRS) 
(Note: Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For 
children over 13 years of age, caregiver involvement 
is strongly encouraged. Questions should be directed 
to the child, but the caregiver should be encouraged to 
add relevant information. The children’s C SSRS 
questionnaire will only be presented to patients aged 
≥12 years.) 
 Extrapyramidal Symptom Rating Scale (ESRS) 
subscales I and II (week 16 data from Study 
TV50717 CNS 30080 will be used) 
- Unified Huntington’s Disease Rating Scale-Total 
Motor Score (UHDRS TMS) 
- Canadian Occupational Performance Measure 
(COPM) 
• dispense TEV-50717 
• inquire about adverse events 
• review concomitant medications 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
191 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
 Child Behavior Checklist (for ages 6 18) (CBCL) (full 
assessment [Competence and Syndrome Scales]) 
(Competence part [Parts I to VII] week 15 and 
Syndrome Scale [behavioral items] week 16 data from 
Study TV50717 CNS 30080 will be used)  
 Epworth Sleepiness Scale (ESS) (for children and 
adolescents) (week 16 data from Study TV50717
CNS 30080 will be used) 
• dispense TEV-50717 
• inquire about adverse events 
• review concomitant medications 
i In-clinic Visits (Weeks 14, 27, 40, and 53/Early 
Termination) 
• 
evaluate and, if required, adjust TEV-50717 dose at 
weeks 14, 27, and 40  
i In-clinic Visits (Weeks 14, 27, 40, and 53/Early 
Termination) 
• 
evaluate and, if required, adjust TEV-50717 dose at 
weeks 14, 27, and 40  
Clarification 
Appendix D 
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 GCP guidelines; 
noncompliance to investigational medicinal product (IMP) 
administration; use of prohibited medications. Important 
protocol deviations will be identified and recorded by 
investigational center personnel in the case report form 
(CRF). All important protocol deviations will be reported to 
the responsible IEC/IRB, as required. 
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 GCP guidelines; 
noncompliance to investigational medicinal product (IMP) 
administration; use of prohibited medications. All important 
protocol deviations will be reported to the responsible 
IEC/IRB, as required. 
Clarification 
Appendix F 
Females (aged 12 years or older) of childbearing potential 
are defined as the following: 
Females of childbearing potential are defined as the 
following: 
Clarification 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
192 
Protocol text with changes shown 
New wording 
Reason/Justification for change 
Table 10: 
Allowed Medications 
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 (where 
applicable according to local regulation), 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 (where 
applicable according to local regulation), under the 
guidance, supervision, or prescription of a clinician.  
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
193 
Letter of Clarification 01 text with changes shown 
New wording 
Reason/Justification for change 
Synopsis [General Study Design] (Other sections affected by these changes: Brief Summary of Study Design for the Trial Registry(s), 3.1, and 16.3) 
For all patients, the week 16 visit from Study TV50717-
CNS-30080 may be the day 1 visit for Study TV50717-
CNS-30081. Day 1 assessments for Study 
TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/16 visit assessments, whichever is the 
most current, do not need to be repeated, except for 
orthostatic pulse rate and blood pressure, which need to be 
repeated at day 1. 
In addition, the following applies for day 1 baseline 
assessments for this study: 
• 
clinically significant laboratory abnormalities 
identified at week 15 in Study TV50717-CNS-30080 
are to be repeated at week 16 of the parent study for 
eligibility of Study TV50717-CNS-30081 and will 
serve as day 1 baseline values in this study. These 
findings are only required to be shared with the 
medical monitor as required per the 
inclusion/exclusion criteria. Any abnormalities which 
are listed in the inclusion/exclusion criteria must be 
discussed with the medical monitor prior to patient 
enrollment into the study.   
• 
electrocardiograms (ECGs) are to be performed on 
day 1 of Study TV50717-CNS-30081 and will serve 
as day 1 baseline values in this study. These findings 
can be shared with the medical monitor at the 
investigator’s discretion.   
• 
vital signs (respiratory rate and body temperature) are 
performed at week 16 in Study TV50717-CNS-30080, 
these findings will serve as day 1 baseline values in 
this study. These findings can be shared with the 
medical monitor at the investigator’s discretion. 
• 
physical examinations are performed at week 15 (and 
week 16, if applicable) in 
Study TV50717-CNS-30080. The findings from the 
last assessment taken will serve as day 1 baseline 
For all patients, the week 16 visit from Study TV50717-
CNS-30080 may be the day 1 visit for Study TV50717-
CNS-30081. Day 1 assessments for Study TV50717-
CNS-30081 that are identical to Study TV50717-
CNS-30080 week 15/16 visit assessments, whichever is the 
most current, do not need to be repeated, except for 
orthostatic pulse rate and blood pressure, which need to be 
repeated at day 1. 
In addition, the following applies for day 1 baseline 
assessments for this study: 
• clinically significant laboratory abnormalities identified 
at week 15 in Study TV50717-CNS-30080 are to be 
repeated at week 16 of the parent study for eligibility of 
Study TV50717-CNS-30081 and will serve as day 1 
baseline values in this study. Any abnormalities which 
are listed in the inclusion/exclusion criteria must be 
discussed with the medical monitor prior to patient 
enrollment into the study. 
• electrocardiograms (ECGs) are to be performed on day 
1 of Study TV50717-CNS-30081 and will serve as day 
1 baseline values in this study. 
• vital signs (respiratory rate and body temperature) are 
performed at week 16 in Study TV50717-CNS-30080; 
these findings will serve as day 1 baseline values in this 
study. 
• physical examinations are performed at week 15 (and 
week 16, if applicable) in Study TV50717-CNS-30080. 
At the investigator’s discretion, abnormal findings can be 
discussed with the medical monitor. 
To clarify some of the day 1 
procedures in Study TV50717-
CNS-30081 relative to the same 
assessments performed at weeks 
15 and 16 in the parent 
Study TV50717-CNS-30080 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
194 
Letter of Clarification 01 text with changes shown 
New wording 
Reason/Justification for change 
values in this study. These findings can be shared with 
the medical monitor at the investigator’s discretion.   
At the investigator’s discretion, abnormal findings can be 
discussed with the medical monitor. 
For patients with new clinically significant laboratory 
abnormalities, electrocardiogram (ECG) results, or vital 
signs/physical examination findings at week 16 in 
Study TV50717 CNS 30080, their findings should be shared 
with the medical monitor and assessments should be 
repeated for eligibility on day 1 of Study TV50717
CNS 30081 and will serve as day 1 baseline values in this 
study.  
Appendix C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
2. Procedures Before TEV-50717 Treatment (Day 1) 
For all patients, the week 16 visit from Study TV50717-
CNS-30080 may be the day 1 visit for Study TV50717-
CNS-30081. Day 1 assessments for Study 
TV50717-CNS-30081 that are identical to Study TV50717-
CNS-30080 baseline/week 15/16 visit assessments, 
whichever is the most current, do not need to be repeated, 
except for orthostatic pulse rate, blood pressure (BP), 
Pediatric Evaluation Disability Inventory-Computer Adapted 
Test (PEDI-CAT), and Unified Huntington’s Disease Rating 
Scale-Total Motor Score (UHDRS-TMS) which need to be 
repeated at day 1. 
a. Assessments carried over from Study TV50717-
CNS-30080 - Baseline 
• 
Medical history and psychiatric history 
• 
Demographics 
b. Assessments carried over from Study TV50717-
CNS-30080 - Week 15/16 
• 
W16 vital signs (pulse, BP, body temperature, 
and respiratory rate) 
• 
W16 weight (Note: Weight must be measured 
 
To clarify some of the day 1 
procedures in Study TV50717-
CNS-30081 relative to the same 
assessments performed at weeks 
15 and 16 in the parent 
Study TV50717-CNS-30080 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
195 
Letter of Clarification 01 text with changes shown 
New wording 
Reason/Justification for change 
with shoes and outerwear off.) 
• 
W15 height 
• 
W16 urine drug screen 
• 
W16 urine pregnancy (beta-human chorionic 
gonadotropin [?-HCG]) test (required for all 
females who are postmenarchal or ?12 years of 
age) 
• 
clinically significant laboratory abnormalities 
identified at week 15 in Study TV50717-CNS-
30080 are to be repeated at week 16 of the 
parent study for eligibility of Study TV50717-
CNS-30081 and will serve as day 1 baseline 
values in this study. These findings are only 
required to be shared with the medical monitor 
as required per the inclusion/exclusion criteria. 
Any abnormalities which are listed in the 
inclusion/exclusion criteria must be discussed 
with the medical monitor prior to patient 
enrollment into the study.   
• 
electrocardiograms (ECGs) are to be performed 
on day 1 of Study TV50717 CNS 30081 and 
will serve as day 1 baseline values in this study. 
These findings can be shared with the medical 
monitor at the investigator’s discretion.   
• 
vital signs are performed at week 16 in 
Study TV50717 CNS 30080, these findings 
will serve as day 1 baseline values in this study. 
These findings can be shared with the medical 
monitor at the investigator’s discretion. 
• 
W15 physical examinations are performed at 
week 15 (and week W16, if applicable) in 
Study TV50717-CNS-30080. The findings 
from the last assessment taken will serve as 
day 1 baseline values in this study. These 
findings can be shared with the medical 
monitor at the investigator’s discretion.   
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
 
196 
Letter of Clarification 01 text with changes shown 
New wording 
Reason/Justification for change 
For patients with new clinically significant laboratory 
abnormalities, electrocardiogram (ECG) results, or vital 
signs/physical examination findings at week 16 in 
Study TV50717 CNS 30080, their findings should be shared 
with the medical monitor and assessments should be 
repeated for eligibility on day 1 of Study TV50717
CNS 30081 and will serve as day 1 baseline values in this 
study.  
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
197 
16.9. 
Letter of Clarification 02 Dated 02 July 2019  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
198 
16.10. 
Letter of Clarification 01 Dated 07 June 2019  
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
199 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
200 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
201 
APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS  
Sponsor’s Authorized Representative 
 
  
Teva Pharmaceutical Industries 
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: 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
202 
Central Clinical Laboratory 
Q2 Solutions – Global Headquarters 
5827 South Miami Blvd. 
Morrisville, NC 27560 
Tel: 
 
Central Electrocardiogram Evaluation 
Spaulding Medical, LLC 
525 S. Silverbrook Drive 
West Bend, WI 53095 
Tel: 
 
Trial Supply Management vendor 
Calyx 
4 Canal Street 
Nottingham, United Kingdom, NG1 7EH 
Tel: 
 
Bioanalytic Laboratory 
 
 
Watson Pharma Pvt, Ltd. 
Seawoods Grand Central Tower 2, 
Level-11, Wing-E, Plot N0 R-1, 
Sector 40, Nerul, Navi Mumbai-400706 
India  
Tel. No. 
 
 
Scales and Central Reading 
Signant Health 
785 Arbor Way 
Blue Bell, PA 19422 
Tel: 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
203 
APPENDIX B. INDEPENDENT DATA MONITORING COMMITTEE  
During the conduct of this study, an Independent Data Monitoring Committee (IDMC) will 
review accumulating safety data on a regular basis to ensure the continuing safety of the study 
patients and to review any study conduct issues. 
The IDMC will be composed of independent physicians with expertise in the relevant therapeutic 
field and other relevant experts, such as a statistician. The IDMC will regularly monitor safety 
data throughout the open-label extension study and provide recommendations whether to 
(1) proceed as planned, (2) perform safety-related modifications, (3) suspend study until further 
notice, or (4) prematurely terminate the study due to safety concerns. 
Each IDMC meeting is composed of an open session, in the presence of sponsor representatives, 
and a closed session, with only IDMC members and the unblinded statistician. Unblinded data 
may be reviewed only in the closed session. Following both sessions, the IDMC reconvenes with 
representatives of the sponsor to review recommendations. 
Following the regular or ad hoc IDMC meeting, the chairperson will deliver the IDMC 
recommendation form to the IDMC project manager, who will then forward the IDMC 
recommendation form to the sponsor clinical lead/clinical study physician or designee. 
The conduct and specific details regarding the IDMC sessions are outlined in the IDMC Charter. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
204 
APPENDIX C. STUDY PROCEDURES AND ASSESSMENTS BY VISIT  
1. Procedures for Screening and Enrollment 
Informed consent/assent, as appropriate, based on the patient’s age and condition, will be 
obtained from the patient/parent(s)/legally acceptable representative and caregiver (as 
applicable) at baseline/day 1 or screening visit (whichever comes first), and before any study 
procedures are performed. Informed consent/assent process can begin within 4 weeks before 
possible participation in the open-label study to allow patients adequate time to engage and 
ask questions. 
Patients can either enroll in the study at the week 16 visit of Study TV50717-CNS-30080 or 
up to 4 weeks following the week 15 visit of Study TV50717-CNS-30080. The time when 
the patient enrolls (baseline/day 1) in this study will determine the assessments that will need 
to be performed at the initial visit for the study (Figure 2). 
2. Procedures Before TEV-50717 Treatment 
2.1 Procedures for Patients Who Enroll Between 1 and <2 Weeks After 
Study TV50717-CNS-30080 Week 15 Visit 
a. Data carried over from Study TV50717-CNS-30080 - Screening 
• Demographics 
b. Assessments carried over from Study TV50717-CNS-30080 - Week 15/16 
• W16 vital signs (body temperature and respiratory rate). If the day 1 visit in Study 
TV50717-CNS-30081 is on the same day as the week 16 visit of Study 
TV50717-CNS-30080, these assessments will serve as day 1 baseline values in 
this study. Otherwise, these assessments will be performed at day 1. 
• W16 weight (Note: Weight must be measured with shoes and outerwear off.) 
• W15 height 
• W16 urine drug screen 
• clinically significant laboratory abnormalities identified at week 15 in 
Study TV50717-CNS-30080 are to be repeated at week 16 of the parent study for 
eligibility in Study TV50717-CNS-30081 and will serve as day 1 baseline values 
in this study. Any abnormalities which are listed in the inclusion/exclusion criteria 
must be discussed with the medical monitor prior to patient enrollment into the 
study.  
• W15 physical examination (W16, if applicable). The findings from the last 
assessment taken will serve as day 1 baseline values in this study.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
205 
• W15 neurological examination (W16, if applicable). The findings from the last 
assessment taken will serve as day 1 baseline values in this study. 
c. Day 1 Assessments 
• obtain informed consent/assent  
• review of eligibility criteria 
• medical history and psychiatric history 
• urine pregnancy (beta-human chorionic gonadotropin [β-HCG]) test (required for 
all females who are postmenarchal or ≥12 years of age) 
• orthostatic blood pressure and pulse should be measured after standing for at least 
3 minutes (for patients who are able to stand) 
• perform 12-lead electrocardiogram (ECG) (after at least 5-minute rest in a supine 
or semi-supine position) 
• administer the following assessments: 
− Movement Disorder-Childhood Rating Scale (MD-CRS) part I (centrally read) 
− MD-CRS part II (centrally read) 
− MD-CRS part I (physician rated, video recording) 
− MD-CRS part II (physician rated, video recording) 
− Clinical Global Impression of Severity (CGI-S)  
− Pediatric Evaluation Disability Inventory-Computer Adapted Test 
(PEDI-CAT) 
− Child Behavior Checklist (CBCL) (for ages 6 to 18) (Competence Scale [Parts 
I to VII] and Syndrome Scale [behavioral items]) 
− Unified Huntington’s Disease Rating Scale-Total Motor Score 
(UHDRS-TMS)  
− Unified Huntington’s Disease Rating Scale-Total Maximal Chorea 
(UHDRS-TMC) (centrally read) 
− Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia 
(UHDRS-TMD) (centrally read) 
− UHDRS-TMC (physician rated) 
− UHDRS-TMD (physician rated) 
− Canadian Occupational Performance Measure (COPM) 
– Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit (Note: 
Children 13 years of age and under must be interviewed in conjunction with 
the caregiver. For children over 13 years of age, caregiver involvement is 
strongly encouraged. Questions should be directed to the child, but the 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
206 
caregiver should be encouraged to add relevant information. The children’s 
C-SSRS questionnaire will only be presented to patients aged ≥12 years.). 
If the patient turned 12 years old during or after Study TV50717-CNS-30080, 
but before screening or day 1 visit (whichever comes first) of Study TV50717-
CNS-30081, C-SSRS baseline/screening scale will be completed.   
– Extrapyramidal Symptom Rating Scale (ESRS) subscales I and II 
– Epworth Sleepiness Scale (ESS) (for children and adolescents)  
• inquire about adverse events 
• review concomitant medications 
• dispense TEV-50717 
• contact Interactive Web Response Systems (IWRS) 
Any scales/questionnaires administered at the week 16 visit for Study TV50717-CNS-30080 do 
not need to be repeated if the day 1 visit of Study TV50717-CNS-30081 is the same day as the 
week 16 visit Study TV50717-CNS-30080. 
If all inclusion/exclusion criteria have been reviewed and are met, and the patient is eligible for 
treatment, he/she will be dispensed with study drug. 
2.2 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-
CNS-30080 Week 15 Visit with No Clinically Significant Changes Since the Week 15 
Visit of Study TV50717-CNS-30080 
Patients who enroll in the study between 2 and ≤4 weeks after the Study TV50717-CNS‑30080 
week 15 visit with no clinically significant changes since the week 15 visit of Study TV50717-
CNS-30080 will undergo the following assessments: 
a. Assessments carried over from Study TV50717-CNS-30080 - Week 15/16 
• W15 or W16 (whichever is the most current) chemistry, hematology, urinalysis 
• W16 urine drug screen 
b. Day 1 Assessments  
• obtain informed consent/assent  
• review of eligibility criteria 
• medical history and psychiatric history 
• demographics 
• vital signs (orthostatic pulse and BP, body temperature, and respiratory rate) 
• weight 
• physical examination 
• neurological examination 
• height 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
207 
• 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• urine pregnancy (β-HCG) test (required for all females who are postmenarchal or 
≥12 years of age) 
• MD-CRS part I (centrally read) 
• MD-CRS part II (centrally read) 
• MD-CRS part I (physician rated, video recording) 
• MD-CRS part II (physician rated, video recording) 
• CGI-S 
• PEDI-CAT 
• UHDRS-TMS 
• UHDRS-TMC (centrally read) 
• UHDRS-TMD (centrally read) 
• UHDRS-TMC (physician rated) 
• UHDRS-TMD (physician rated) 
• COPM 
• C-SSRS Since Last Visit (Note: Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to add relevant information. The 
children’s C-SSRS questionnaire will only be presented to patients aged ≥12 
years.)  If the patient turned 12 years old during or after Study TV50717-
CNS-30080, but before screening or day 1 visit (whichever comes first) of Study 
TV50717-CNS-30081, the C-SSRS baseline/screening scale will be completed.   
• ESRS subscales I and II 
• CBCL (for ages 6 to 18) (full assessment Competence Scale [Parts I to VII] and 
Syndrome Scale [behavioral items])  
• ESS (for children and adolescents)  
• inquire about adverse events 
• review concomitant medications 
• dispense TEV-50717 
• contact IWRS 
If all inclusion/exclusion criteria have been reviewed and are met, and the patient is eligible for 
treatment, he/she will be dispensed with study drug. 
For patients who enroll in the study between 2 and ≤4 weeks after the Study TV50717-
CNS‑30080 week 15 visit, the investigator is required to consult with the medical monitor 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
208 
regarding eligibility prior to baseline/day 1. The patient’s file should include all related 
correspondence with the medical monitor.  
2.3 Procedures for Patients Who Enroll Between 2 and ≤4 Weeks After Study TV50717-
CNS-30080 Week 15 Visit with Clinically Significant Changes  
The patient will undergo all screening procedures. Patients who remain eligible for participation 
in the study will be asked to return for day 1 assessments.   
a. Screening 
• obtain informed consent/assent  
• review of eligibility criteria 
• medical history and psychiatric history 
• demographics 
• vital signs (pulse, BP, body temperature, and respiratory rate) 
• weight 
• physical examination 
• neurological examination 
• height 
• 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• chemistry, hematology, urinalysis 
• urine drug screen 
• serum pregnancy (β-HCG) test (required for all females who are postmenarchal or 
≥12 years of age) 
• C-SSRS Since Last Visit (Note: Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to add relevant information. The 
children’s C-SSRS questionnaire will only be presented to patients aged ≥12 
years.)  If the patient turned 12 years old during or after Study TV50717-
CNS-30080, but before screening or day 1 visit (whichever comes first) of Study 
TV50717-CNS-30081, the C-SSRS baseline/screening scale will be completed.   
• CBCL (for ages 6 to 18) (full assessment Competence Scale [Parts I to VII] and 
Syndrome Scale [behavioral items])  
• ESS (for children and adolescents)  
• inquire about adverse events 
• review concomitant medications 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
209 
b. Day 1 
• review of eligibility criteria 
• vital signs (orthostatic pulse and BP, body temperature, and respiratory rate) 
• weight 
• physical examination 
• neurological examination 
• urine pregnancy (β-HCG) test (required for all females who are postmenarchal or 
≥12 years of age) 
• MD-CRS part I (centrally read) 
• MD-CRS part II (centrally read) 
• MD-CRS part I (physician rated, video recording) 
• MD-CRS part II (physician rated, video recording) 
• CGI-S 
• PEDI-CAT 
• UHDRS-TMS 
• UHDRS-TMC (centrally read) 
• UHDRS-TMD (centrally read) 
• UHDRS-TMC (physician rated) 
• UHDRS-TMD (physician rated) 
• COPM 
• C-SSRS Since Last Visit (Note: Children 13 years of age and under must be 
interviewed in conjunction with the caregiver. For children over 13 years of age, 
caregiver involvement is strongly encouraged. Questions should be directed to the 
child, but the caregiver should be encouraged to add relevant information. The 
children’s C-SSRS questionnaire will only be presented to patients aged 
≥12 years.) If the patient turned 12 years old between screening and day 1, the 
C-SSRS baseline/screening scale will be completed.   
• ESRS subscales I and II 
• CBCL (for ages 6 to 18) Syndrome Scale (behavioral items)  
• ESS (for children and adolescents)  
• inquire about adverse events 
• review concomitant medications 
• dispense TEV-50717 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
210 
• contact IWRS 
If all inclusion/exclusion criteria have been reviewed and are met, and the patient is eligible for 
treatment, he/she will be dispensed with study drug. 
For patients who enroll in the study more than 2 weeks and up to 6 months after the Study 
TV50717-CNS‑30080 week 15 visit, the investigator is required to consult with the medical 
monitor regarding eligibility prior to baseline/day 1. The patient’s file should include all related 
correspondence with the medical monitor.  
3. Procedures During TEV-50717 Treatment 
a. Titration Period (Weeks 1 to 7) 
i. 
Telephone Contacts (Weeks 1, 2, 4, 5, and 6) 
Patients will be contacted by telephone to evaluate adverse events. Dose adjustment will be 
made by the investigator after telephone contact with the patient and caregiver/parent. The 
following procedures/assessments will be performed via telephone contact at weeks 1, 2, 4, 
5, and 6: 
• evaluate/adjust TEV-50717 
• administer Clinical Global Impression of Improvement (CGI-I) (Note: Children 13 
years of age and under must be interviewed in conjunction with the caregiver. For 
children over 13 years of age, caregiver involvement is strongly encouraged. 
Questions should be directed to the child, but the caregiver should be encouraged to 
add relevant information.) 
• assess TEV-50717 accountability/compliance/supply status to ensure the patient has 
adequate tablets, inform the patient if they should titrate, and remind them to bring 
used and unused TEV-50717 bottles to the next in-clinic visit 
• inquire about adverse events 
• review concomitant medications 
If a patient experiences an adverse event that is reported during a telephone contact and is 
probably related to TEV-50717, he or she will be brought to the clinic for evaluation. Based 
on the telephone evaluation, the investigator will determine whether, with the medication 
already provided, the patient should titrate up, stay at that dose, or reduce the dose. If 
additional TEV-50717 tablets are required, it would be ordered from the distributor and 
provided to the patient at an unscheduled visit. 
ii. 
In-clinic Visits (Weeks 3 and 7) 
The following procedures/assessments will be performed at in-clinic visits at weeks 3 and 7: 
• evaluate and, if required, adjust TEV-50717 dose (see Section 5.1.1.1) 
• vital signs measurements (pulse, BP, body temperature, and respiratory rate) and 
weight 
• perform 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• perform clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
211 
• administer the following questionnaires: 
– CGI-I (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information.) 
– C-SSRS (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information. C-SSRS 
questionnaire will only be presented to patients aged ≥12 years.) 
– ESRS subscales I and II 
– CBCL (Syndrome Scale part only) 
– ESS 
• dispense/collect TEV-50717 (During the week 3 visit, the investigator (or designee) 
will make sure the patient receives the evening dose to complete the week 3 dosing 
for that day. Refer to the pharmacy manual for further details.) 
• collect used and unused TEV-50717 bottles (Note: At the week 3 in-clinic visit, 
accountability will be performed on all bottles returned except for bottles from 
patients who receive 1 bottle back to complete the week 3 in-clinic evening dose. 
Refer to the pharmacy manual for further details.) 
• assess TEV-50717 accountability/compliance/supply (Note: At the week 3 in-clinic 
visit, accountability will be performed on all bottles returned except for patients who 
receive 1 bottle back to complete the week 3 in-clinic evening dose. Refer to the 
pharmacy manual for further details.) 
• inquire about adverse events 
• review concomitant medications 
• contact IWRS 
b. Maintenance Period (Weeks 14 to 53/Early Termination) 
i. 
In-clinic Visits (Weeks 14, 27, 40, and 53/Early Termination) 
The following procedures/assessments will be performed at weeks 14, 27, 40, and 53/early 
termination (ET): 
• evaluate and, if required, adjust TEV-50717 dose at weeks 14, 27, and 40  
• measure vital signs (pulse, BP, body temperature, and respiratory rate); at weeks 14 
and 53/ET, orthostatic BP and pulse should be measured after standing for at least 
3 minutes (for patients who are able to stand) 
• measure weight (Note: weight must be measured with shoes and outerwear off) 
• perform full physical examination at weeks 27 and 53/ET 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
212 
• perform neurological examination at week 53/ET  
• measure height at weeks 27 and 53/ET 
• perform 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• perform clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• perform urine drug screen at weeks 27 and 53/ET 
• perform pregnancy (β-HCG) test in females who are postmenarchal or ≥12 years of 
age (serum test at week 53/ET and urine test at other visits) 
• administer the following questionnaires: 
− MD-CRS part I (centrally read) at weeks 27 and 53/ET 
− MD-CRS part II (centrally read) at weeks 27 and 53/ET 
− MD-CRS part I (physician rated, video recording) 
− MD-CRS part II (physician rated, video recording) 
− Caregiver Global Impression of Improvement (CaGI-I) (to be assessed before all 
other investigator-rated scales during these visits) 
− CGI-I (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information.) 
− CGI-S (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information.) 
− PEDI-CAT at weeks 27 and 53/ET 
− UHDRS-TMS  
− UHDRS-TMC (centrally read) at weeks 27 and 53/ET 
− UHDRS-TMD (centrally read) at weeks 27 and 53/ET 
− UHDRS-TMC (physician rated) 
− UHDRS-TMD (physician rated) 
− COPM at weeks 27 and 53/ET 
− C-SSRS (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information. C-SSRS 
questionnaire will only be presented to patients aged ≥12 years.) 
− ESRS subscales I and II 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
213 
− CBCL (full assessment at week 53/ET and Syndrome Scale part only on other 
visits) 
− ESS 
• dispense TEV-50717 (weeks 14, 27, and 40)  
• collect TEV-50717 
• assess TEV-50717 accountability/compliance/supply  
• collect used and unused TEV-50717 bottles 
• inquire about adverse events 
• review concomitant medications 
• contact IWRS 
ii. 
Telephone Contacts (Weeks 21, 33, and 46) 
Patients will be contacted by telephone to evaluate adverse events. The following 
procedures/assessments will be performed via telephone contact at weeks 21, 33, and 46: 
• evaluate and, if required, adjust TEV-50717 dose 
• administer CGI-I (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but the 
caregiver should be encouraged to add relevant information.) 
• assess TEV-50717 accountability/compliance/supply status to ensure the patient has 
adequate tablets and remind them to bring used and unused TEV-50717 bottles to the 
next in-clinic visit 
• inquire about adverse events 
• review concomitant medications 
If a patient experiences an adverse event that is reported during a telephone contact and is 
probably related to TEV-50717, he or she will be brought to the clinic for evaluation. Based 
on the telephone evaluation, the investigator will determine whether, with the medication 
already provided, the patient should titrate up, stay at that dose, or reduce the dose. If 
additional TEV-50717 is required, it would be ordered from the distributor and provided to 
the patient at an unscheduled visit. 
4. Procedures After TEV-50717 Treatment (Follow-Up) 
a. In-clinic Visit (Week 54) 
The following procedures/assessments will be performed at week 54: 
• measure vital signs (pulse, BP, body temperature, and respiratory rate) 
• measure weight (Note: Weight must be measured with shoes and outerwear off.) 
• perform neurological examination 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
214 
• perform 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• perform clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• perform urine pregnancy (β-HCG) test in females who are postmenarchal or 
≥12 years of age 
• administer the following questionnaires: 
− MD-CRS part I (centrally read) 
− MD-CRS part II (centrally read) 
− MD-CRS part I (physician rated, video recording) 
− MD-CRS part II (physician rated, video recording) 
− CaGI-I (to be assessed before all other investigator-rated scales during these 
visits) 
− CGI-I (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver/adult 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information.) 
− CGI-S (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information.) 
− UHDRS-TMC (centrally read) 
− UHDRS-TMD (centrally read) 
− C-SSRS (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information. C-SSRS 
questionnaire will only be presented to patients aged ≥12years.) 
− ESRS subscales I and II 
− CBCL (Syndrome Scale part only) 
− ESS 
• inquire about adverse events 
• review concomitant medications 
b. Telephone Contact (Week 55) 
The following procedures/assessments will be performed at week 55: 
• inquire about adverse events 
• review concomitant medications 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
215 
Patients who participate in the study in compliance with the protocol for at least 53 weeks of 
treatment will be considered to have completed the treatment. See Section 5.4 for the 
definition of the end of study. 
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at an end-of-treatment visit or on the last day the patient receives the TEV-50717, 
or as soon as possible thereafter. Procedures for patients who withdraw prematurely from the 
study are described in Section 4.3. Patients should be treated with standard of care after 
termination of the study as appropriate. 
Patients with ongoing adverse events will be monitored as described in Section 7.1.2. 
Otherwise, the follow-up visit will be the last study visit. 
5. Unscheduled Visits 
An unscheduled telephone contact may be performed at the discretion of the investigator. 
An in-clinic unscheduled visit should be performed if a patient requires a dose adjustment for 
adverse events reported during a telephone contact. An unscheduled visit may be performed 
at any time during the study at the patient’s request and as deemed necessary by the 
investigator. The date and reason for the unscheduled visit will be recorded in the patient’s 
source document and on the CRF as well as any other data obtained (eg, adverse events, 
concomitant medications and treatments, and results from procedures or tests). 
The following procedures/assessments will be performed at all in-clinic unscheduled visits: 
• evaluate and, if required, adjust TEV-50717 dose (see Section 5.1.1.1) 
• measure vital signs (pulse, BP, body temperature, and respiratory rate) 
• measure weight (Note: Weight must be measured with shoes and outerwear off.)  
• measure height 
• inquire about adverse events 
• review concomitant medications 
• contact IWRS 
The following procedures/assessments may be performed at unscheduled visits per the 
investigator’s discretion: 
• perform physical examination  
• perform neurological examination  
• perform 12-lead ECG (after at least 5-minute rest in a supine or semi-supine position) 
• perform clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
• perform urine drug screen 
• perform a urine/serum pregnancy (β-HCG) test (only in females who are 
postmenarchal or ≥12 years of age) 
• administer the following questionnaires 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
216 
− C-SSRS (Note: Children 13 years of age and under must be interviewed in 
conjunction with the caregiver. For children over 13 years of age, caregiver 
involvement is strongly encouraged. Questions should be directed to the child, but 
the caregiver should be encouraged to add relevant information. C-SSRS 
questionnaire will only be presented to patients aged ≥12 years.) 
− ESRS subscales I and II 
− CBCL (full or Syndrome Scale part only) 
− ESS 
• if applicable, dispense additional TEV-50717 
• collect used and unused TEV-50717 bottles 
• assess TEV-50717 accountability/compliance/supply  
Other procedures may also be performed at the discretion of the investigator. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
217 
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 GCP guidelines; noncompliance to 
investigational medicinal product (IMP) administration; 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 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
218 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures, 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
219 
APPENDIX E. ETHICS  
Informed Consent/Assent 
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 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. 
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. 
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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
220 
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 investigational medicinal products [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 initiated at least 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 day 1 
• 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
221 
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 adult(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.” 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
222 
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 11. 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 interval corrected for heart 
rate (QTc) prolongation or that is a known strong cytochrome P450 (CYP) inhibitor. The 
addition of a strong CYP2D6 inhibitor is prohibited during the study. 
Prohibited medications that are associated with QTc prolongation are listed in Table 12.  
For COVID-19 updates, refer to Appendix M. 
Table 11: 
Allowed Medications  
Generic/Drug class 
Condition 
Stable medications 
Hormonal birth control 
Must be receiving stable treatment (including dose) for at least 3 months 
before day 1 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 or day 1 (whichever comes first) and anticipated to remain 
stable (dose and frequency) within the study duration 
Benzodiazepines, trihexyphenidyl, 
baclofen (oral and intrathecal), 
tizanidine, muscle relaxants, 
gabapentin, levetiracetam, and 
carbamazepine, topiramate, and other 
anticonvulsants, neuroleptics, typical 
and atypical antipsychotics, 
metoclopramide 
Dosing must have been stable for at least 4 weeks before screening or day 1 
(whichever comes first) 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 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 (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.  
Additional medications allowed with preapproval from medical monitor 
Albuterol, levalbuterol 
Asthma 
Guaifenesin 
Cold symptoms 
Antihistamines 
Allergies 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
223 
Generic/Drug class 
Condition 
Melatonin 
Insomnia 
Table 11: 
Allowed Medications (Continued) 
Generic/Drug class 
Condition 
Stable medications 
Allowed strong CYP inhibitorsa and anticipated to remain stable (dose and frequency) within the study duration 
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 7. 
Note:  Changes to the allowed medications may be permitted in the context of this study if pre-approved by the 
medical monitor. 
BoNT=botulinum toxin; CYP=cytochrome P450; PRN=as needed. 
 
Table 12: 
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 US 
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 US 
Sparfloxacin 
Antibiotic/bacterial infection 
Not available in the US 
a Systemic use only. Topical use is allowed. 
QTc=QT interval corrected for heart rate; GI=gastrointestinal; US=United States. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
224 
APPENDIX I. TOTAL BLOOD VOLUME  
Total blood volume to be collected for each patient in this study is approximately 77.5 mL. 
Total Blood Volumes 
Type of samples 
Screening or 
Baseline (day 1)a 
(mL)  
Weeks 3, 7, 14, 
27, and 40 
(mL) 
Week 
53/ET(mL) 
Week 54 
(mL) 
Unscheduled 
(mL) 
Chemistry 
(1.25-3.5) 
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 
(1.0-2.0) 
β-HCGb  
1.25-3.5 
-- 
1.25-3.5 
-- 
(1.25-3.5) 
Prothrombin/INR 
(4.5) 
4.5 
4.5 
4.5 
(4.5) 
TEV-50717 
concentrationc  
-- 
-- 
4.0 
-- 
4.0 
Total volume (mL) 
per patient  
  
50 
17.5 
10 
  
a Not needed if taken as part of the week 15 or week 16 visit from parent Study TV50717-CNS-30080. 
b Serum β-HCG to be performed at screening for patients who enroll between 2 and ≤4 weeks after Study TV50717-
CNS-30080 week 15 visit and had a clinically significant change and for patients who enroll >4 weeks and up to 
6 months after Study TV50717-CNS-30080 week 15 visit and at week 53 for all patients. 
c Patients experiencing an adverse event leading to discontinuation of TEV-50717, or experiencing any other 
adverse event, should have a single blood sample collected for the measurement of TEV-50717, α-HTBZ and 
β-HTBZ concentrations, if possible. This should be done (at the discretion of the investigator) as soon as possible 
after the onset of the ongoing adverse event and within 48 hours after the last dose intake in the case of 
TEV-50717 discontinuation. To permit the assessment of a potential relationship of the adverse event and plasma 
concentration, an estimate of the date and time of the last dose intake of study drug should be recorded along with 
the date and time of the sample collection. If the estimate of the dose intake cannot be established within a 2-hour 
window, then a blood sample should not be obtained. 
β-HCG=beta human chorionic gonadotropin; ET=early termination visit; HTBZ= dihydrotetrabenazine (active 
metabolite); INR=International Normalized Ratio. 
 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
225 
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: 
• 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 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue. 
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving 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 protocol Yes/No 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
226 
• description or nature of complaint 
• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP. 
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
227 
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] genotyping results) will be sent to the investigational center, where they 
will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. These 
data may also be sent electronically to the sponsor (or organization performing data 
management). 
The medical experts, study monitors, auditors, 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, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (US) 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), 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
228 
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 acknowledgement 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 
• CRFs for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary) 
• safety reports 
• financial disclosure reports/forms 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
229 
• reports of receipt, use, and disposition of the investigational medicinal products 
• 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 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. 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
230 
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 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. 
 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
231 
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 (eg, geopolitical situation) 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. Site will be allowed to conduct remote assent and consent by phone. Site will obtain 
and document a verbal confirmation from patient and legally acceptable representative that they 
received this information and understood it. 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 (Tables 4 and 5) 
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 
evaluate patients at the investigational site. All virtual visits replacing a scheduled in-clinic visit 
must be approved prior to proceeding by the medical monitor. After any week 3, week 7, 
week 14, week 27, or week 40 visit is performed remotely, the patient should come to the 
research site for an unscheduled visit as soon as the COVID-19 situation permits, and this plan 
for unscheduled visit should be discussed with the medical monitor to determine the timing and 
the assessments to be done. In case it is not possible, the medical monitor should be contacted 
and possibility of early termination of the patient may be considered based on the safety 
assessments.  
After remote week 53/end of treatment (ET) or week 54 visits, the patient should attend a study 
visit at the research site as soon as the COVID-19 situation permits. All week 53/ET and 
week 54 assessments required in the protocol will be performed during the in-clinic visit (eg, 
some assessments will be repeated from the remote week 53/ET or week 54 visit). 
Modifications to other procedures and assessments (electrocardiogram [ECG], laboratory sample 
collection, etc) will be performed per implemented contingency measures according to the 
Sponsor's instructions and the corresponding manual. For example, if central laboratory samples 
cannot be collected for safety assessments, sites may have patients visit a local laboratory to 
perform the assessments. At-home nursing visits may be used to perform safety assessments such 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
232 
as ECG, laboratory sample collection, and other assessments to determine any new adverse 
events. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. The original protocol instructions should be followed 
whenever the new instructions are not required. 
Section 4.3 Withdrawal Criteria and Procedures for the Patient 
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 who cannot complete their ECG assessments during the 
titration period (local or at site) at week 3 and week 7 visits will be early terminated from the 
study. In addition, patients who cannot complete the Columbia-Suicide Severity Rating Scale 
(C-SSRS) and pregnancy test as per protocol will also be early terminated from the study. 
In the event the patient cannot continue in the study due the current emergency situation (eg, the 
COVID-19 pandemic), the patient will be terminated early from the study. However, patients 
may be allowed to re-enter the study as soon as the current emergency situation (eg, the 
COVID-19 pandemic) permits, following approval by the medical monitor and full screening 
assessments. As a consequence, it is possible that a patient may participate in the study for longer 
than initially planned and, therefore, may receive treatment for more than 53 weeks. 
Section 5.1.1.2 Dose Modification and Dose Stratification 
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 can remain on the same dose at week 3 and week 7 for up to 
2 additional weeks if the patient is tolerating investigational medicinal product (IMP) well and 
the medical monitor confirms the ECGs have been normal (including QTc intervals). Further 
titration at week 3 cannot occur until ECG, C-SSRS, and pregnancy test (as relevant) are 
performed and results confirmed as acceptable for continued titration. Additional IMP can be 
supplied to patient without the need for an in-clinic visit. The medical monitor should be 
contacted to approve and confirm the duration of the extension of the dosing.  
If the patient is unable to come to the site at week 14, week 27, week 40, or week 53, is 
tolerating IMP adequately, and the medical monitor confirms the ECGs have been normal 
(including QTc intervals), the patient can remain on the same dose until the patient can return for 
an in-clinic visit, up to 4 additional weeks. If the patient is unable to return to the site at the time, 
the patient may be early terminated from the study at the decision of the medical monitor.  
5.2. Handling, Labeling, Storage, and Accountability 
IMP direct to patient delivery is being setup as long term solution and will be available in 
countries that support this under the COVID-19 restrictions; the common solution is to allow 
sites to mitigate any IMP shipment to patient according to local practice (eg, courier). Due to 
local regulatory restrictions, this will likely be the predominant practice. 
The IMP will continue to be administered at home. Following patient’s/parent’s consent, IMP 
will be shipped to patient if his or her family cannot reach site to collect the study drug.  All 
shipping arrangements will be the site’s responsibility and will occur between site and patient.  
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
233 
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), remote assessment may be allowed for the following:  
• via nonrecording live video for the Clinical Global Impression of Improvement [CGI-
I] mandatory at week 3 and week 7, Clinical Global Impression of Severity [CGI-S], 
Movement Disorder-Childhood Rating Scale [MD-CRS] parts I and II, Unified 
Huntington’s Disease Rating Scale-Total Motor Score [UHDRS-TMS], and the 
Canadian Occupational Performance Measure [COPM], as applicable. The results of 
the questionnaires will be entered to the case report form (CRF) per the usual process 
indicating that the rating has been performed remotely. 
• via iPhone® (Apple, Inc) or via paper back-up copy instead of iPad® (Apple Inc) for 
the Caregiver Global Impression of Improvement [CaGI-I] and the Pediatric 
Evaluation Disability Inventory-Computer Adapted Test [PEDI-CAT], as applicable.  
The results of the questionnaires will be transferred to the CRF per the usual process 
(either from iPhone or from paper back-up copy). 
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-TMS should be completed as much as possible; some fields (ie, rigidity, stability) may 
be left blank as they cannot be assessed remotely. The pull test should not be done due to safety 
considerations.   
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), remote assessment of safety scales (as well as inquiries regarding 
adverse events and use of concomitant medication) via teleconference and/or video conference, 
with video conference being the preferred method, may be allowed.  
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. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation.  The original protocol instructions should be followed 
whenever the new instructions are not required. 
Section 7.2 Safety Rating Scales 
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), remote assessment of safety scales may be allowed for the following: 
• via a phone call, supported by nonrecording live video for the C-SSRS (mandatory) 
and for the Extrapyramidal Symptom Rating Scale (ESRS), which should be 
completed as much as possible; some fields [ie, rigidity, stability] may be left blank 
as they cannot be assessed remotely; the pull test should not be done due to safety 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
234 
considerations. The results of the questionnaires will be entered to the case report 
form (CRF) per the usual process indicating that the rating has been performed 
remotely. 
• via iPhone or via paper back-up copy instead of iPad for Child Behavior Checklist 
[for ages 6-18] [CBCL] and for Epworth Sleepiness Scale [for children and 
adolescents] [ESS].  
The results of the questionnaires will be transferred to CRF per the usual process (either from 
iPhone or from paper back up copy). 
Section 7.5 Clinical Laboratory Tests 
If central laboratory samples cannot be collected for safety assessments, patients may have a 
home nursing visit, if available, to collect the required samples or have the patient visit a local 
laboratory to perform the assessments. The laboratory results will be sent to the investigator for 
review. 
• Laboratory tests are optional at week 3 and week 14, mandatory at week 7, mandatory 
at week 27 and week 40 if not done at the respective previous visit, and mandatory at 
week 53/ET and week 54.  
• Urine drug screen is optional in case laboratory tests are not mandatory.  
• Urine beta-human chorionic gonadotropin (β–HCG) kits may be shipped to the 
patient’s home when a safety laboratory test is not mandatory. Urine β–HCG test is 
mandatory for all visits when it is required as per protocol. 
Section 7.6 Vital Signs 
Vital Signs are optional at week 3 and week 14, mandatory at Week 7, mandatory at Week 27 
and at week 40 if not done at the respective previous visit and mandatory at week 53/ET and 
week 54. Vital Signs can be measured at home, at a local pharmacy or by the home nursing. 
Orthostatic blood pressure and pulse are optional. 
Section 7.9 Electrocardiography 
ECG is mandatory at week 3 and week 7, optional at week 14 (depending on the results of 
previous ECG satisfying the safety requirements per protocol), mandatory at week 27 and 
week 40 (if not done at the respective previous visit), and mandatory at week 53/ET and 
week 54.  ECGs can be obtained at home or at the local clinic. The ECGs will be sent to the 
investigator for review and then forwarded for central assessment. 
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 
VV-00471159 v6.0


 
Uncontrolled Study–Dyskinesia in Cerebral Palsy 
Clinical Study Protocol Amendment 04 
Study TV50717-CNS-30081 
235 
safety and/or efficacy data) will be described in the appropriate sections of the clinical study 
report as applicable. 
Appendix D. Quality Control and Quality Assurance 
Important 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) will be described in the appropriate sections of the clinical study 
report as applicable. 
Study Monitoring 
In case of an emergency situation (eg, the COVID-19 pandemic), monitors may not be able to 
access the investigational centers for on-site visits in a timely manner. A remote monitoring risk 
mitigation plan will be utilized for sites where on-site monitoring visits are not permitted. 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 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. Please consult with the medical 
monitor for further advice. 
VV-00471159 v6.0

SAP_001.pdf: 
 
 
 
 
St atistic al A n al ysis Pl a n  
 
 
A n O pe n -La bel, L o n g -Ter m Safet y, T olera bilit y, a n d Efficac y St u d y of T E V -
5 0 7 1 7 ( De utetra be nazi ne) f or t he Treat me nt of D ys ki nesia i n Cere bral Pals y i n 
C hil dre n a n d A d olesce nts ( O pe n R E C L AI M -D C P)  
 
 
St u d y N u m ber T V 5 0 7 1 7 -C N S -3 0 0 8 1  
 
 
N C T 0 4 2 0 0 3 5 2  
 
 
S A P A p pr o val Date: 0 8 J ul y 2 0 2 2  


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1  
 
 
  
St atistic al A n al ysis Pl a n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
(O pe n R E C L AI M -D C P)  
A n O pe n -L a bel, L o n g -Ter m S afet y, T oler a bilit y, a n d Effic ac y St u d y of T E V -5 0 7 1 7 
( De utetr a be n azi ne) f or t he Tre at me nt of D ys ki nesi a i n Cere br al P als y i n C hil dre n a n d 
A d olesce nts  
S h ort title: Re d ucti o n  of C hil d h o o d a n d A d olesce nt A b n or m al I n v ol u nt ar y M o ve me nts  i n 
P ati e nts wit h  D ys ki netic Cere br al P als y i n C hil dre n a n d A d olesce nts  
(O pe n R E C L AI M -D C P)  
L a y pers o n title: A St u d y t o Test if T E V -5 0 7 1 7 is S afe a n d Effecti ve i n Relie vi n g A b n or m al 
I n v ol u nt ar y M o ve me nts i n Cere br al P als y 
P h ase 3  
 
I N D N u m ber: 1 3 9 7 0 0;  N D A N u m ber: N A;  E u dr a C T N u m ber: 2 0 1 9 -0 0 1 8 0 7 -1 9  
 
 
 
 
A p pr o v al D ate: 0 8 J ul y  2 0 2 2  
 
S p o ns or  
Te v a Br a n de d P h ar m ace utic al  
Pr o d ucts R & D, I nc.  
1 4 5  Br a n d y wi ne P ar k w a y  
West C hester, Pe n ns yl v a ni a 1 9 3 8 0  
U nite d St ates  of A meric a  
 
 
 
 
Pre p are d b y:  
 
Gl o bal Statistics , Te va  
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L   
 
St u d y N o.:  
T V 5 0 7 1 7 -C N S -3 0 0 8 1  
 
A n O pe n -L a bel, L o n g -Ter m S afet y, T oler a bilit y, a n d Effic ac y St u d y of T E V -5 0 7 1 7  
( De utetr a be n azi ne) f or t he Tre at me nt of D ys ki nesi a i n Cere br al P als y i n C hil dre n a n d 
A d olesce nts  ( O pe n R E C L AI M-D C P)  
S h ort title: Re d ucti o n  of C hil d h o o d a n d A d olesce nt A b n or m al I n v ol u nt ar y M o ve me nts i n 
P ati e nts wit h  D ys ki netic Cere br al P als y i n C hil dre n a n d A d olesce nts  
(O pe n R E C L AI M -D C P)  
 
 
 
St atistic al A n al ysis Pl a n f or:  
 I nteri m A n al ysis   
 
 I nte gr ate d S u m m ar y of Effic ac y 
 
 Fi n al A n al ysis  
 
 
 I nte gr ate d S u m m ar y of S afet y 
 
 
 
A ut h or:  
 Te v a Gl o b al St atistics 
 T e v a Gl o b al St atistics 
 
 
<I nsert si g n at ure >  
 
 
 
 
 
E xec ute d si g n at ure p a ges are m ai nt ai ne d se p ar ately wit hi n t he Tri al M aster File/ Tev a’s re p osit ory 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3  
T A B L E  O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L  ..........................................................................2  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ..................................................7  
I N T R O D U C TI O N ...........................................................................................................................9  
1.  
S T U D Y O BJ E C TI V E S  ..............................................................................................1 0  
1. 1.  
Pri mar y a n d Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts  ..........................................1 0  
2.  
S T U D Y D E SI G N  .......................................................................................................1 2  
2. 1.  
Ge neral  Desi g n  ...........................................................................................................1 2  
2. 2.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts  ........................................................1 6  
2. 3.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................2 4  
2. 4.  
Data M o nit ori n g C o m mittee  .......................................................................................2 4  
2. 5.  
Sa m ple Siz e a n d P o wer C o nsi derati o ns  .....................................................................2 4  
2. 6.  
Se q ue nce of Pla n n e d A n al yses  ...................................................................................2 4  
2. 6. 1.  
Pla n ne d I nteri m A nal yses  ...........................................................................................2 4  
2. 6. 2.  
Fi nal A nal yses a n d Re p orti n g  .....................................................................................2 4  
3.  
A N A L Y SI S S E T S  ......................................................................................................2 5  
3. 1.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................2 5  
3. 2.  
A d diti o nal A nal ysis Set  ..............................................................................................2 5  
4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S  ..........................................................2 6  
4. 1.  
Ge neral  ........................................................................................................................2 6  
4. 2.  
S pecificati o n of Baseli ne Val ues  ................................................................................2 6  
4. 3.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................2 7  
4. 4.  
St u d y Da ys a n d Visits  .................................................................................................2 7  
4. 5.  
Ha n dli n g D ata Fr o m Patie nts w h o Wit h dra w a n d Re -E nter t he St u d y  ......................3 0  
4. 5. 1.  
Baseli ne Val ues  ..........................................................................................................3 0  
4. 5. 2.  
P ost baseli ne Data  ........................................................................................................3 0  
5.  
S T U D Y P O P U L A TI O N  .............................................................................................3 1  
5. 1.  
Ge neral  ........................................................................................................................3 1  
5. 2.  
Patie nt Dis p ositi o n  ......................................................................................................3 1  
5. 3.  
De m o gra p hics a n d Baseli ne C haract eristics  ...............................................................3 1  
5. 4.  
Disease C haracteristics  ...............................................................................................3 1  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4  
5. 5.  
Me dical Hist or y  ..........................................................................................................3 1  
5. 6.  
Pri or T hera p y a n d Me dic ati o n  ....................................................................................3 2  
5. 7.  
St u d y Dr u g Titrati o n  ...................................................................................................3 2  
5. 8.  
St u d y Dr u g C o m plia nce  .............................................................................................3 2  
5. 9.  
St u d y Pr ot o c ol De viati o ns  ..........................................................................................3 4  
6.  
E F FI C A C Y A N A L Y SI S  ............................................................................................3 5  
6. 1.  
Ge neral  ........................................................................................................................3 5  
6. 2.  
Efficac y E n d p oi nts a n d A nal ysis  ................................................................................3 5  
6. 2. 1.  
Efficac y E n d p oi nts  ......................................................................................................3 5  
6. 2. 2.  
Efficac y A nal ysis  ........................................................................................................3 6  
6. 2. 2. 1.  
M o ve me nt Dis or der -C hil d h o o d Rati n g Scale  ............................................................3 6  
6. 2. 2. 2.  
Care gi ver Gl o b al I m pressi o n of I m pr o v e me nt Scale  .................................................3 7  
6. 2. 2. 3.  
Cli nical Gl o bal I m pr essi o n of I m pr o ve me nt Scal e  ....................................................3 7  
6. 2. 2. 4.  
Cli nical Gl o bal I m pr essi o n of Se verit y  ......................................................................3 8  
6. 2. 2. 5.  
Pe diatric  E val uati o n Disa bilit y I n v e nt or y -C o m p ut er A da pte d Test ( Acti vities 
of Dail y Li vi n g, Care gi v er C o m plete d, C o nte nt -Bala nce d Versi o n  ...........................3 8  
6. 2. 2. 6.  
U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal M ot or Sc ore  ................................3 9  
6. 2. 2. 7.  
Ca na dia n Occ u pati o nal Perf or ma n ce M eas ure  ...........................................................3 9  
6. 3.  
S u b gr o u p A n al ys es  .....................................................................................................4 0  
7.  
M U L TI P L E C O M P A RI S O N S  A N D M U L TI P LI CI T Y  ............................................4 1  
8.  
S A F E T Y A N A L Y SI S  ................................................................................................4 2  
8. 1.  
Ge neral  ........................................................................................................................4 2  
8. 2.  
D urati o n of E x p os ure t o St u d y Dr u g  ..........................................................................4 2  
8. 3.  
A d verse E v e nts  ...........................................................................................................4 2  
8. 4.  
Deat hs  .........................................................................................................................4 3  
8. 5.  
Cli nical La b orat or y Tests  ...........................................................................................4 3  
8. 6.  
P h ysical E x a mi nati o ns  ................................................................................................4 3  
8. 7.  
Ne ur ol o gical E x a mi nati o ns  ........................................................................................4 3  
8. 8.  
Vital Si g ns  ..................................................................................................................4 3  
8. 9.  
Electr ocar di o gra p h y  ....................................................................................................4 5  
8. 1 0.  
C o nc o mita nt Me dicati o ns or T hera pi es  ......................................................................4 6  
8. 1 1.  
C hil dre n’s C ol u m bia -S uici de Se verit y Rati n g Scal e  ..................................................4 7  
8. 1 2.  
C hil d Be ha vi or C hec klist f or A ges 6 -1 8 ( C B C L)  ......................................................4 8  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5  
8. 1 2. 1.  
C o m pete nce Scale  .......................................................................................................4 8  
8. 1 2. 2.  
S y n dr o me Scale  ..........................................................................................................5 0  
8. 1 3.  
E p w ort h Slee pi ness Scal e  ...........................................................................................5 2  
8. 1 4.  
E xtra p yra mi dal S y m pt o m Rati n g Scale  ......................................................................5 2  
8. 1 4. 1.  
E S R S I  ........................................................................................................................5 2  
8. 1 4. 2.  
E S R S I I .......................................................................................................................5 3  
9.  
T O L E R A BI LI T Y V A RI A B L E S A N D A N A L Y SI S ..................................................5 4  
1 0.  
S T A TI S TI C A L S O F T W A R E  ....................................................................................5 5  
1 1.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N T H E S T U D Y P R O T O C O L  ..............5 6  
1 2.  
R E F E R E N C E S  ...........................................................................................................5 7  
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
6  
LI S T O F T A B L E S  
Ta ble 1:  
Pri mar y a n d Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts  ..........................................1 0  
Ta ble 2:  
St u d y Pr oce d ures a n d Assess me nts –  Scree ni n g a n d/ or Da y 1  ..................................1 6  
Ta ble 3:  
St u d y Pr oce d ures a n d Assess me nts –  Titrati o n, Mai nte na nce, a n d F oll o w -u p 
Peri o ds  ........................................................................................................................2 0  
Ta ble 4:  
Visit Wi n d o ws f or Earl y Ter mi nati o n Visit f or Efficac y Assess me nts  ......................2 7  
Ta ble 5:  
Visit Wi n d o ws f or Earl y Ter mi nati o n Visit f or Safet y Ass ess me nts  .........................2 8  
Ta ble 6 : 
Dis pe nsi n g Dr u g Kits base d o n Wei g ht Gr o u p at Baseli ne/ D a y 1 Ti trati o n 
Sc he me –  N o n -I m p aire d C Y P 2 D 6 Meta b olizers .......................................................3 3  
Ta ble 7:  
Dis pe nsi n g Dr u g Kits base d o n Wei g ht Gr o u p at Baseli ne/ D a y 1 Titrati o n 
Sc he me –  I m paire d C Y P 2 D 6 Meta b olizers ................................................................3 3  
Ta ble 8:  
Criteria f or P ote ntiall y Cli nicall y Si g nifica nt Vital Si g ns  ..........................................4 4  
Ta ble 9:  
P ote ntiall y Cli nicall y Si g nifica nt Val ues f or E C G Varia bles b y A ge  ........................4 6  
Ta ble  1 0:  S uici dal I deati o n Cate g or y  .........................................................................................4 7  
Ta ble  1 1:  S uici dal Be ha vi or Cat e g or y  ........................................................................................4 8  
Ta ble 1 2:  C B C L C o m pete n ce Scal e  ...........................................................................................4 8  
Ta ble 1 3:  C B C L C o m pete n ce Scal e Sc ori n g  ..............................................................................4 9  
Ta ble 1 4:  C B C L S y n dr o me Scale  ...............................................................................................5 1  
 
LI S T O F FI G U R E S  
Fi g ure 1:  
O verall St u d y Sc h e matic Dia gra m  .............................................................................1 4  
Fi g ure 2:  
Fl o w C hart f or Patie nt Scree ni n g a n d Da y 1 Visit Assess me nts  ................................1 5  
 
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
7  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S   
A b bre vi ati o n  
Ter m  
A D L  
acti vities of dail y li vi n g  
B MI  
b o d y m ass in de x  
b p m  
beats per mi n ute  
C -S S R S  
C ol u m bia -S uici de  Se verit y Rati n g Scale  
Ca GI -I 
Care gi ver Gl o bal I m pressi o n of I m pr o ve me nt  
C B C L  
C hil d Be ha vi or C hec klist (f or a ges 6 -1 8)  
C GI  
Cli nical Gl o bal I m pressi o n  
C GI -I 
Cli nical Gl o bal I m pressi o n of I m pr o ve me nt  
C GI -S  
Cli nical Gl o bal I m pressi o n of Se verit y  
C O P M  
Ca na dia n Occ u pati o nal Perf or ma nce Meas ure  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C P  
cere bral pals y  
C R F  
case re p ort f or m  
C S R  
cli nical st u d y re p ort  
C T M S  
Cli nical Trial Ma na ge me nt S yste m  
C Y P  
c yt oc hr o me P 4 5 0 
C Y P 2 D 6  
c yt oc hr o me P 4 5 0 2 D 6  
D C P  
d ys ki nesia i n cere bral pals y 
E C G  
Electr ocar di o gra m/ Electr ocar di o gra p h y  
E S R S  
E xtra p yra mi dal S y m pt o m Rati n g Scale (s u bscales I a n d II)  
E S S  
E p w ort h Slee pi ness Scale (f or c hil dre n a n d a d olesce nts)  
E T  
earl y ter mi nati o n  
H R  
 
heart rate  
i D M C 
i n de pe n de nt Data M o nit ori n g C o m mittee  
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I T T 
I nte nt-t o-Treat  
M D -C R S  
M o ve me nt Dis or der -C hil d h o o d Rati n g Scale  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
n  
n u m ber  
N D A  
Ne w Dr u g A p plicati o n  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
8  
A b bre vi ati o n  
Ter m  
P E DI -C A T  
Pe diatric E val uati o n Disa bilit y I n ve nt or y -C o m p uter A da pte d T est  
P R   
Ti me fr o m t he be gi n ni n g of t he P wa ve t o t he be gi n ni n g of t he Q R S c o m ple x i n 
electr ocar di o gra m  
Q R S  
Gra p hical deflecti o ns c orres p o n di n g t o ve ntric ular de p olarizati o n i n a t y pical 
electr ocar di o gra m  
Q T c  
Q T c orrecte d f or heart rate 
Q T c F  
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ula  
R R  
Ti me bet wee n t he start of o ne R wa ve a n d t he start of t he ne xt R wa ve i n t he E C G  
S D  
Sta n dar d De viati o n  
S E  
 
Sta n dar d Err or  
S O C  
s yste m or ga n class 
S O P  
sta n dar d o perati n g pr oce d ure  
U H D R S -T M C  
U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal C h orea  
U H D R S -T M D  
U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal D yst o nia  
U H D R S -T M S  
U nifie d H u nti n gt o n’s Disease Rati n g Scale - T otal M ot or Sc ore  
W H O  
W orl d Healt h Or g a nizati o n 
α -H T B Z  
al p ha-di h y dr otetra be nazi ne  
β -H C G  
beta -h u ma n c h ori o nic g o na d otr o pi n  
β -H T B Z  
beta -di h y dr otetra be nazi ne  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
9  
I N T R O D U C TI O N  
T his Statistical A nal ysis Pla n descri bes  t he pla n n e d a nal ysis a n d re p orti n g f or Te va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc.  S t u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 , A n O pe n -La bel, L o n g -T er m 
Safet y, T olera bilit y, a n d  Efficac y St u d y of T E V -5 0 7 1 7 ( De utetra be nazi ne) f or t he Treat me nt of 
D ys ki nesia i n Cere bral P als y ( C P) i n C hil dre n a n d A d olesce nts, a n d was writte n i n acc or da n ce 
wit h  S O P  G S D -S O P -7 0 2  ( Statistical A nal ysis Pla n). 
T he rea der of t his Statistical A nal ysis Pla n  is e nc o ura ge d t o r ea d t he st u d y pr ot oc ol f or details o n 
t he c o n d uct of t his st u d y, t he o perati o nal as p ects of cli nical assess me nts , a n d t he ti mi n g f or 
c o m pleti n g t he p artici pati o n of a patie nt i n t his st u d y.  
T he  Statistical A nal ysis Pla n  is i nte n de d t o be i n a gree m e nt wit h t he pr ot o c ol, es peciall y wit h 
re gar ds t o t he pri mar y a n d all sec o n dar y e n d p oi nts a n d t heir res p ecti ve a n al ys es. H o we ver, t he 
Statistical A nal ysis Pla n ma y c o ntai n m ore det ails re gar di n g t hes e partic ul ar p oi nts of i nterest, or 
ot her t y p es of a n al ys es (e. g. ot her e n d p oi nts). W he n differe n ces e xist i n descri pti o ns or 
e x pla nati o ns pr o vi de d i n t he st u d y pr ot oc ol a n d t his Statistical A nal ysis Pla n , t he Statistical 
A nal ysis Pla n  pre vails; t he differe nces  will be e x plai ne d i n t he Cli nical St u d y Re p ort  ( C S R). 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 0  
1.  
S T U D Y  O B J E C TI V E S   
1. 1.  
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves  a n d E n d p oi nts   
T he pri mar y a n d s ec o n d ar y st u d y o bje cti ves a n d e n d p oi nts are pres e nte d bel o w i n Ta ble 1 .  
T a ble 1 : 
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nts   
O bjecti ves  
Me as ures/ E n d p oi nts  
T he pri m ar y o bjecti ve  of t h is 
st u d y is t o e val uate t h e safet y 
a n d t olera bilit y of l o n g -ter m 
t hera p y wit h T E V-5 0 7 1 7 i n 
c hil dre n a n d a d ol esce nts wit h  
d ys ki nesia i n cere bral pals y  
(D C P ). 
T he safet y meas ures/ e n d p oi nts are as f oll o ws:  
•  a d verse e ve nts  
•  vital si g ns  
•  c hil dre n’s C -S S R S  
•  E C G para meters  
•  cli nical la b orat or y p ara m eters ( he m at ol o g y, s er u m 
c he mistr y, a n d uri nal ysis)  
•  E S R S (s u bscales I a n d II)  
•  C B C L  
•  E S S  
A sec o n d ar y o bjecti ve of t his 
st u d y is t o e val uate t h e efficac y 
of l o n g -t er m t hera p y wit h 
T E V -5 0 7 1 7 i n re d u ci n g t he 
se verit y of D C P. 
T he  effi cac y m eas ures/e n d p oi nts are as f oll o ws : 
•  M D -C R S part I t otal sc ore (ce ntrall y rea d)  
•  M D -C R S part II t otal sc ore (ce ntrall y rea d)  
•  M D -C R S part  I t otal sc ore ( p h ysicia n rate d) 
•  M D -C R S part II t otal sc ore ( p h ysicia n rate d)  
•  M D -C R S Gl o bal I n de x (calc ulate d fr o m M D -C R S parts 
I a n d II t otal sc ores) 
•  Ca GI -I ( gl o bal, care gi ver rate d) 
•  C GI -I ( gl o bal, p h ysicia n rate d) 
•  C GI -S ( gl o b al, p h ysi cia n rate d)  
•  P E DI -C A T ( A D L , care gi ver c o m plete d, 
c o nte nt-bala nce d versi o n ) 
•  U H D R S -T M C (ce ntr all y rea d)  
•  U H D R S -T M D (ce ntrall y rea d)  
•  U H D R S -T M S ( p h ysici a n rate d ) 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 1  
O bjecti ves  
Me as ures/ E n d p oi nts  
•  U H D R S -T M C ( p h ysici a n rate d)  
•  U H D R S -T M D ( p h ysicia n rate d)  
•  C O P M ( p h ysicia n rate d)  
Ca GI -I = Care gi ver Gl o bal I m pressi o n of I m pr o ve me nt; C B C L = C hil d Be ha vi or C hec klist (f or a ges 6 t o 1 8);  
C GI -I = Cli nical Gl o bal I m pressi o n of I m pr o ve me nt; C GI-S = Cli nical Gl o bal I m pressi o n of Se verit y;  
C O P M = Ca na dia n Occ u pati o nal P erf or ma nce Meas ure; C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale;  
D C P = d ys ki nesia i n cere bral pal s y; E C G =electr ocar di o gra m; E S R S = E xtra p yra mi dal S y m pt o m Rati n g Scale  
(s u bscales I a n d II); E S S = E p w ort h Slee pi ness Scale (f or c hil dre n a n d a d olesce nts); M D-C R S = M o ve me nt  
Dis or der -C hil d h o o d Rati n g Sc ale; P E DI -C A T = P e diatric E val uati o n Disa bilit y I n ve nt or y-C o m p uter A da pte d T est;  
A D L =acti vities of dail y li vi n g; U H D R S -T M C = U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal C h orea; 
U H D R S -T M D = U nifie d  H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal D yst o nia; U H D R S -T M S = U nifie d 
H u nti n gt o n’s Disease Ra ti n g Scale -T otal M ot or Sc ore.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 2  
2.  
S T U D Y D E SI G N   
2. 1.  
Ge ner al  Desi g n   
T his is a 5 5 -wee k, o p e n -l a bel, si n gle-ar m st u d y i n w hic h patie nts w h o ha ve s uccessf ull y 
c o m plete d t he pare nt st u d y ( St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0) ma y b e eli gi ble t o e nr oll i n t his st u d y 
after t he y c o m plete a 1 -w ee k was h o ut p eri o d a n d t he fi nal e val u ati o n at wee k 1 6. F or p atie nts 
r olli n g o ver fr o m St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0, t he wee k 1 6 visit ma y be t h e da y 1 visit f or 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 . If t he patie nt d oes n ot wis h t o e nr oll i n St u d y T V 5 0 7 1 7-C N S -
3 0 0 8 1 at t hat visit, or f or a n y ot h er reas o n, t he p ati e nt ca n e nr oll u p t o 4 wee ks  f oll o wi n g t he 
wee k 1 5 visit o f St u d y T V 5 0 7 1 7-C N S -3 0 0 8 0 . T h e e n d of st u d y T V 5 0 7 1 7-C N S -3 0 0 8 1 is defi ne d 
as t he date of t h e wee k 5 5 f oll o w -u p tele p h o ne c o ntact of t he last partici p a nt.   
T his st u d y will i ncl u de c hil dre n a n d a d oles ce nts b et wee n 6 a n d 1 8 years of a ge at t he ti me w h e n 
t he y e nr olle d i n t he pare nt st u d y ( St u d y T V 5 0 7 1 7-C N S -3 0 0 8 0). I nf or me d c o nse nt/asse nt, as 
a p pr o priate, b ase d o n t he patie nt’s a ge a n d c o n diti o n, will be o btai ne d fr o m t he 
patie nt/ pare nt(s)/le gall y acce pta ble re pres e ntati ve a n d care gi ver (as a p plica ble) at  baseli ne/ da y 1 
or scree ni n g visit ( w hic h e ver c o m es first), a n d b ef ore a n y st u d y pr oce d ure s are perf or m e d.  
Patie nts ca n eit her e nr oll i n t he st u d y at t he wee k 1 6 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 or u p 
t o 6 m o nt hs f oll o wi n g t he wee k 1 5 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0. T he ti me w he n t he 
patie nt e nr olls ( baseli ne/ da y 1) i n t his st u d y will deter mi ne t he ass ess me nts t hat will nee d t o be 
perf or me d at t h e i nitial visit f or t he st u d y. Detaile d descri pti o ns of eac h assess me nt are pr o vi de d 
i n Ta ble 2 , Fi g ure 2  a n d Secti o n  4. 2 . 
Titrati o n peri o d ( 7 wee ks) : All patie nts will u n der g o T E V -5 0 7 1 7 d ose titrati o n i n t his  st u d y i n 
or der t o mai ntai n t he bli n d of t he pare nt St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0. Pati e nts will  recei ve 6 m g 
of T E V -5 0 7 1 7 . T his d ose will be a d mi nistere d i n t he m or ni n g o n d a ys 2 a n d 3, f oll o we d b y 
e ve ni n g a d mi nistrati o n starti n g o n d a y 3 f or t he re mai n der of t he wee k (if b o d y wei g ht is ≥4 0 
k g/ 8 8 l bs). T E V -5 0 7 1 7 d ail y d oses of 1 2 m g a n d hi g her will be a d mi nistere d as 2 di vi de d e q ual 
d oses, a p pr o xi matel y 8 t o 1 0 h o urs a part d uri n g t he da y. A mi ni m u m of 6 h o urs s h o ul d ela pse 
bet wee n d oses.  
T he titrati o n sc he me a n d ma xi m u m d ose  will be deter mi ne d b y b o d y wei g ht at da y 1 a n d  
c yt o c hr o me P 4 5 0 2 D 6  (C Y P 2 D 6 ) i m pair me nt stat us. Patie nts will be classifie d as C Y P 2 D 6 
i m paire d if t he y are recei vi n g a str o n g C Y P 2 D 6 i n hi bit or. Patie nts w h o are C Y P 2 D 6 i m paire d 
will ha ve a d ose ca p i n t he  o pe n -la b el st u d y. Safet y e v al uati o ns d uri n g t he titrati o n  peri o d 
i ncl ude assess me nt of vit al si g ns, m o nit ori n g f or a d verse e v e nts a n d c o n c o mita nt  me dicati o ns, 
1 2 -lea d ele ctr ocar di o gra ms ( E C G )s, i de ntif yi n g p atie nts at ris k f or s uici de, assess me nt of dr u g-
i n d uce d par ki ns o nis m acc or di n g t o t he  E xtra p yra mi dal S y m pt o m Rati n g S ca le (E S R S ) s u bscales 
I a n d II, assess me nt of c h a n ge i n be ha vi or acc or di n g t o t he  C hil d Be h a vi or C hec klist  (C B C L ) 
q uesti o n naire, a n d assess me nt of se dati o n acc or di n g t o t he E p w ort h Slee pi ness Scale ( E S S ) 
q uesti o n naire.  
I n-pers o n (i n -cli nic) st u d y visits will  be sc he d ule d at wee ks 3 a n d 7, a n d tel e p h o ne c o ntacts ( wit h  
n o n -rec or di n g li ve vi de o) will be sc he d ule d f or wee ks 1, 2, 4, 5, a n d 6 i n or der t o assess 
d ys ki nesia a n d a d verse e ve nts.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 3  
Mai nte na nce p eri o d ( 4 6 wee ks):  At t he e n d of t he titrati o n peri o d ( wee k 7 ), t he patie nt’s i nitial 
d ose f or t he mai nte n a nce peri o d ( u p t o wee k 5 3) will be esta blis he d. D ose a dj ust me nts of  T E V -
5 0 7 1 7 ( u p war d or d o w n war d) ma y b e ma de d uri n g t he mai nte n a nce peri o d, if necessar y,  bas e d 
o n effic ac y, safet y, a n d/ or t olera bilit y c o nsi de rati o ns b ut n ot m ore ofte n t ha n e ver y 5 da ys  a n d 
o nl y i n i ncre m e nts of 6 m g u p t o t he ma xi m u m all o we d d ose ( see Ta ble 6  a n d Ta ble 7 ).  
D uri n g t h e mai nte na nce peri o d, i n -pers o n (i n -cli nic) st u d y visits will be s c he d ule d at wee ks 1 4,  
2 7, 4 0, a n d 5 3 f or ass ess me nts of safet y a n d effi cac y, a n d tel e p h o ne c o nt acts ( wit h n o n -rec or di n g 
li ve vi de o) will be sc he d ule d f or wee ks 2 1, 3 3, a n d 4 6 i n or der t o assess a d verse e v e nts a n d 
d ys ki nesia. At w ee k 5 3/e arl y t er mi nati o n ( E T), p atie nts will u n der g o a c o m plete e val uati o n .  
Was h o ut a n d f oll o w -u p peri o d : All patie nts s h o ul d c o nti n ue t heir us ual treat me nt re gi me n u p t o 
wee k 5 3 visit (ie, t he last d ose ca n be a d mi nistere d u ntil visit c o m pleti o n, if a p plica ble). N o 
d osi n g will be gi ve n after t he wee k 5 3 visit. All patie nts will disc o nti n ue T E V -5 0 7 1 7 at t he wee k 
5 3 visit a n d  will ret ur n 1 wee k later ( w ee k 5 4) f or e val uati o n of safet y. Patie nts will ha ve a 
f oll o w-u p  tele p h o ne c o ntact ( n o li ve vi de o strea mi n g) f or safet y e val u ati o n 1 wee k after t he e n d 
of t he  was h o ut peri o d ( 2 wee ks after t heir l ast d ose of T E V -5 0 7 1 7) ( wee k 5 5).  
St u d y pr oce d ures a n d ass ess me nts wit h t heir ti me p oi nts are pres e nte d f or scree ni n g a n d/ or da y 1  
i n Ta ble 2  a n d f or t h e titrati o n, mai nte na nce, a n d f oll o w -u p peri o ds i n  Ta bl e 3 . T he st u d y  
sc he matic dia gra m is prese nte d i n Fi g ure 1 . A fl o w c hart f or patie nt scree ni n g a n d d a y 1 visit 
assess me nts is prese nte d i n Fi g ure 2 . 
F or c or o na vir us disease 2 0 1 9 ( C O VI D -1 9) u p dat es,  refer t o pr ot oc ol  A p pe n di x M.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Sta tistical A nal ysis Pla n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 4  
Fi g ure 1 : 
O ver all St u d y Sc he m ati c Di a gr a m   
≥ 4 0 k g
3 0 k g t o < 4 0 k g
6 ( 6)
m g
1 2 (1 2 ) 
m g
1 8 ( 1 8) 
m g
2 4 ( 2 4) 
m g
3 0 ( 2 4) 
m g
3 6 ( 2 4) 
m g
4 2 ( 2 4) 
m g
St a bl e m a x m ai nt e n a nc e d os e 4 2 ( 2 4) m g/ d a y
1 7 k g t o < 3 0 k g
6 ( 6)
m g
1 2 ( 1 2) 
m g
1 8 ( 1 8) 
m g
2 4 ( 1 8) 
m g
3 0 ( 1 8) 
m g
St a bl e m a x m ai nt e n a nc e d os e 3 0 ( 1 8) m g/ d a y
6 ( 6) 
m g
1 2 (1 2 ) 
m g
2 4 (2 4 ) 
m g
3 0 ( 3 0) 
m g
3 6 ( 3 6) 
m g
4 2 ( 3 6) 
m g
4 8 ( 3 6) 
m g
St a bl e m a x m ai nt e n a nc e d os e 4 8 ( 3 6) m g/ d a y
1 8 ( 1 8) 
m g
1 2 k g t o < 1 7 k g
6 ( 6)
m g
1 2 ( 1 2) 
m g
1 8 ( 1 2) 
m g
2 4 ( 1 2) 
m g
St a bl e m a x m ai nt e n a nc e d os e 2 4 ( 1 2) m g/ d a y
Titr ati o n P eri o d
D os e a dj ust m e nts s h o ul d b e m a d e o n all av ail a bl e i nf or m ati o n, i ncl u di ng 
t h e p ati e nt a n d c ar e gi v er r e p orts of a d v ers e e v e nts a n d d ys ki n esi a 
r e d ucti o n, a n d t h e cli nic al ass ess m e nt of s af et y a n d effic ac y b y t h e 
i n v esti g at or
M ai nt e n a nc e P eri o d
W as h o ut
F oll o w U p
  
 
  
  
   
 
  
  
  
  
 
 
     
   
  
  
 
    
   
  
  
    
  
    
     
  
 
    
  
  
  
  
  
  
    
  
  
    
    
 
  
  
  
   
  
  
    
  
 
  
  
    
    
  
  
  
 
  
  
  
  
 
 
W e e k 
3
B as eli n e
D a y 
1
W e e k 
7
W e e k  
1 4
D a y 
2
D a y
 
W e e k 
3 3
W e e k 
2 7
W e e k 
1
W e e k 
2
W e e k 
4
W e e k 
5
W e e k 
6
W e e k 
2 1
W e e k 
4 0
W e e k 
4 6
W e e k 
5 4
W e e k 
5 5
W e e k 
5 3/ E T
W e e k 
5 3
I n-cli nic visit
T el e p h o n e c all
T el e p h o n e c o nt act 
wit h n o n-r ec or di n g 
li v e vi d e o
 
A E =a d verse e ve nt; C GI -I = Cli nical Gl o bal I m pressi o n of I m pr o ve me nt; C Y P 2 D 6 =c yt oc hr o me P 4 5 0 2 D 6; D = d a y; E T =earl y ter mi nati o n; ma x = ma xi m u m; 
W k = wee k.  
N ote: If a patie nt is C Y P 2 D 6 -i m paire d, t he d ose a d mi nistere d is i n dicate d i n pare nt heses. T he d ose of T E V-5 0 7 1 7 s h o ul d be i ncrease d u ntil a n y of t he f oll o wi n g 
e ve nt s occ ur: cli nicall y mea ni n gf ul re d ucti o n i n d ys ki nesia (ie, C GI -I) as deter mi ne d b y t he i n vesti gat or, cli nicall y si g nifica nt A E, or t he ma xi m u m all o wa ble 
d ose is reac he d. T he mai nte na nce peri o d starts at wee k 7; h o we ver, st u d y pr oce d ures a n d assess me nts ar e c o n d ucte d bet wee n wee ks 1 4 a n d  5 3/ E T.  
 
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Sta tistical A nal ysis Pla n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 5  
Fi g ure 2 : 
Fl o w C h art f or P atie nt Scree ni n g a n d D a y 1 Visit Assess me nts   
 
a Defi ne d as a n y cli nicall y si g nif ica nt c ha n ge si nce t he W 1 5 visit of St u d y T V 5 0 7 1 7-C N S -3 0 0 8 0 i n healt h, c o nc o mita nt me dicati o ns, cli nical assess me nts, 
la b orat ories, E C Gs, or n o n-me dical i nter ve nti o ns.  
E C G =electr ocar di o gra m; W 1 5 = wee k 1 5.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis P la n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 6  
2. 2.  
Sc he d ule of St u d y Pr oce d ures a n d Assess me nts   
St u d y pr oce d ures a n d ass ess me nts wit h t heir ti me p oi nts are pres e nte d f or s cree ni n g a n d/ or da y 1 
i n Ta ble 2  a n d f or t h e titrati o n, mai nte na nce, a n d f oll o w -u p peri o ds i n Ta bl e 3 . D uri n g a visit, 
st u d y pr oce d ures a n d ass ess me nts s h o ul d be perf or me d i n t he or der s pecifi e d i n t he st u d y 
ma n ual.  
Detail descri pti o ns of eac h assess me nt are pr o vi de d i n Secti o n  6  (efficac y assess me nts) a n d 
Secti o n  8  (safet y ass ess me nts). 
F or C O VI D -1 9  u p dates, refer t o pr ot oc ol  A p pe n di x M . 
T a ble 2 : 
St u d y Pr oce d ures a n d Assess me nts –  Scree ni n g a n d/ or D a y 1   
 
D a y 1  
B et w ee n 1 a n d 
< 2  w ee ks after 
St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 
w ee k  1 5 visit a 
D a y 1  
Bet w ee n 2 a n d ≤4  w ee ks 
after St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 w ee k 1 5 visit 
wit h n o cli nic all y 
si g nific a nt c h a n ges b  
D a y 1  
Bet w ee n 2 a n d ≤4 w ee ks  
after St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 w ee k 1 5 visit 
a n d wit h cli nic all y 
si g nific a nt c h a n ges b  
St u d y d a y  
D a y 1/ B L  
D a y 1/ B L  
Scree ni n g  
D a y 1/ B L 
( wit hi n 3 1 d a ys 
fr o m scree ni n g) 
I n-cli nic visit  
X  
X  
X  
X  
I nf or me d c o nse nt/asse ntc 
X  
X  
X  
 
Eli gi bilit y criteria  
X  
X  
X  
X  
Me dical hist or y a n d 
ps yc hiatric hist or y  
X  
X  
X  
 
De m o gra p hics  
[ X] 
X  
X  
 
Vital si g ns a n d wei g ht d, e 
[ X]f 
X e 
X e 
X e 
P h ysical e xa mi nati o n  
[ X] 
X  
X  
X  
Ne ur ol o gical e xa mi nati o n  
[ X] 
X  
X  
X  
Hei g ht  
[ X] 
X  
X  
 
1 2 -lea d E C Gg 
X  
X  
X  
 
C he mistr y/ he mat ol o g y/  
uri nal ysis  
[ X]h 
[ X]h 
X  
 
Uri ne dr u g scree n  
[ X]h 
[ X]h 
X  
 
β -H C G test  
X i 
X j 
X k 
X j 
M D -C R S part I (ce ntrall y 
rea d) 
X  
X  
 
X  
M D -C R S part II (ce ntrall y 
rea d) 
X  
X  
 
X  
M D -C R S part I ( p h ysicia n 
rate d, wit h vi de o rec or di n g )l 
X  
X  
 
X  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis P la n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 7  
 
D a y 1  
B et w ee n 1 a n d 
< 2  w ee ks after 
St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 
w ee k  1 5 visit a 
D a y 1  
Bet w ee n 2 a n d ≤4  w ee ks 
after St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 w ee k 1 5 visit 
wit h n o cli nic all y 
si g nific a nt c h a n ges b  
D a y 1  
Bet w ee n 2 a n d ≤4 w ee ks  
after St u d y T V 5 0 7 1 7 -
C N S -3 0 0 8 0 w ee k 1 5 visit 
a n d wit h cli nic all y 
si g nific a nt c h a n ges b  
St u d y d a y  
D a y 1/ B L  
D a y 1/ B L  
Scree ni n g  
D a y 1/ B L 
( wit hi n 3 1 d a ys 
fr o m scree ni n g) 
M D -C R S part II ( p h ysicia n 
rate d, wit h vi de o rec or di n g )l 
X  
X  
 
X  
C GI -S ( gl o bal, p h ysicia n 
rate d) 
X  
X  
 
X  
P E DI -C A T ( A D L, care gi ver 
c o m plete d, c o nte nt -bala nce d 
versi o n)  
X  
X  
 
X  
U H D R S -T M C (ce ntrall y 
rea d) 
X  
X  
 
X  
U H D R S -T M D (ce ntrall y 
rea d) 
X  
X  
 
X  
U H D R S -T M S ( p h ysicia n 
rate d) 
X  
X  
 
X  
U H D R S -T M C ( p h ysicia n 
rate d) 
X  
X  
 
X  
U H D R S -T M D ( p h ysicia n 
rate d) 
X  
X  
 
X  
C O P M ( p h ysicia n rate d) 
X  
X  
 
X  
C -S S R S (c hil dre n’s 
baseli ne/scree ni n g) m  
X n 
X n 
X n 
X n 
C -S S R S (c hil dre n’s si nce 
last visit)m  
X  
X  
X  
X  
E S R S (s u bscales I a n d II)  
X  
X  
 
X  
C B C L  
X o 
X o 
X o 
X p 
E S S  
X  
X  
X  
X  
Assess a d verse e ve nts  
X  
X  
X  
X  
C o nc o mita nt me dicati o ns q 
X  
X  
X  
X  
Dis pe nse T E V -5 0 7 1 7 r 
X  
X  
 
X  
C o ntact I W R S  
X  
X  
 
X  
a Assess me nts i n dicate d i n brac kets b y “[ X]” are re prese ntati ve of data carrie d o ver fr o m we e k 1 5/ 1 6 of St u d y 
T V 5 0 7 1 7 -C N S -3 0 0 8 0, w hic he ver is m ore c urre nt. A n y scal es/ q uesti o n naires a d mi nistere d at t he wee k 1 6 visit f or 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 d o n ot nee d t o be re peate d if t he da y 1 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 is t he 
sa me da y as t he wee k 1 6 visit St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis P la n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 8  
b Defi ne d as cli nicall y si g nifica nt c ha n ge si nce t he wee k 1 5 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 i n healt h, 
c o nc o mita nt me dicati o ns, cli nical assess me nts, la b orat ories, E C Gs, or n o n -me dical i nter ve nti o ns, i n t he j u d g me nt 
of t he i n vesti gat or . 
c I nf or me d c o nse nt/asse nt, as a p pr o priate, base d o n t he patie nt’s a ge, will be o btai ne d fr o m t he patie nt/ pare nt/le gall y 
acce pta ble re prese ntati ve a n d care gi ver (as a p plica ble) at baseli ne/ da y 1 or scree ni n g visit ( w hic he ver c o mes first), 
a n d bef ore a n y st u d y  pr oce d ur es are perf or me d. T he i nf or me d c o nse nt/asse nt pr ocess ca n b e gi n wit hi n 4  wee ks 
bef ore p ossi ble partici pati o n i n t he o pe n -la bel st u d y t o all o w patie nts a de q uate ti me t o e n ga ge a n d as k q uesti o ns. 
d Ort h ostatic B P a n d p ulse will be meas ure d after t he  patie nt is i n a sta n di n g p ositi o n f or at l east 3 mi n utes (f or 
patie nts w h o are a ble t o sta n d).  
e W ei g ht m ust b e meas ure d wit h s h oes a n d o uter wear off. Bef ore p ulse a n d B P are meas ure d, t he patie nt m ust b e i n 
a s u pi ne or se mi -erect/seate d p ositi o n a n d rest i n g f or at least 3 mi n utes (t he sa me p ositi o n a n d ar m/le g s h o ul d be 
use d eac h ti me vital si g ns are meas ure d f or a gi ve n patie nt).  
f Ort h ostatic bl o o d press ure a n d ort h ostatic p ulse rate will be meas ure d at da y 1. Wei g ht me as ure me nts will be 
carrie d o ver fr o m t he wee k  1 6 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0. All ot her vital si g n assess me nts (res pirat or y 
rate a n d b o d y te m perat ure) will be carrie d o ver fr o m t he we e k 1 6 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0, if t he da y  1 
visit i n St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 is o n t he sa me d a y as t he wee k 1 6 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0. 
Ot her wise, t hese vital si g n ass ess me nts will be perf or me d at da y 1.  
g All E C Gs will be perf or me d after at least a 5 -mi n ute rest i n a s u pi ne or se mi -s u pi ne p ositi o n. 
h T hese data will be ta ke n fr o m t he wee k 1 5 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0, u nless m ore c urre nt data fr o m t he 
wee k 1 6 visit are a vaila ble.  
i F or fe males w h o are p ost me narc hal or ≥1 2 years of a ge. If t he da y 1 visit i n St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 is o n t he 
sa me da y as t he wee k 1 6 visit of St u d y T V5 0 7 1 7 -C N S -3 0 0 8 0, t he res ults of β -H C G tests i n uri ne will be carri e d 
o ver fr o m t he wee k 1 6 visit.  Ot her wise, t he β H C G tests i n uri ne will be a d mi nistere d at da y 1.  
j F or fe males w h o are p ost me narc hal or ≥1 2 years of a ge, a β -H C G test i n uri ne will be a d mi nistere d. A patie nt wit h 
a p ositi ve β -H C G test i n uri ne ca n n ot b e e nr olle d u ntil a β -H C G test i n ser u m has bee n perf or me d a n d is ne gati ve.  
k F or fe males w h o are p ost me narc hal or ≥1 2 years of a ge, a β -H C G test i n ser u m will be a d mi nistere d.  
l M D -C R S parts I  a n d II assess me nts are d o ne l ocall y at t he i n vesti gati o nal ce nter b y t he i n vesti gat or, vi de o 
rec or de d. I n certai n i nsta nces, base d o n t he e x perie nce of t he rater, certai n n o n-p h ysicia ns ma y be a p pr o ve d t o rate 
t he M D-C R S.  
m  C hil dre n 1 3 years of a ge a n d u n der m ust b e i nter vie we d i n c o nj u ncti o n wit h t he care gi ver. F or c hil dre n o ver 
1 3  years of a ge, care gi ver i n v ol ve me nt is str o n gl y e nc o ura ge d. Q uesti o ns s h o ul d be directe d t o t he c hil d, b ut t he 
care gi ver s h o ul d be e nc o ura ge d t o a d d rele va nt i nf or mati o n. T he c hil dre n’s C -S S R S q uesti o n naire will o nl y be 
prese nte d t o patie nts a ge d ≥1 2 years.  
n  If t he patie nt t ur ne d 1 2 years ol d d uri n g or after St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0, b ut bef ore scree ni n g or da y 1 visit 
of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1, w hic he ver c o mes first, t he C -S S R S baseli ne/scree ni n g sc ale is a d mi nistere d . If 
t he patie nt t ur ns 1 2 years ol d d uri n g t he st u d y, C-S S R S bas eli ne/scree ni n g will be c o m plete d as t he i nitial 
assess me nt a n d t he C -S S R S Si nce Last Visit will be c o m plet e d as per  T a ble 5 . 
o A f ull C B C L assess me nt ( C o m pete nce Scale [ P arts I t o VII] a n d a S y n dr o me Scale [ be ha vi oral ite ms]) will be 
perf or me d.  
p O nl y t he C B C L S y n dr o me Sc ale ( be ha vi oral ite ms) will be perf or me d.  
q P atie nts a n d/ or care gi vers will be i nstr ucte d d uri n g t he c o urs e of t he st u d y t o n otif y t he i n vesti gat or if a n y ne w 
me dicati o n is prescri be d or if t here is a n y c ha n ge i n c urre nt me dicati o ns, i ncl u di n g o ver -t he-c o u nter me dicati o ns. 
A n y prescr i be d me dicati o n s h o ul d be re vie we d wit h t he i n vesti gat or. 
r T E V -5 0 7 1 7 will b e dis pe nse d o nce all pr oce d ures a n d eli gi bilit y -relate d assess me nts are c o m plete d a n d patie nt 
eli gi bilit y is c o nfir me d.  
A D L =acti vities of dail y li vi n g; β -H C G = beta -h u ma n c h ori o nic g o na d otr o pi n; B L = baseli ne visit; B P = bl o o d press ure; 
C B C L = C hil d B e ha vi or C hec klist (f or a ges 6 t o 1 8 years); C GI -S = Cli nical Gl o bal I m pressi o n of Se verit y; 
C O P M = Ca na dia n Occ u pati o nal P erf or ma nce Meas ure; C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; 
E C G =ele ctr ocar di o gra m; E S R S = E xtra p yra mi dal S y m pt o m Rati n g Scale (s u bscales I a n d II); E S S = E p w ort h 
Slee pi ness Scale (f or c hil dre n a n d a d olesce nts); I W R S =I nter acti ve We b Res p o nse S yste ms; M D -C R S = M o ve me nt 
Dis or der -C hil d h o o d Rati n g Sc ale; P E DI -C A T = P e diatric E val uati o n Disa bilit y I n ve nt or y -C o m p uter A da pte d T est; 
U H D R S -T M C = U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal C h orea; U H D R S -T M D = U nifie d 
H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal D yst o ni a;  U H D R S -T M S = U nifie d H u nti n gt o n’s Disease Rati n g 
Scale -T otal M o t or Sc ore; W 1 5 = wee k 1 5; W 1 6 = wee k 1 6. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis P la n 
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
1 9  
N ote: It is r ec o m me n de d t hat t he sa me or der of a d mi nistrati o n/c o m pleti o n of t he scales b e ke pt 
per patie nt t hr o u g h o ut t h e st u d y, as b est as p ossi ble (refer t o t he St u d y T V 5 0 7 1 7-C N S -3 0 0 8 1 
O pe n -R E C L AI M -D C P: Or der of scale s a d mi nistrati o n/c o m pleti o n d oc u me nt). T he i n vesti gat or 
s h o ul d re vie w t he scales i n a ti mel y ma n ner f or a n y p ote ntial re p orti n g of a d verse e v e nts a n d 
d oc u me nt t his re vie w acc or di n gl y.  
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 0  
T a ble 3 : 
St u d y Pr oce d ures a n d Assess me nts –  Titr ati o n, M ai nte n a nce, a n d F oll o w -u p Peri o ds   
 
Titr ati o n  
M ai nte n a nc e
a  
F oll o w -u p  
U  
St u d y w ee k b   
1  
2  
3  
4  
5  
6  
7  
1 4  
2 1  
2 7  
3 3  
4 0  
4 6  
5 3/  
E T c 
5 4  
5 5 d 
 
St u d y d a y  
7  
1 4  
2 1  
2 8  
3 5  
4 2  
4 9  
9 8  
1 4 7  
1 8 9  
2 3 1  
2 8 0  
3 2 2  
3 7 1  
3 7 8  
3 8 5  
 
Visit wi n d o w ( d a ys)  
+ 1 d a y 
fr o m 
D a y 
1/ B L  
± 1 d a y 
fr o m 
D a y 
1/ B L  
± 3 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 7 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 2 d a ys 
fr o m 
w ee k 5 3  
± 2 d a ys 
fr o m 
w ee k 5 4  
 
I n-cli nic visit 
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X  
Tele p h o ne c o ntact e  
X  
X  
 
X  
X  
X  
 
 
X  
 
X  
 
X  
 
 
X  
X f 
E val u ate/a dj ust T E V -5 0 7 1 7 g   
X  
X  
X  
X  
X  
X  
X  
X h 
X  
X  
X  
X  
X  
 
 
 
X  
Vital si g ns a n d wei g ht i  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X  
P h ysical e xa mi n ati o n  
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
X f 
Ne ur ol o gical e xa mi n ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
X f 
Hei g ht  
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
X  
1 2 -Lea d E C G j  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
C he mistr y/ h e mat ol o g y/ uri n al ysis  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
Uri ne dr u g scree n  
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
X f 
β -H C G test k   
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
X f 
M D -C R S part I ( ce ntrall y rea d)l   
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X  
 
 
M D -C R S part II ( ce ntrall y rea d) l 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X  
 
 
M D -C R S part I ( p h ysicia n rate d  
wit h vi d e o rec or di n g ) m   
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
 
M D -C R S part II ( p h ysicia n rate d  
wit h vi d e o rec or di n g )m  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
 
Ca GI -I ( gl o bal, care gi ver rate d) n   
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
 
C GI -I ( gl o bal, p h ysicia n rate d) o   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C GI -S ( gl o b al, p h ysicia n rate d) o 
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 1  
 
Titr ati o n  
M ai nte n a nc e
a  
F oll o w -u p  
U  
St u d y w ee k b   
1  
2  
3  
4  
5  
6  
7  
1 4  
2 1  
2 7  
3 3  
4 0  
4 6  
5 3/  
E T c 
5 4  
5 5 d 
 
St u d y d a y  
7  
1 4  
2 1  
2 8  
3 5  
4 2  
4 9  
9 8  
1 4 7  
1 8 9  
2 3 1  
2 8 0  
3 2 2  
3 7 1  
3 7 8  
3 8 5  
 
Visit wi n d o w ( d a ys)  
+ 1 d a y 
fr o m 
D a y 
1/ B L  
± 1 d a y 
fr o m 
D a y 
1/ B L  
± 3 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 7 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 2 d a ys 
fr o m 
w ee k 5 3  
± 2 d a ys 
fr o m 
w ee k 5 4  
 
P E DI -C A T ( A D L, care gi ver 
c o m plete d, c o nte nt -bala nce d 
versi o n)  
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
U H D R S -T M C (ce ntrall y rea d) l 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X  
 
 
U H D R S -T M D (ce ntrall y rea d) l 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
X  
 
 
U H D R S -T M S ( p h ysicia n rate d)  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
 
 
U H D R S -T M C ( p h ysicia n rate d)  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
 
 
U H D R S -T M D ( p h ysici a n rate d)  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
X  
 
 
 
C O P M ( p h ysicia n rate d) 
 
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
 
C -S S R S (c hil dre n’s si nce last 
visit) o 
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
E S R S (s u bscales I a n d II)  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
C B C L p 
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
E S S  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
X  
 
X f 
Dis pe nse T E V -5 0 7 1 7 q 
 
 
X r 
 
 
 
X  
X  
 
X  
 
X  
 
 
 
 
X f 
C ollect T E V -5 0 7 1 7  
 
 
X r 
 
 
 
X  
X  
 
X  
 
X  
 
X  
 
 
X f 
Assess T E V -5 0 7 1 7 acc o u nta bilit y/ 
c o m plia nce/s u p pl y s 
X  
X  
X r 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
X f 
Assess a d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d sa m ple c ollecti o n f or 
T E V -5 0 7 1 7 c o nce ntrati o n t 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
X  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 2  
 
Titr ati o n  
M ai nte n a nc e
a  
F oll o w -u p  
U  
St u d y w ee k b   
1  
2  
3  
4  
5  
6  
7  
1 4  
2 1  
2 7  
3 3  
4 0  
4 6  
5 3/  
E T c 
5 4  
5 5 d 
 
St u d y d a y  
7  
1 4  
2 1  
2 8  
3 5  
4 2  
4 9  
9 8  
1 4 7  
1 8 9  
2 3 1  
2 8 0  
3 2 2  
3 7 1  
3 7 8  
3 8 5  
 
Visit wi n d o w ( d a ys)  
+ 1 d a y 
fr o m 
D a y 
1/ B L  
± 1 d a y 
fr o m 
D a y 
1/ B L  
± 3 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 7 d a ys fr o m D a y 1/ B L a n d  
≥5 d a ys fr o m l ast d ose c h a n ge  
± 2 d a ys 
fr o m 
w ee k 5 3  
± 2 d a ys 
fr o m 
w ee k 5 4  
 
C o nc o mita nt me dicati o ns u 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o ntact I W R S  
 
 
X  
 
 
 
X  
X  
 
X  
 
X  
 
X  
 
 
X  
a T he mai nte na nce peri o d starts at wee k 8; h o we ver, st u d y pr oce d ures a n d assess me nts are c o n d ucte d bet wee n wee ks 1 4 a n d 5 3/ E T.  
b Assess me nt t o occ ur at t he e n d of st u d y wee k, u nless state d ot her wise.  
c F or patie nts w h o wit h dra w pre mat urel y, a n E T visit s h o ul d be c o n d uct e d as s o o n as p ossi bl e after t he last d ose of T E V -5 0 7 1 7. All patie nts w h o disc o nti n ue 
earl y will ha ve a f oll o w -u p tel e p h o ne c o ntact f or safet y e val uati o n 2 wee ks after t heir last d ose of T E V -5 0 7 1 7; e val uati o ns will b e as descri be d f or t he wee k  5 5 
visit.  
d T his visit is a tele p h o ne c o nta ct f or safet y e val uati o n.  
e T ele p h o ne c o ntacts at wee ks 1, 2, 4, 5, 6, 2 1, 3 3, a n d 4 6 will be c o n d ucte d wit h n o n -rec or di n g li ve vi de o. T ele p h o ne c o ntact at wee k 5 5 is a p h o ne c o nt act o nl y 
(ie, n o li ve vi de o strea mi n g). 
f Assess me nt t o be c o m plete d at i n vesti gat or’s discreti o n.  
g D ose i ncreases ma y n ot o cc ur m ore fre q ue ntl y t ha n e ver y 5 da ys, e xce pt f or patie nts ≥4 0 k g. F or patie nts ≥4 0 k g, t he first d o se i ncrease s h o ul d be perf or me d i n 
a n i nter val less t ha n 5 da ys, o nl y o nce, o n da y 3.  
h P atie nts will c o nti n ue t o recei ve t heir mai nte na nce d ose fr o m wee k 8 t o wee k 5 3. D ose re d ucti o ns or s us pe nsi o ns f or a d verse e ve nts are all o we d.  
i W ei g ht m ust b e meas ure d wit h s h oes a n d o uter wear off. Bef ore p ulse a n d B P are meas ure d, t he patie nt m ust b e i n a s u pi ne or se
mi -erect/seate d p ositi o n a n d 
resti n g f or at least 3 mi n utes (t he sa me p ositi o n a n d ar m/le g s h o ul d be use d eac h ti me vital si g ns are meas ure d f or a gi ve n patie nt). Ort h ostatic B P a n d p ulse 
will b e meas ure d after t he pati e nt is i n a sta n di n g p ositi o n f or at least 3 mi n utes (f or patie nts w h o are a ble t o sta n d) a n d s h o ul d be meas ure d at W 1 4 a n d 
W 5 3/ E T.  
j All E C Gs will be perf or me d after at least 5 -mi n ute rest i n a s u pi ne or se mi -s u pi ne p ositi o n. 
k F or fe males w h o are p ost me narc hal or ≥1 2 years of a ge, a uri ne pre g na nc y test will be a d mi nistere d at wee ks 1 4, 2 7, 4 0, a n d 5 4/f oll o w -u p visit w hile a s er u m 
pre g na nc y test will be a d mi nistere d at wee k 5 3/ E T, a n d if cli nicall y i n dicate d.  
l Ce ntral rea di n g is base d o n t he vi de o rec or di n gs, a n d is d o ne i n a bli n de d ma n ner 
m  M D -C R S parts I a n d II assess me nts are d o ne l ocall y at t he i n vesti gati o nal ce nter b y t he i n vesti gat or, vi de o rec or de d. I n certai n i nsta nces, base d o n t he 
e x perie nce of t he rater, certai n n o n -p h ysicia ns ma y be a p pr o ve d t o rate t he M D -C R S.   
n Ca GI -I is t o be assesse d bef ore all ot her i n vesti gat or-rate d s cales d uri n g visits w here Ca GI -I is c ollecte d. 
o C hil dre n 1 3 years of a ge a n d u n der m ust b e i nter vie we d i n c o nj u ncti o n wit h t he care gi ver. F or c hil dre n o ver 1 3 years of a ge, care gi ver i n v ol ve me nt is str o n gl y 
e nc o ura ge d. Q uesti o ns s h o ul d be directe d t o t he c hil d, b ut t he care gi ver s h o ul d be e nc o ura ge d t o a d d rele va nt i nf or mati o n. T he c hil dre n’s C -S S R S 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 3  
q uesti o n naire will o nl y be prese nte d t o patie nts a ge d ≥1 2 ye ars. C hil dre n w h o t ur n 1 2 years ol d d uri n g t he st u d y will be a d mi nistere d C -S S R S 
( baseli ne/scree ni n g) as i nitial assess me nt d uri n g t he st u d y. 
p A f ull C B C L assess me nt ( C o m pete nce Scale [ P arts I t o VII] a n d a S y n dr o me Scale [ be ha vi oral ite ms]) will be perf or me d at wee k 5 3/ E T. T he S y n dr o me Scale 
part of t he C B C L assess me nt will b e perf or me d at wee ks 3, 7, 1 4, 2 7, 4 0, 5 3 / E T visit, a n d 5 4/f oll o w-u p visits.  
q F or a n y d ose a dj ust me nt, t he i n vesti gat or or desi g nee s h o ul d c o nfir m t hat patie nts ha ve t he b ottle t hat c o ntai ns t he a p pr o pri ate ta blet stre n gt h a n d q ua ntit y t o 
c o m plete t he rec o m me n de d dail y re gi me n.  
r D uri n g t he wee k  3 visit, t he i n vesti gat or ( or desi g nee) will ma ke s ure t he patie nt recei ves t he e ve ni n g d ose t o c o m plete t he wee k 3 d osi n g f o r t hat da y. Refer t o 
t he p har mac y ma n ual f or f urt her details. 
s St u d y dr u g acc o u nta bilit y will be assesse d d uri n g i n -cli nic visits o nl y. A c hec k f or c o m pli a nce wit h T E V -5 0 7 1 7 i nta ke will b e perf or me d d uri n g eac h i n -cli nic 
visit a n d tele p h o ne c o ntact aft er T E V -5 0 7 1 7 has bee n dis pe nse d.  
t P atie nts e x perie nci n g a n a d verse e ve nt lea di n g t o disc o nti n uati o n of T E V -5 0 7 1 7, or e x perie nci n g a n y ot her a d verse e ve nt, s h o ul d ha ve a si n gle bl o o d sa m ple 
c ollecte d f or t he meas ure me nt of T E V -5 0 7 1 7, α -H T B Z a n d β H T B Z c o nce ntrati o ns, if p ossi ble. T his s h o ul d be d o ne (at t he discreti o n of t he i n vesti gat or) as 
s o o n as p ossi ble after t he o nset of t he o n g oin g a d verse e ve nt a n d wit hi n 4 8 h o urs after t he last d ose i nta ke i n t he case of T E V 5 0 7 1 7 disc o nti n uati o n. T o per mit 
t he assess me nt of a p ote ntial relati o ns hi p of t he a d verse e ve nt a n d plas ma c o nce ntrati o n, a n esti mate of t he date a n d ti me of t he last d ose i nta ke of st u d y dr u g 
s h o ul d be rec or de d al o n g wit h t he date a n d ti me of t he sa m ple c ollecti o n. If t he esti mate of t he d ose i nta ke ca n n ot b e esta bl is he d wit hi n a 2-h o ur wi n d o w, t he n 
a bl o o d sa m ple s h o ul d n ot b e o btai ne d.  
u P atie nts a n d/ or care gi vers will be  i nstr ucte d d uri n g t he c o urs e of t he st u d y t o n otif y t he i n vesti gat or if a n y ne w me dicati o n is prescri be d, or if t here is a n y 
c ha n ge i n c urre nt me dicati o n , i ncl u di n g o ver-t he-c o u nter me dicati o ns. A n y prescri be d me dicati o n s h o ul d be re vie we d wit h t he i n vest i gat or. 
A D L =acti vities of dail y li vi n g; β -H C G = beta h u ma n c h ori o ni c g o na d otr o pi n; B L = baseli ne visit; B P = bl o o d press ure; Ca GI -I = Care gi ver Gl o bal I m pressi o n of 
I m pr o ve me nt; C B C L = C hil d B e ha vi or C hec klist (f or a ges 6 t o 1 8 years); C GI-I = Cli nical Gl o bal I m pressio n of I m pr o ve me nt; C GI -S = Cli nical Gl o bal I m pressi o n 
of Se verit y; C O P M = Ca na dia n Occ u pati o nal P erf or ma nce M eas ure; C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; E C G =electr ocar di o gra m; 
E S R S = E xtra p yra mi dal S y m pt o m Rati n g Scale (s u bscales I a n d II); E S S = E p w ort h Slee pi ness Scale (f or c hil dre n a n d a d olesce nts); E T =earl y ter mi nati o n visit; 
H T B Z =  di h y dr otetra b e nazi ne (acti ve meta b olite) ; I W R S =I nt eracti ve We b Res p o nse S yste ms; M D-C R S = M o ve me nt Dis or der -C hil d h o o d Rati n g Scale; P E DI -
C A T = P e diatric E val uati o n Disa bilit y I n ve nt or y-C o m p uter A da pte d T est; U = u nsc he d ule d visit; U H D R S -T M C = U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal 
Ma xi mal C h orea; U H D R S -T M D = U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal D yst o nia; U H D R S -T M S = U nifie d H u nti n gt o n’s Disease Rati n g 
Scale -T otal M ot or Sc ore.  
N ote: It is r ec o m me n de d t hat t he sa me or der of a d mi nistrati o n/c o m pleti o n of t he scales b e ke pt per patie nt t hr o u g h o ut t he st u d y, as 
best as p ossi ble (refer t o t he St u d y T V 5 0 7 1 7-C N S -3 0 0 8 1 O pe n -R E C L AI M -D C P: Or der of scales a d mi nistrati o n/c o m pleti o n 
d oc u me nt) . T he i n vesti gat or s h o ul d re vie w t he scales i n a ti mel y ma n ner f or a n y p ote ntial re p orti n g of a d verse e ve nts a n d d o c u me nt 
t his re vie w acc or di n gl y. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 4  
2. 3.  
R a n d o miz ati o n a n d Bli n di n g   
T his is a n o pe n-la bel, si n gle-ar m st u d y, a n d t here is n o bli n di n g.  
2. 4.  
D at a M o nit ori n g C o m mittee   
T here will be a n  I n de p e n de nt Data M o nit ori n g C o m mittee (i D M C) i n t his st u d y. D uri n g t he 
c o n d uct of t his st u d y, a n i D M C  will re vie w acc u m ulati n g safet y data o n a re g ul ar basis t o e ns ure 
t he c o nti n ui n g safet y of t he st u d y p atie nts a n d t o re vie w a n y st u d y c o n d u ct iss ues. 
2. 5.  
S a m ple Size a n d P o wer C o nsi der ati o ns   
T his st u d y is o pe n -la bel a n d safet y ori e nte d i n nat ure; t heref ore, n o f or mal h y p ot hesis testi n g is 
pla n ne d. T he sa m ple siz e f or t his st u d y is n ot base d o n statistical c o nsi derati o ns; he nce, o nl y 
descri pti ve statistics will be prese nt e d.  
Base d o n t h e n u m ber of patie nts i n t he pare nt stu d y ( St u d y T E V 5 0 7 1 7 -C N S -3 0 0 8 0) 
a p pr o xi matel y 4 5 patie nts w h o c o m plete d t he pare nt st u d y ma y e nr oll i n t his st u d y.  
2. 6.  
Se q ue nce of Pl a n ne d A n al yses   
2. 6. 1.  
Pl a n ne d I nteri m A n al yses  
T here is n o pla n ne d i nteri m a nal ysis of t his st u d y. I nter me diate a nal ysis ma y be p erf or me d f or 
s u b missi o n of a Ne w Dr u g A p plic ati o n ( N D A) or ot her pur p oses.  
2. 6. 2.  
Fi n al A n al yses a n d Re p orti n g   
All a nal ys es i de ntifie d i n t his Statistical A nal ysis Pla n will be perf or me d after t he e n d of st u d y as 
defi ne d i n  t he st u d y pr ot oc ol . 
T his  fi nal versi o n of t he Statistical A nal ysis Pla n  a n d a n y c orres p o n di n g a me n d me nts will be 
a p pr o ve d  bef ore  d ata bas e l oc k , i n acc or da nce t o S O P G B P _ R D _ 7 0 2 ( Statistical A nal ysis Pla n). 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 5  
3.  
A N A L Y SI S S E T S   
3. 1.  
I nte nt-t o-Tre at A n al ysis Set   
T he i nte nt t o treat (I T T) a nal ysis  s et will i ncl u de all e nr olle d patients, re gar dless of w het her or 
n ot a patie nt t o o k a n y T E V -5 0 7 1 7. A patie nt is c o nsi dere d e nr olle d acc or di n g t o t he stat us i n t he 
data base.  
B ot h safet y a n d efficac y  a nal ys es will be base d o n t he I T T a nal ysis set.  
3. 2.  
A d diti o n al A n al ysis Set   
N o a d diti o nal a nal ysis set is pla n ne d.  
I n case of a patie nt w h o e nr olle d b ut wit h o ut ta ki n g a n y i n v esti gati o nal me dici nal pr o d uct (I M P), 
a safet y a nal ysis set will be c o nsi dere d as a n e x pl orat or y a n al ysis set f or safet y assess me nts. T his  
safet y a n al ysis set will i ncl u de all e nr olle d p atie nts w h o recei ve at least 1 d ose of  I M P. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 6  
4.  
G E N E R A L I S S U E S F O R D A T A A N A L Y SI S   
4. 1.  
Ge ner al   
Descri pti ve statistics f or c o nti n u o us varia bles i ncl u de n u m ber ( n), mea n, st a n dar d de vi ati o n 
( S D), sta n dar d err or ( S E), me dia n, mi ni m u m, a n d ma xi m u m. Mea n, S D a n d S E will n ot be 
prese nte d if t he n u m b er of patie nts i n t he a nal ysis is less t ha n 5 ( n < 5).  
Descri pti ve statistics f or cate g orical varia bl es i ncl u de patie nt c o u nts  a n d perce nta ges. Missi n g 
cate g or y will be dis pla ye d as a p pr o priat e.   
4. 2.  
S pecific at i o n of B aseli ne V al ues  
Ge nerall y,  t he b aseli ne v al ue is t he last o bser ve d data bef ore t he first d ose of I M P, u nless 
ot her wise n ote d . If t he baseli ne assess me nts occ ur o n t he sa me da y as t h e first d ose of I M P, it is 
ass u me d t hat t he patie nts f oll o w st u d y pr oce d ure a n d t h ose baseli ne assess me nts will be use d.  
T he baseli ne assess me nts t hat will nee d t o be perf or me d at t he i nitial visit f or t he st u d y will be 
deter mi ne d at t he ti me w h e n t he patie nt e nr olls ( baseli ne/ da y 1).  
D a y 1: Bet wee n 1 a n d < 2 w ee ks after St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 wee k 1 5 visit:  
T o re d uce patie nt b ur de n a n d n ot c ollect d u plicate i nf or mati o n, after o bt ai ni n g a p pr o priate 
i nf or me d c o nse nt/asse nt, rele va nt dat a c ollect e d i n St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 will be use d t o 
pr o vi de c orres p o n di n g data i n t his o pe n -la bel st u d y bas eli ne/ da y 1 visit. 
Da y 1 assess me nts f or St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 t hat are i de ntical t o St u d y T V 5 0 7 1 7 -C N S -
3 0 0 8 0 wee k 1 5/ wee k 1 6 visit assess me nts, w h ic he ver is m ost c urre nt, d o n ot nee d t o be 
re peat e d, e x ce pt f or ort h ostatic p ulse rate a n d bl o o d press ure, E C G , b eta-h u ma n c h ori o nic 
g o na d otr o pi n ( β -H C G) tests i n uri ne, t he site -a d mi nistere d scales, a n d t he patie nt/care gi v er -
c o m plete d q uesti o n naires, w hic h nee d t o be re peat e d at da y 1.  
A n y s cales/ q uesti o n nair es a d mi nistere d at t he wee k 1 6 visit f or St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 d o 
n ot nee d t o be re p eate d if t he da y 1 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1 is t he sa me da y as t h e 
wee k 1 6 visit St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0.  S ee pr ot oc ol Secti o n 3 f or a d diti o n details f or da y 1 
baseli ne assess me nts.  
D a y 1: Bet wee n 2 a n d ≤4 w ee ks after St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 wee k 1 5 visit:  
If, i n t he j u d gm e nt of t he i n vesti gat or, t he p atie nt has n ot  ha d a n y cli nicall y si g nifica nt c ha n ge 
si nce t he wee k 1 5 visit of St u d y T V 5 0 7 1 7-C N S -3 0 0 8 0 i n healt h, c o nc o mita nt me dicati o ns, 
cli nical assess me nts, la b orat ories, E C Gs, or n o n -me dical i nter ve nti o ns, t he patie nt will u n der g o 
all da y 1 assess me nts o utli ne d i n Ta ble 2 , e x ce pt he mat ol o g y, c he mistr y, a n d uri nal ysis 
la b orat ories a n d uri ne dr u g scree n, w hic h ca n be carri e d o ver fr o m St u d y T V 5 0 7 1 7-C N S -3 0 0 8 0 
wee k 1 5 o r wee k 1 6 visit, w hic he ver is m or e c urre nt.  
If, i n t he j u d gm e nt of t he i n vesti gat or, t he p atie nt has ha d a cli nicall y si g nifica nt c ha n ge si nce t he 
wee k 1 5 visit of St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 0 i n healt h, c o nc o mita nt me dicati o ns, cli nical 
assess me nts, la b orat or ies, E C Gs, or n o n-me dical i nter ve nti o ns, t he patie nt will u n der g o all 
scree ni n g pr oce d ures o utli ne d i n Ta ble 2 . Patie nts w h o re mai n eli gi ble f or p artici p ati o n i n t he 
st u d y will be as ke d t o r et ur n f or da y 1 assess me nts.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 7  
St u d y dr u g will be dis pe nse d at da y 1 o nce all pr oce d ures a n d i n vesti gat or -relate d ass ess me nts 
are c o m plet e d a n d patie nt eli gi bilit y is c o nfir me d.  
4. 3.  
H a n dli n g Wit h dr a w als a n d Missi n g D at a   
F or m ost varia bles, o nl y o bser ve d dat a fr o m t he p atie nts will be use d i n t he statistical a nal ys es, 
ie, t here is n o pla n t o i m p ute missi n g data f or t hese varia bles, u nless ot her wise s pecifie d.  
R ules f or ha n dli n g missi n g ite ms i n effi cac y a n d safet y rati n g scales/q uesti o n naire  are pres e nte d 
i n Secti o n  6. 2. 2  a n d Secti o n  8 .  
4. 4.  
St u d y  D a ys a n d Visits   
St u d y d a ys will be n u m b ere d relati ve t o t he bas eli ne visit date. Da y 1 is defi ne d as t he date of t he 
baseli ne visit, a n d t he first d ose of t he I M P will be ta ke n t he ne xt m or ni n g ( da y 2). Da ys will  be 
n u m bere d relati ve t o bas eli ne  (ie, ..., – 2, – 1, 1, 2, ...; da y – 1 b ei n g t h e da y bef ore t h e baseli ne 
visit ). 
F or efficac y a n d s afet y b y-visit a nal yses, d ata c oll ecte d at p ost -b aseli ne sc h e d ule d visits will be 
i ncl u de d usi n g t heir s c he d ule d visit. 
D ata c ollecte d at earl y ter mi nati o n a n d u nsc he d ul e d visits will be i ncl u de d a n d assi g n e d t o a visit 
wi n d o w as descri be d bel o w.  
T a ble 4 : 
Visit Wi n d o ws f or E arl y Ter mi n ati o n Visit f or Effic ac y A ssess me nts   
Assess me nt a  
St u d y D a y Wi n d o w  
Sc he d ule d D a y  
Sc he d ule d Visit/ Wee k  
M D -C R S , Ca GI-I, 
C GI -S  
Da y 2 - 1 4 3  
Da y 9 8   
Wee k 1 4  
Da y 1 4 4 - 2 3 4  
Da y 1 8 9  
Wee k 2 7  
Da y 2 3 5 - 3 2 5  
Da y 2 8 0  
Wee k 4 0  
Da y 3 2 6 - 3 7 4  
Da y 3 7 1   
Wee k 5 3  
D a y 3 7 5  
Da y 3 7 8  
Wee k 5 4  
U H D R S -T M S, 
U H D R S -T M C, 
U H D R S -T M D  
Da y 2 - 1 4 3  
Da y 9 8   
Wee k 1 4  
Da y 1 4 4 - 2 3 4  
Da y 1 8 9   
Wee k 2 7  
Da y 2 3 5  - 3 2 5  
Da y 2 8 0   
Wee k 4 0  
D a y 3 2 6  
Da y 3 7 1  
Wee k 5 3  
P E DI -C A T, C O P M  
Da y 2 - 2 8 0  
Da y 1 8 9   
Wee k 2 7  
D a y 2 8 1  
Da y 3 7 1  
Wee k 5 3  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 8  
Assess me nt a  
St u d y D a y Wi n d o w  
Sc he d ule d D a y  
Sc he d ule d Visit/ Wee k  
C GI -I 
Da y 2 –  1 0  
Da y 7   
Wee k 1  
Da y 1 1 –  1 7  
Da y 1 4   
Wee k 2  
Da y 1 8 –  2 4  
Da y 2 1   
Wee k 3  
Da y 2 5 –  3 1  
Da y 2 8   
Wee k 4  
Da y 3 2 –  3 8  
Da y 3 5   
Wee k 5  
Da y 3 9 –  4 5  
Da y 4 2   
Wee k 6  
Da y 4 6 –  7 3  
Da y 4 9   
Wee k 7  
Da y 7 4 –  1 2 2  
Da y 9 8   
Wee k 1 4  
Da y 1 2 3 - 1 6 8  
Da y  1 4 7   
Wee k 2 1  
Da y 1 6 9 –  2 1 0  
Da y 1 8 9   
Wee k 2 7  
Da y 2 1 1 –  2 5 5  
Da y 2 3 1   
Wee k 3 3  
Da y 2 5 6 –  3 0 1  
Da y 2 8 0   
Wee k 4 0  
Da y 3 0 2 –  3 4 6  
Da y 3 2 2   
Wee k 4 6  
Da y 3 4 7 –  3 7 4  
Da y 3 7 1   
 Wee k 5 3  
Da y 3 7 5 –  3 8 1  
Da y 3 7 8   
Wee k 5 4  
D a y 3 8 2  
Da y 3 8 5  
Wee k 5 5  
a M D -C R S = M o ve me nt Dis or der -C hil d h o o d Rati n g Scale; C a GI -I = Care gi ver Gl o bal I m pressi o n of I m pr o ve me nt; 
C GI -I = Cli nical Gl o bal I m pressi o n of I m pr o ve me nt; C GI-S = Cli nical Gl o bal I m pressi o n of Se verit y; U H D R S -
T M S = U nifie d H u nti n gt o n’s Disease Rati n g Scale – T otal M ot or Sc ore; U H D R S -T M C = U nifie d H u nti n gt o n’s Disease 
Rati n g Scale – T otal Ma xi mal C h orea; U H D R S -T M D = U nifi e d H u nti n gt o n’s Disease Rati n g Scale – T otal Ma xi mal 
D yst o nia; P E DI -C A T = P e diatric E val uati o n Disa bilit y I n ve nt or y -C o m p uter A da pte d T est; C O P M = Ca na dia n 
Occ u pati o nal P erf or ma nce Me as ure ;  
T a ble 5 : 
Vis it Wi n d o ws f or E arl y Ter mi n ati o n Visit f or S afet y Assess me nts   
Assess me nt a  
St u d y D a y Wi n d o w  Sc he d ule d D a y  
Sc he d ule d 
Visit/ Wee k  
Vital si g ns a n d wei g ht, 1 2 -Lea d 
E C G, C -S S R S, E S R S, C B C L - 
S y n dr o me Scale , E S S, 
C he mistr y/ he mat ol o g y/  
uri nal ysis  
Da y 2 –  3 5  
Da y 2 1   
Wee k 3  
Da y 3 6 –  7 3  
Da y 4 9   
Wee k 7  
Da y 7 4 –  1 4 3  
Da y 9 8   
Wee k 1 4  
Da y 1 4 4 –  2 3 4  
Da y 1 8 9   
Wee k 2 7  
Da y 2 3 5 –  3 2 5  
Da y 2 8 0   
Wee k 4 0  
Da y 3 2 6 –  3 7 4  
Da y 3 7 1   
Wee k 5 3  
D a y 3 7 5  
Da y 3 7 8  
Wee k 5 4  
P h ysical e xa mi nati o n, Hei g ht  
Da y 2 –  2 8 0  
Da y 1 8 9  
Wee k 2 7  
D a y 2 8 1  
Da y 3 7 1  
Wee k 5 3  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
2 9  
Assess me nt a  
St u d y D a y Wi n d o w  Sc he d ule d D a y  
Sc he d ule d 
Visit/ Wee k  
Ort h ostatic Vital Si g ns  
Da y 2 –  2 3 4  
Da y 9 8  
Wee k 1 4  
> Da y 2 3 5  
Da y 3 7 1  
Wee k 5 3  
Ne ur ol o gical e xa mi nati o n  
Da y 2 –  3 7 4  
Da y 3 7 1  
Wee k 5 3  
D a y 3 7 5 
Da y 3 7 8  
Wee k 5 4  
C B C L -f ull assess me nt  
Da y 2  
Da y 3 7 1  
Wee k 5 3  
  a C B C L = C hil d B e ha vi or C hec klist (f or a ges 6 -1 8); C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; 
E C G =electr ocar di o gra m; E S R S = E xtra p yra mi dal S y m pt o m Rati n g Scale (s u bscales I a n d II); E S S = E p w ort h 
Slee pi ness Scale (f or c hil dre n a n d a d olesce nts) ;  
After ma p pi n g t he d ata t o  t he a nal ysis visits of u nsc he d ule d a n d earl y ter mi nati o n visits, t he 
f oll o wi n g r ules will a p pl y u nless ot her ha n dli n g is s pecifie d f or a partic ular a nal ysis:  
•  If t here is a sc he d ule d visit i n t he a nal ysis wi n d o w, t he last n o n-missi n g sc h e d ule d 
visit will be selecte d.  
•  If t here is n o s c he d ule d visit, b ut earl y ter mi nati o n visit, earl y ter mi nati o n visit will be 
selecte d.  
•  If t here are n o sc he d ule d or earl y ter mi nati o n visits, t he rec or d cl osest t o t he pla n ne d 
assess me nt da y will be selecte d f or a nal ysis.  
•  If t here are n o sc he d ule d or earl y ter mi nati o n visits, a n d 2 rec or ds are e q ui dista nt 
fr o m t he sc he d ule d d a y, t he n t he later rec or d will be selecte d.  
•  If a patie nt  h as n o sc he d ule d rec or d or earl y ter mi n ati o n/ u nsc he d ule d visits i n a n 
a nal ysis wi n d o w, t h e pati e nt  will be c o nsi dere d m issi n g at t hat visit. 
F or t hese a nal yses p erf or me d b y ti me peri o d, e g, a d verse e v e nts, t he f oll o wi n g defi niti o ns will 
be use d:  
•  Titrati o n Peri o d - fr o m t h e first d ose of treat me nt u ntil t he da y of  t he wee k 7 visit . F or 
patie nt s disc o nti n ue d bef ore t he wee k 7 , t he Titrati o n Peri o d is u ntil t he later of t he 
last d ose of treat me nt a n d t he earl y ter mi nati o n visit.  
•  Mai nte na nce Peri o d - fr o m t he da y after t he wee k 7 visit  u ntil t he da y of t he wee k 5 3  
visit. If a p atie nt  e nters t h e Mai nte na nce Peri o d b ut disc o nti n ues treat me nt earl y, t he 
Mai nte na nce Peri o d is u ntil t he later of t he last d ose of treat me nt a n d t he earl y 
ter mi nati o n visit.  
•  O verall Treat me nt Peri o d - i ncl u des t he Titrati o n a n d t he Mai nte na nce Peri o ds, if 
a p plica ble.  
•  F oll o w -u p Peri o d - fr o m t he e n d of t he O v erall Treat me nt Peri o d t hr o u g h t he e n d of 
t he st u d y. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 0  
4. 5.  
H a n dli n g D at a Fr o m P atie nts w h o Wit h dr a w a n d Re -E nter t he 
St u d y   
Patie nts w h o ter mi nate earl y fr o m t he st u d y d ue t o e mer ge n c y cir c u msta nces (s uc h as 
c or o na vir us disease 2 0 1 9 [ C O VI D -1 9]) ma y be all o we d t o re -e nter t he st u d y at a later date.  
Patie nts re -e nteri n g t h e st u d y will re d o t he e ntire st u d y fr o m t he start.  
4. 5. 1.  
B aseli ne V al ues   
I n ge neral, baseli ne v al ues fr o m t he re-e ntere d partici pati o n will be use d. Missi n g baseli ne 
val ues will be ha n dle d i n t he sa me met h o d as ot her n o n -wit h dra wal patie nts.  
Res ults fr o m t he ori gi nal partici pati o n of t he C Y P 2 D 6 i m pair me nt stat us at baseli ne will be 
carri e d o ver t o t he re peate d partici pati o n (re -e nt ere d) p orti o n.  
4. 5. 2.  
P ost b aseli ne D at a   
F or eac h patie nt t hat re -e ntere d t he st u d y, o nl y dat a fr o m t he re peat e d parti ci pati o n will be 
i ncl u de d i n t he I T T a n al ysis set. T he ori gi nal p arti ci pati o n data will be liste d se parat el y a n d will 
n ot be i ncl u de d i n a n y s u m mar y ta bl es. I n case of a S A E t hat occ urre d d uri n g t he ori gi nal 
partici pati o n a n d res ol ve d pri or t o re -e nteri n g, t he S A E will be d oc u me nte d i n me dical hist or y 
data base. Missi n g p ost baseli ne data will be ha n dle d i n t he sa me met h o d as ot her n o n -wit h dra wal 
patie nts.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 1  
5.  
S T U D Y P O P U L A TI O N   
5. 1.  
Ge ner al   
T he I T T a n al ysis set will be use d f or all st u d y p o p ulati o n s u m ma ries u nless ot her wise s pecifie d . 
S u m maries will be p rese nte d f or all patie nts.  
5. 2.  
P atie nt Dis p ositi o n   
Data fr o m p atie nts w h o are e nr olle d ; p atie nts e nr olle d b ut n ot treate d ; patie nts i n t he I T T; 
patie nts w h o c o m plete t h e treat me nt peri o d; patie nts w h o wit h dra w fr o m t h e treat me nt peri o d; 
patie nts w h o c o m plete t h e e n d of st u d y visit , a n d patie nts w h o wit h dra w fr o m t he st u d y will be 
s u m marize d usi n g descri pti ve statistics.  
Data fr o m p atie nts w h o wit h dra w fr o m t he tr eat me nt peri o d a n d wit h dra w fr o m t he st u d y will 
als o be s u m marize d b y reas o n f or wit h dra wal usi n g des cri pti ve statistics.  
5. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics   
Patie nt de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d u si n g descri pti ve statistics.  
B o d y mass i n de x ( B MI ) will be c o m p ute d  as: 
B MI ( k g/ m 2) = Wei g ht at baseli ne ( k g)/[ Hei g ht at scree ni n g ( m)2] 
N or mal a ge a n d se x -base d z -sc ores a n d perce ntiles f or B MI will be deter mi ne d usi n g t he W orl d 
Healt h Or ga niz ati o n ( W H O ) gr o wt h c harts. A ge a n d se x -base d B MI cat e g ories i ncl u des: 
U n der wei g ht ( < 5 perce ntile), N or mal ( ≥ 5 - < 8 5 p erce ntile), O ver wei g ht ( ≥ 8 5 - < 9 5 
perce ntile), O bese ( ≥ 9 5 perce ntile) . 
T he c o nti n u o us varia bles of patie nt a ge, wei g h t, hei g ht, B MI, B MI W H O a dj uste d z-sc ores a n d 
perce ntile,  will be s u m m arize d usi n g des cri pti ve statistics.   
T he cate g orical varia bles of patie nt wei g ht gr o u p, se x, race, et h nicit y, re gi o n ( U nite d States ( U S) 
a n d n o n-U S), c o u ntr y f or n o n -U S, a ge gr o u p ( 6 t o 1 1 years, 1 2 t o 1 8  years), C Y P 2 D 6 
i m pair me nt stat us (I m p aire d/ N ot i m paire d), a n d B MI cate g ori es will be s u m marize d usi n g 
descri pti ve statistics f or eac h cate g or y. Missi n g cat e g ories will be pres e nte d if necessar y.  
5. 4.  
Dise ase C h ar acteristics   
N ot a p plica ble.  
5. 5.  
Me dic al Hist or y   
All me dical hist or y will be c o de d usi n g t he Me di cal Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). T h e i nci de n ce of me dic al hist or y a b n or malities will be s u m marize d usi n g 
descri pti ve statistics b y s yste m or ga n class ( S O C) a n d preferre d ter m. Patie nts are c o u nte d o nl y 
o nce i n eac h preferre d ter m a n d S O C cate g or y. S u m maries will be prese nt e d f or all patie nts.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 2  
5. 6.  
Pri or T h er a p y a n d Me dic ati o n   
A n y pri or or c o n c o mita nt me dicati o n a patie nt has ha d wit hi n 3 0 da ys  pri or  t o baseli ne a n d u p t o 
t he e n d of st u d y, i ncl u di n g f oll o w u p, will be rec or de d o n t he case re p ort f or m (C R F ). Ge neric or 
tra de na me, i n dic ati o n, d ose, a n d start a n d e n d dat es of t he a d mi nistere d m e dicati o n will be 
rec or de d. T he s p o ns or will e nc o de all me dicati o n acc or di n g t o t he WH O  dr u g dicti o nar y . 
T he i nci de nce of pri or t h era pies a n d me dicati o ns will be s u m marize d usi n g des cri pti ve statistics 
b y t hera pe utic class , preferre d b ase na m e  a n d preferre d t er m.  Patie nts are c o u nte d o nl y o nce i n 
eac h t hera pe utic class cate g or y, a n d o nl y o nce i n eac h preferre d ter m cate g or y.  Pri or t h era pies 
a n d me dicati o ns will i ncl u de all me dicati o ns ta ke n a n d t hera pies a d mi nistere d bef ore  t he first 
da y of  I M P a d mi nistrati o n . 
5. 7.  
St u d y Dr u g Titr ati o n   
T he  n u m ber a n d p erce nt of patie nts at eac h d ose l e vel b y wei g ht gr o u p a n d C Y P 2 D 6 i m pair me nt 
stat us d uri n g t he titrati o n peri o d will be s u m marize d b y wee k.  T he latest a d mi nistere d d ose i n 
eac h st u d y wee k will be use d.  
Reas o ns f or t he d e viati o n fr o m t he I M P a d mi nistrati o n  will be s u m marize d o verall a n d b y peri o d 
(titrati o n a n d mai nte na nce).  
Descri pti ve statistics of t he mai nte na nce d ose ( l ast d ose ta ke n i n t he mai nte na nce peri o d; 
n o mi nal a n d as perce nt of t he ma xi mal pla n ne d d ose f or t he patie nt) will be pre se nte d. 
5. 8.  
St u d y Dr u g C o m pli a nce   
St u d y dr u g c o m plia nce d uri n g t he tr eat me nt peri o d will be assesse d at des cri be d i n t he pr ot oc ol 
Secti o n 5. 7 . 
S t u d y dr u g c o m plia nce will be deter mi ned b y prese nti n g t he n u m b er of ta blets ta ke n as a 
perce nt a ge of t h e e x pecte d n u m ber of ta blets bas e d o n t he d ose (s) of t h e patie nt at t he rele va nt 
ti me peri o d (see T a ble 6  a n d Ta ble 7 ; pr ot oc ol  Secti o n 5. 1) . 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 3  
T a ble 6 : 
Dis pe nsi n g Dr u g Kits b ase d o n Wei g ht Gr o u p at B aseli ne/ D a y 1 Titr ati o n 
Sc he me –  N o n -I m p aire d C Y P 2 D 6 Met a b olizers  
Wei g ht Gr o u p  
1 2 k g t o < 1 7  k g  
1 7 k g t o < 3 0  k g  
3 0 k g t o < 4 0 k g  
≥4 0 k g  
St u d y Ti me 
Peri o d  
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D a y 2   
6  
6  
6  
6  
6  
6  
6  
6  
W ee k 1  
6  
6  
6  
6  
6  
6  
1 2  
6, 6  
W ee k 2  
6   
6  
1 2  
6, 6  
1 2  
6, 6  
1 8  
9, 9  
W ee k 3  
1 2  
6, 6  
1 8  
9, 9  
1 8  
9, 9  
2 4  
1 2, 1 2  
W ee k 4  
1 2  
6, 6  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 0  
1 5, 1 5  
W ee k 5  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 0  
1 5, 1 5  
3 6  
1 8, 1 8  
W ee k 6  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 6  
1 8, 1 8  
4 2  
1 5, 6 A M  
1 5, 6 P M  
W ee k 7  
2 4  
1 2, 1 2  
3 0  
1 5, 1 5  
4 2  
1 5, 6 A M  
1 5, 6 P M  
4 8  
1 2, 1 2 A M  
1 2, 1 2 P M  
C Y P 2 D 6 =c yt oc hr o me P 4 5 0 2 D 6.  D ose a n d ta bles refer t o I M P. Ma xi mal d ose acc or di n g t o t he titrati o n sc he me is 
prese nte d . 
T a ble 7 : 
Dis pe nsi n g Dr u g Kits b ase d o n Wei g ht Gr o u p at B aseli ne/ D a y 1 Titr ati o n 
Sc he me –  I m p aire d C Y P 2 D 6 Met a b olizers  
Wei g ht Gr o u p  
1 2 k g t o < 1 7  k g  
1 7 k g t o < 3 0  k g  
3 0 k g t o < 4 0 k g  
≥4 0 k g  
St u d y Ti me 
Peri o d  
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D ose 
( m g/ d a y) 
T a blets 
( m g) 
D a y 2  
6  
6  
6  
6  
6  
6  
6  
6  
W ee k 1  
6  
6  
6  
6  
6  
6  
1 2  
6, 6  
W ee k 2  
6   
6  
1 2  
6, 6  
1 2  
6, 6  
1 8  
9, 9  
W ee k 3  
1 2  
6, 6  
1 8  
9, 9  
1 8  
9, 9  
2 4  
1 2, 1 2  
W ee k 4  
1 2  
6, 6  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 0  
1 5, 1 5  
W ee k 5  
1 2  
6, 6  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 6  
1 8, 1 8  
W ee k 6  
1 2  
6, 6  
1 8  
9, 9  
2 4  
1 2, 1 2  
3 6  
9, 9 A M 9, 
9 P M  
W ee k 7  
1 2  
6, 6  
1 8  
9, 9  
2 4  
6, 6 A M  
6, 6 P M  
3 6  
9, 9 A M  
9, 9 P M  
C Y P 2 D 6 =c yt oc hr o me P 4 5 0 2 D 6. D ose a n d ta bles refer t o I M P. Ma xi mal d ose acc or di n g t o t he titrati o n sc he me is 
prese nte d.  
T he n u m ber of ta bl ets use d is  t he n u m ber of ta blets dis pe nse d mi n us the n u m ber of ta blets 
ret ur ne d. If a p atie nt d oes n ot ret ur n a pill b ottle, it will be ass u me d t hat t he patie nt t o o k n o I M P 
fr o m t hat b ottle f or t he p ur p oses of calc ulati n g c o m plia nce.  
T he de n o mi nat or of “e x pecte d n u m ber  of ta blets” will be calc ulate d base d o n patie nts’ 
partici pati o n i n t he st u d y ( ie, last da y of st u d y dr u g –  first da y of st u d y dr u g + 1) a n d t he 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 4  
e x pecte d d ose acc or di n g t o t he  R a n d o mizati o n T rial S u p pl y M a na ge me nt  s yste m. A dj ust me nts 
ma y b e re q uir e d f o r t h e d oses s plit bet wee n t he m or ni n g a n d t he e ve ni n g d ose. Of n ote, t he 
pr ot oc ol all o ws t he i n vesti gat or n ot t o titrate a p atie nt u p t o t he ma xi mal p ossi ble d ose b y w ei g ht 
gr o u p a n d C Y P 2 D 6 i m pair me nt stat us; t heref ore t he e x pecte d n u m ber of ta blets will be 
calc ulate d i n di vi d uall y. M ore o ver, d r u g s us pe nsi o ns a n d re d ucti o ns bas e d o n i n vesti gat or 
i nstr ucti o ns are c o nsi dere d as c ha n ge i n t he e x pecte d n u m ber of ta bl ets a n d are n ot c o nsi dere d 
n o n -c o m plia nce. F or patie nts w h o c o m plete t he st u d y, t he last da y of st u d y dr u g us e d i n t he 
de n o mi nat or calc ul ati o n will be t he last e x pecte d d osi n g da y. F or earl y ter mi nati o n patie nts, t he 
last da y of st u d y dr u g us e d i n t he de n o mi nat or calc ulati o n will be t he last e x pecte d d osi n g da y 
bef ore t er mi nati o n da y . 
A patie nt will be dee me d c o m plia nt o ver t he treat me nt peri o d if t he patie nt has ta ke n 8 0 % t o 
1 0 5 % of t he e x pecte d ta blets of st u d y dr u g.  
Treat me nt c o m plia nce ( %) will be s u m marize d as c o nti n u o us data usi n g d escri pti ve statistics. I n 
a d diti o n, treat me nt c o m plia nce will be s u m marize d as cate g orical data usi n g des cri pti ve statistics 
f or t he f oll o wi n g cat e g ories: < 8 0 %, 8 0 % t o 1 0 5 %, > 1 0 5 %. C o m plia nce will be prese nte d b y 
visit , b y o v erall i n t he titr ati o n a n d mai nte na nce  peri o ds, a n d b y o v erall i n t he treat me nt peri o d.  
A n a d diti o nal  assess me nt of t he I M P c o m plia nce ma y  b e perf or me d w hile ta ki n g i nt o acc o u nt 
t he patie nt’s d ose.  
5. 9.  
St u d y Pr ot oc ol De vi ati o ns   
A n y  pr ot oc ol  de viati o n (as rec or de d i n t he Cli nical T rial M a na ge me nt S yst e m [ C T M S] ) t hat 
affects, t o a si g nifi ca nt d e gree, (a) t h e safet y, p h ysical, or me ntal i nte grit y of t he patie nts i n t he 
st u d y a n d/ or ( b) t he scie ntific val ue of t he st u d y will be c o nsi dere d a n i m p orta nt pr ot oc ol 
de viati o n.  
I m p ort ant pr ot oc ol de viati o n will be s u m marize d o verall a n d f or eac h cate g or y usi n g des cri pti ve 
statistics. All pr ot oc ol de viati o ns will be liste d.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 5  
6.  
E F FI C A C Y A N A L Y SI S   
6. 1.  
Ge ner al   
T he I T T a n al ysis set s will be use d f or all  efficac y a nal ys es.  All efficac y e n d p oi nts will be 
s u m marize d usi n g descri pti ve statistics.  
6. 2.  
Effic ac y E n d p oi nt s a n d A n al ysis   
Descri pti ve statistics f or c o nti n u o us varia bles i ncl u de n, mea n, S D, S E of t he mea n, me dia n, 
mi ni m u m, a n d ma xi m u m . Mi ni m u m a n d ma xi m u m will ha ve t he sa me n u m ber of deci mal p oi nt s 
as t he ori gi nal data. Mea n a n d me dia n will ha ve 1 m ore deci mal p oi nt t ha n t he ori gi nal d ata. S D 
a nd S E will ha ve 2 m ore deci mal p oi nts t ha n t he ori gi nal dat a.  
N ote, descri pti ve statistics of c ha n ge fr o m bas eli ne will utilize da y 1 fr o m t he prese nt o p e n -la bel 
st u d y ( St u d y T E V-5 0 7 1 7 -3 0 0 8 1)  or  w ee k 1 6 visit fr o m t he pare nt d o u ble-bli n d  st u d y (St u d y 
T V 5 0 7 1 7 -C N S -3 0 0 8 0) . 
6. 2. 1.  
Effic ac y  E n d p oi nt s  
Efficac y  e n d p oi nts  will be assesse d i n t his s t u d y as f oll o ws:  
•  M D -C R S  par t I t otal sc ore (ce ntrall y rea d)  
•  M D -C R S  part II t otal sc ore (ce ntrall y rea d)  
•  M D -C R S part I t otal sc ore ( p h ysicia n rate d)  
•  M D -C R S part II t otal sc ore ( p h ysicia n rate d)  
•  M D -C R S Gl o bal I n de x (calc ulate d fr o m M D -C R S parts I a n d II t otal sc ores) 
•  C are gi ver Gl o b al I m pressi o n of I m pr o v e me nt ( Ca GI -I) Scale ( gl o bal, care gi ver rate d) 
•  C li nical G l o bal Im pr essi o n of Im pr o ve me nt ( C GI -I) Scale ( gl o bal, p h ysici a n rate d)  
•  C li nical G l o bal Im pr essi o n of S e verit y ( C GI-S)  S cale ( gl o bal, p h ysici a n rate d) 
•  P e diatric E val uati o n D isa bilit y In v e nt or y -C o m p ut er A da pter T est ( P E DI-C A T) 
( A D L, care gi ver c o m plet e d, c o nte nt-bal a nce d v ersi o n)  
•  U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal C h orea ( U H D R S -T M C) 
(ce ntr all y rea d) 
•  U nifie d H u nti n gt o n’s Disease Rati n g Scale -T otal Ma xi mal D yst o nia ( U H D R S -T M D) 
(ce ntr all y rea d) 
•  U nifie d H u nti n gt o n’s D isease R ati n g S cale -T otal M ot or S c ore ( U H D R S -T M S)  
( p h ysici a n rate d) 
•  U H D R S -T M C  ( p h ysici a n rate d) 
•  U H D R S -T M D  ( p h ysicia n rate d) 
•  C a na dia n O cc u pati o nal P erf or ma n ce M eas ure ( C O P M)  ( p h ysicia n rate d)  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 6  
6. 2. 2.  
Effic ac y A n al ysis   
6. 2. 2. 1.  
M o ve me nt Dis or der -C hil d h o o d R ati n g Sc ale   
T he  M D -C R S i ncl u de s 2 parts:  part I f or ge neral assess me nt of t he patie nt’s f u ncti o ni n g a n d 
i m pact of cere bral pals y o n t he acti vities of t he patie nt a n d part II f or a s p ecific m ot or assess me nt 
of t he se verit y of t h e m o ve me nt dis or der. All  ite ms are sc ore d o n a 5-p oi nt or di nal scale ( 0 -4). 
Zer o c orres p o n ds t o n o si g ns, a n d 4 c orres p o n ds t o t he m ost se vere fi n di n gs.  
T he M D -C R S P art I: 
T here are 1 5 ite ms i n M D -C R S part I t o  e val uate t he i m pact of  D C P o n t he acti vities  of t he 
patie nt a n d pr o vi des a  ge neral assess m e nt of t he m o ve me nt dis or der of m ot or f u ncti o n ( 7 ite ms), 
oral/ ver bal f u n cti o n  ( 3 ite ms), self-care ( 3 ite ms), a n d atte nti o n/alert ness ( 2 ite ms) o n a scale of 0 
( prese nt) t o 4 (a bse nt).  It e ms A 1-A 7 ( M ot or f u n ct i o n), C 1 ( Self-dressi n g) a n d D 1 
( Atte nti o n/alert ness d uri n g t he o bs er vati o n) are s c ore d b y t he rater i n t he cli nic a n d t hese are 
vi de o rec or de d f or ce ntr al rea di n g, all ot her part I ite ms are sc ore d b y t he rater bas e d o n t he 
pare nt/care gi ver i nter vie w . Eac h ite m is o n a 0 ( prese nt) t o 4 (a bse nt) scale.  T he mi ni m u m sc ore 
is 0 a n d t he ma xi m u m sc ore is 6 0.  
I n case of a n y missi n g ite ms, M D -C R S part I t otal sc ore will be deri ve d b y calc ulati n g t he M D -
C R S I i n d e x bel o w, a n d m ulti pl yi n g b y t he ma xi m u m sc ore o f 6 0.  
N ote t hat t he ce ntr all y -rea d M D-C R S part I t otal sc ore is o btai ne d b y s u m mi n g t he ce ntrall y -rea d 
ite ms ( 9 ite ms) a n d t he ite ms t hat are sc ore d o nl y b y t he rater i n t he cli nic ( 6 ite ms). T he 
p h ysicia n rate d  M D -C R S part I t otal sc ore is o btai ne d b y s u m mi n g all 1 5 ite ms b y t he rater i n t he 
cli nic.  
M D -C R S P art II: 
T here are 7 ite ms i n M D -C R S part II t o  e v al uate t he se verit y of t he m o v e me nt dis or der i n a scale 
of 0 t o 4 i n 7 b o d y  re gi o ns. I n rati n g t he m o ve me nt dis or der of t he b o d y part, 0 refers t o a bse nce  
of a m o ve me nt dis or der a n d 4 refers t o a sit uati o n  w here m o ve m e nt dis or der is prese nt d uri n g all 
of t he tas ks f or t he re gi o n e x a mi ne d a n d/ or  i n v ol ves 3 or m ore of t h e ot her re gi o ns, ma ki n g 
c o m pleti o n i m p ossi ble. All ite ms are sc ore d b y t he rater i n t he cl i nic a n d are ce ntrall y rea d bas e d 
o n vi de o rec or di n g. T h e mi ni m u m sc ore is 0 (a bse nt) a n d t he ma xi m u m  sc ore is 2 8 
( mar ke d/ pr ol o n ge d).  
I n case of a n y missi n g ite ms, M D -C R S part II t otal sc ore will be deri v e d b y calc ulati n g t he M D -
C R S II i n de x bel o w, a n d m u lti pl yi n g b y t he ma xi m u m sc ore of 2 8.  
T he M D -C R S Gl o bal I n d e x : 
T he M D -C R S Gl o bal I n d e x  is a gl o bal meas ure of t he M D-C R S t hat c o ns oli dates t he  
i nf or mati o n fr o m parts I a n d II usi n g t he met h o d of wei g hte d mea ns of t he 2 n or malize d i n de xes 
o btai ne d fr o m eac h part. T he mi ni m u m sc ore is 0 a n d t he ma xi m u m sc ore  is 1.  
T he sta n dar dize d/ n or maliz e d sc ore f or eac h ite m of M D -C R S parts I a n d II  wit h val ue 𝑋 is 
calc ulate d usi n g t he f or m ula  
𝑋𝑠𝑡=
𝑋−𝑋𝑚𝑖𝑛
𝑋𝑚𝑎𝑥−𝑋𝑚𝑖𝑛
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 7  
w here 𝑋𝑋𝑠𝑡 is t he ma xi m u m val ue f or t he s c ore, a n d 𝑋𝑋𝑚𝑖 is t he mi ni m u m val ue f or t he sc ore, or 
4 a n d 0 res pecti vel y.  
T he n or malize d i n de x f or t he scale, M D -C R S parts I or  II, I n d e x I or II, is c alc ulate d as t he m ea n 
val ue of 𝑛𝑋𝑚. 
T he M D -C R S Gl o bal I n d e x  is t he wei g hte d mea n of t he nor malize d i n de xes f or M D -C R S parts I 
a n d II usi n g t he f or m ula:  
𝑎𝑥𝑋𝑚𝑖𝑛 𝐼𝑛𝑑𝑒𝑥= 𝑛𝐼× 𝐼𝑛𝑑𝑒𝑥𝐼+ 𝑛𝐼𝐼× 𝐼𝑛𝑑𝑒𝑥𝐼𝐼
𝑛𝐼+ 𝑛𝐼𝐼
 
 
w here 𝑛𝐼 a n d 𝑛𝐼𝐼 are t he n u m b ers of ite ms i n M D -C R S parts I a n d II res p ecti vel y.  
T he act ual v al ues a n d c h a n ge fr o m b aseli ne f or t h e M D-C R S Part I, Part II  a n d Gl o bal I n de x 
sc ores will be s u m mariz e d.  
6. 2. 2. 2.  
C are gi ve r Gl o b al I m pressi o n of I m pr o ve me nt Sc ale   
Ca GI -I is si n gle ite m q uesti o n naire t o assess t he care gi ver’s i m pressi o n of i m pr o ve me nt i n  
d ys ki nesia s y m pt o ms aft er i nitiati n g t hera p y. It is t o be c o m plete d bef ore all ot her i n vesti gat or-
rate d scales d uri n g visits w here Ca GI-I is c ollecte d. T he care gi ver h as t o select t he 1 res p o nse 
fr o m t he res p o ns e o pti o ns t hat gi ves t he m ost acc urate des cri pti o n of c ha n ge i n d ys ki nesia 
s y m pt o ms of t he patie nt t he y care f or fr o m t he be gi n ni n g of t he st u d y:  
1 = ver y m uc h i m pr o v e d (si nce t he i nitiati o n of treat me nt i n t his st u d y);  
2 = m uc h i m pr o ve d;  
3 = mi ni mall y i m pr o ve d;  
4 = n o c ha n ge fr o m da y 1 (s y m pt o ms re mai n esse ntiall y u nc h a n ge d);  
5 = mi ni mall y w orse;  
6 = m uc h w orse;  
7 = ver y m uc h w orse (si n ce t he i nitiati o n of treat me nt).  
T he  Ca GI -I is a si n gle ite m q uesti o n naire, n o i m p ute is use d. 
T he a ct ual v al ue i n  Ca GI -I t o eac h p ost-baseli ne visit will be s u m marize d.  
6. 2. 2. 3.  
Cli nic al Gl o b al I m pressi o n of I m pr o ve me nt Sc ale   
T he Cli nical Gl o bal I m pressi o n of I m pr o ve me nt ( C GI -I) is a cli nicia n-re p orte d o utc o me t hat 
uses a 7 -p oi nt Li k ert scale t hat all o ws t he cli nicia n t o c o m pare t he patie nt’s c o n diti o n at t he visit 
t o t he da y 1 c o n diti o n as f oll o ws ( wit h a nc h or p oi nts f or c h o osi n g t h e m ost a p pr o priate 
i m pr o ve me nt le vel):  
1 = ver y m uc h i m pr o v e d si nce t he i nitiati o n of treat me nt i n t his st u d y ( nearl y all better; 
g o o d le v el of f u ncti o ni n g; mi ni mal s y m pt o ms; re prese nts a ver y s u bsta ntial c ha n ge);  
2 = m uc h i m pr o ve d ( n ota bl y better wit h si g nifica nt re d ucti o n of s y m pt o ms; i ncreas e i n t he 
le vel of f u ncti o ni n g b ut s o me s y m pt o ms re mai n); 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 8  
3 = mi ni mall y i m pr o ve d (sli g htl y b etter wit h little or n o cli nicall y m ea ni n gf ul re d ucti o n of 
s y m pt o ms; re pres e nts ver y little c ha n ge i n basic cli nical stat us, le vel of care, or 
f u ncti o nal ca p acit y); 
4 = n o c ha n ge fr o m da y 1 (s y m pt o ms re mai n esse ntiall y u nc h a n ge d);  
5 = mi ni mall y w orse (sli g htl y w orse b ut ma y n ot b e cli nicall y m ea ni n gf ul; ma y re prese nt 
ver y little c ha n ge i n basi c cli nical stat us or f u n cti o nal ca pacit y);  
6 = m uc h w orse (cli nicall y si g nifica nt i ncreas e i n s y m pt o m s a n d di mi nis he d f u ncti o ni n g); 
7 = ver y m uc h w orse si nc e t he i nitiati o n of treat me nt i n t his st u d y (se v ere e x acer bati o n of 
s y m pt o ms a n d l oss of f u ncti o ni n g). 
T he  C GI -I is a si n gle ite m q uesti o n naire, n o i m p utati o n is use d.  
T he act ual v al ue i n  C GI -I t o e ac h p ost-b aseli ne visits will be s u m marize d.  
6. 2. 2. 4.  
Cli nic al Gl o b al I m pressi o n of Se verit y   
T he  Cli nical Gl o bal I m pressi o n of Se verit y  (C GI -S ) uses a 7 -p oi nt Li k ert s cale t o  assess 
d ys ki nesia s e verit y as f oll o ws ( wit h a nc h or p oi nts f or c h o osi n g t he m ost a p pr o priate  se v erit y 
le vel ca use d b y D C P): 
1 = n or mal ( n ot at all ill, s y m pt o ms of dis or der n ot prese nt past 7 da ys);  
2 = b or derli ne (s u btle or s us pecte d pat h ol o g y);  
3 = mil d (clearl y esta blis he d s y m pt o ms wit h mi ni mal, if a n y, distress or diffi c ult y i n s ocial  
a n d/ or occ u p ati o nal f u ncti o n);  
4 = m o derate ( o vert s y m pt o ms ca usi n g n oticea ble, b ut m o dest, f u ncti o nal i m pair me nt or  
distress; s y m pt o m le vel ma y w arra nt me dicati o n);  
5 = mar ke d (i ntr usi ve s y m pt o ms t hat disti nctl y i m pair s ocial/ occ u p ati o nal f u ncti o n or 
ca use i ntr usi ve le v els of distress); 
6 =se vere ( disr u pti ve s y m pt o ms, be ha vi or a n d f u ncti o n are fre q ue ntl y i nfl ue nce d b y  
s y m pt o ms, ma y re q uir e assista nce fr o m ot hers); 
7 =e xtre me (s y m pt o ms drasticall y i nterferes i n ma n y life f u ncti o ns; ma y b e h os pitalize d).  
T he C GI -S is a si n gl e ite m q uesti o n naire, n o i m p utati o n is use d.   
6. 2. 2. 5.  
Pe di at ric E v al u ati o n Dis a bilit y I n ve nt or y -C o m p uter A d a pte d Test ( Acti vities of 
D ail y Li vi n g, C are gi ver C o m plete d, C o nte nt -B al a nce d Versi o n   
T he P E DI -C A T (acti vities of dail y li vi n g [ A D L], pare nt/care gi ver c o m plet e d, c o nte nt bala n ce d 
versi o n) is a cli nical assess me nt f or c hil dre n a n d y o ut h. It meas ures f u ncti o n i n 4 d o mai ns : ( 1) 
Dail y A cti vities; ( 2) M o bilit y; ( 3) S ocial/ C o g niti ve, a n d ( 4) Res p o nsi bilit y. Eac h d o mai n is self -
c o ntai ne d a n d ca n be us e d se parat el y or wit h ot her d o mai ns.  T he c o nte nt bala nce d versi o n 
prese nts a bal a nce of ite ms fr o m eac h of t he Dail y Acti vities d o mai n’s c o nte nt areas ( Getti n g 
Dresse d, Kee pi n g Clea n, H o me Tas ks, a n d Eati n g & Mealti me). A t otal of a p pr o xi matel y 3 0 
ite ms are a d mi nistere d (t otal n u m ber of ite ms a d mi nistere d is de pe n de nt u p o n t he res p o nses a n d 
decisi o n tre e p at h). T he P E DI-C A T s oft ware utilizes Ite m Res p o nse T h e or y statistical m o dels t o  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
3 9  
esti mate a c hil d’s a bilities fr o m a mi ni mal n u m ber of t he m ost rele va nt ite ms or fr o m a set 
n u m ber of ite ms wit hi n eac h d o mai n. All res p o n d e nts be gi n wit h t he sa me ite m i n e ac h d o mai n 
i n t he mi d dle of t he ra n ge of diffic ult y or res p o nsi bilit y a n d t he res p o ns e t o t hat ite m t he n 
dictates w hic h ite m will a p pear ne xt (a har der or easier ite m), t h us tail ori n g t he ite ms t o t he c hil d 
a n d a v oi di n g irrele v a nt ite ms. T he C A T pr o gra m t h e n dis pla ys t he res ults: n or mati ve sta n dar d 
sc ores, sc ale d sc ores a n d t he S E. T he scales are a v aila ble f or 2 1 a ge gr o u ps as i nter vals of 1 year.  
N or mati ve (fit) sc ores are base d o n a c hil d’s c hr o n ol o gical a ge a n d i nte n d e d f or use b y cli nicia ns 
s o t hat t hey ma y i nter pret a partic ular c hil d’s f u ncti o ni n g relati ve t o ot hers of t he sa me a ge. T his 
metric is of less rele v a nce f or t he st u die d p o p ulati o n a n d t heref ore will n ot be assesse d.  
Scale d sc ores pr o vi de a wa y t o l o o k at a c hil d’s c urre nt f u ncti o nal s kills a n d pr o gress i n t hese 
s kills o ver ti me. Scale d sc ores are es p eciall y hel pf ul i n d oc u me nti n g i m pr o ve me nts i n f u ncti o nal 
s kills f or c hil dre n n ot e x pecte d t o e x hi bit or re gai n n or mati ve le vels of f u n cti o ni n g. T he s cale d 
sc ores are bas e d o n a n esti mate of t he place m e nt of a n i n di vi d ual c hil d al o n g t he hierarc hical 
scale wit hi n eac h d o mai n. T he P E DI-C A T scale d sc ores are c urre ntl y o n a 2 0 t o 8 0 scale metric. 
See P E DI -C A T ( Versi o n 1. 3. 6) De vel o p me nt, Sta n dar dizati o n a n d A d mi nistrati o n Ma n ual .  
T he S E sc ores i n dicat e t he le vel of t he test precisi o n, a n d are e x pecte d t o b e u p t o 0. 5. 
A descri pti ve s u m mar y of t he P E DI -C A T scale d s c ore will be pr o vi d e d f or all meas ure me nts a n d 
c ha n ge fr o m baseli ne.  
6. 2. 2. 6.  
U nifie d H u nti n gt o n’s Dise ase R ati n g Sc ale -T ot al M ot or Sc ore   
U H D R S -T M S  c o m prises a br oa d ass ess me nt of feat ures ass oci ate d wit h H u nti n gt o n’s Diseas e . 
T he T M S c o m p o ne nt of U H D R S c o m prises 3 1 assess me nts fr o m t he 1 5 ite ms of t he U H D R S. 
T he T M S is calc ulate d as t he s u m of t he 3 1 m ot or assess me nts, eac h of w hi c h ra n ge b et wee n 0 
t o 4. T he mi ni m u m sc ore is 0 (a bse nt) a n d t he m a xi m u m  sc ore is 1 2 4  ( w orst). 
U H D R S -T M C  is part of t he U H D R S-T M S assess me nt a n d assesses t he s e verit y of c h orea i n  t he 
face, m o uth, tr u n k, a n d t he 4 e xtre mities. T he mi ni m u m sc ore is 0 (a bse nt), a n d t he  ma xi m u m 
sc ore is 2 8 ( mar ke d/ pr ol o n ge d). 
U H D R S -T M D  is part of t he U H D R S-T M S assess me nt a n d assesses t he s e verit y of d yst o nia  i n 
t he tr u n k a n d t he 4 e xtre mities. T he mi ni m u m sc ore is 0 (a bse nt), a n d t he ma xi m u m sc ore is 2 0 
( mar ke d/ pr ol o n ge d). 
If res p o ns es of u p t o 2 5 % of ite ms are missi n g i n U H D R S-T M S, U H D R S -T M C, or U H D R S -
T M D (“scale”), t h e missi n g res p o nses will be re place d b y t he a vera ge of t he re mai ni n g res p o nses 
wit hi n eac h of t he s cales. If 8 or m ore of t he ite ms are missi n g, t he missi n g ite ms will n ot be 
re place d a n d t he s cale will be set t o missi n g. 
T he act ual v al ues a n d c h a n ge fr o m b aseli ne f or t h e U H D R S -T M S, T M C a n d T M D will be 
s u m marize d. 
6. 2. 2. 7.  
C a n a di a n  Occ u p ati o n al Perf or m a nce Me as ure   
T he C O P M has bee n desi g ne d t o assess patie nt o ut c o mes i n t he areas of self -care, pr o d ucti vit y 
a n d leis ure. Usi n g a s e mi -str uct ure d i nter vi e w, eac h patie nt will i de ntif y 5 m ost i m p orta nt 
pr o ble m areas, a n d will e val uate perf or ma nce a n d satisfacti o n relate d t o t h ose pr o ble m areas. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 0  
T he C O M P perf or ma n ce a n d satisfacti o n scale is ra n ge fr o m 1 ( p o or perf or ma nce or l o w 
satisfacti o n) t o 1 0 ( ver y g o d perf or ma nce or hi g h satisfacti o n).  
T otal  sc ores are calc ulate d b y a d di n g t o get h er t he perf or ma n ce or satisfacti o n sc ores f or all 
pr o ble ms a n d di vi di n g b y t he n u m ber of pr o ble ms. I n di vi d ual acti vit y pr o ble ms will be liste d. 
6. 3.  
S u b g r o u p A n al yses   
N o effic ac y s u b gr o u p a n al ysis is pla n ne d.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 1  
7.  
M U L TI P L E C O M P A RI S O N S A N D M U L TI P LI CI T Y   
N o m ulti plicit y c o ntr ol wi ll be a p plie d t o t he efficac y a n al ysis or ot her e n d p oi nts.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 2  
8.  
S A F E T Y A N A L Y SI S   
8. 1.  
Ge ner al   
Safet y a nal yses will be perf or me d o n t h e I T T a nal ysis set , u nless ot her wis e n ote d . S u m maries 
will be prese nte d b y  o v erall patie nts . Selecte d safet y data mi g ht als o be prese nte d b y a ge gr o u p, 
as a p plica ble.   
F or c o nti n u o us varia bles, descri pti ve statistics will be pr o vi de d f or act ual v al ues a n d c h a n ges 
fr o m baseli ne t o e ac h ti me p oi nt. F or cate g orical v aria bles, patie nt c o u nts a n d perce nt a ges will 
be pr o vi de d.  
S u m maries of p ote nti all y cli nicall y si g nifica nt a b n or mal val ues will i ncl u de all p ost -baseli ne 
val ues (i ncl u di n g sc he d ul e d, u nsc he d ule d, a n d earl y ter mi nati o n visits).  
Safet y assess me nts a n d ti me p oi nts are pr o vi de d i n Ta ble 3 . 
8. 2.  
D ur ati o n of E x p os ure t o St u d y Dr u g   
D urati o n of e x p os ure t o st u d y dr u g ( da ys) f or i n di vi d ual patie nts is t he n u m ber of da ys p atie nt 
recei v e d dr u g (last d a y of st u d y dr u g –  first d a y of st u d y dr u g + 1). D urati o n of treat me nt ( d a ys) 
will be s u m mariz e d usi n g des cri pti ve statistics. Wee ks o n treat me nt usi n g t he cate g ori es ≤4  
wee ks, > 4  t o ≤7  w ee ks, > 7  t o ≤2 1  wee ks, > 2 1  t o ≤2 7  wee ks,  > 2 7 t o ≤3 3, > 3 3 t o ≤4 0, > 4 0 t o ≤4 6, 
> 4 6 t o ≤5 3, a n d > 5 3  w ee ks will als o be s u m marize d usi n g d escri pti ve statistics.  
8. 3.  
A d verse E ve nts   
A d verse e ve nts will be c ollecte d a n d rec or de d fr o m t he ti me a patie nt  si g ns t he i nf or me d c o nse nt 
t o t he e n d of f oll o w-u p p eri o d. F or t his  st u d y, t he f oll o w-u p peri o d f or rec or di n g o f a d verse 
e ve nts is defi ne d as 2  wee k s after t h e last d ose of T E V -5 0 7 1 7.  
All a d verse e ve nts will be c o de d usi n g Me d D R A . E ac h patie nt will be c o u nte d o nl y o nce i n eac h 
preferre d t er m or S O C  cate g or y f or t he a nal yses of safet y. U nless ot her wise s pecifie d, a d v erse 
e ve nts will be s u m mariz e d b y S O C a n d preferre d t er m , wit h S O Cs a n d preferre d t er ms  wit hi n 
S O Cs prese nte d i n desce n di n g or der of p atie nt  i nci de nce. S u m maries will b e prese nt e d f or all 
a d verse e ve nts ( o v erall a n d b y se v erit y), a d v erse e ve nts deter mi ne d b y t h e i n vesti gat or t o be 
relate d t o test I M P (ie, reas o na ble p ossi bilit y; s ee Ta ble 9  of t he st u d y  pr ot oc ol - defi ne d as 
relate d or wit h missi n g relati o ns hi p), o verall a n d b y se v erit y, seri o us a d v erse e ve nts, a n d a d verse 
e ve nts ca u si n g wit h dra wal fr o m t he st u d y; M ost c o m m o n a d verse e v e nt s, defi ne d as o cc u rri n g i n 
> 4 % of t he p atie nt s i n o ve rall, a n d b y preferre d t er m . S u m maries will be prese nte d b y all 
patie nts.  
S u m maries will i ncl u de treat me nt -e mer ge nt a d verse e ve nts w hic h are d efi n e d as a d verse e v e nts 
occ urri n g at or aft er t he first d ose of t he I M P. T he listi n gs will i ncl u de all a d verse e v e nts 
rec or de d. 
Patie nt listi n gs of all a d verse e v e nts , seri o us a d v erse e ve nts , a d v erse e ve nts  lea di n g t o st u d y dr u g 
disc o nti n uati o n, a d verse e ve nts  lea di n g t o d ose i nt err u pti o n a n d a d v erse e v e nts  lea di n g t o d eat h 
will be prese nte d.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 3  
8. 4.  
De at hs   
If a n y patie nt dies d uri n g t he st u d y, a listi n g of deat hs will be pr o vi de d, a n d all rele va nt 
i nf or mati o n will be disc usse d i n t he patie nt narrati ve i ncl u de d i n t he C S R . 
8. 5.  
Cli nic al  L a b or at or y Tests   
S u m mar y statistics f or c h e mistr y, he m at ol o g y  a n d c oa g ulati o n , a n d uri nal ysis  la b orat or y tests are 
assesse d  at scree ni n g a n d w ee ks 3, 7, 1 4, 2 7, 4 0, 5 3/ E T, a n d 54/f oll o w -u p visits . La b orat or y 
val ues a n d  c h a n ges fr o m baseli ne  t o w ee k 5 3 will be prese nt e d .  
A list of la b orat or y tests is i ncl u de d i n Ta ble 1 0  of t he st u d y pr ot oc ol . 
S hifts ( bel o w, wit hi n, a n d a b o ve t he n or mal ra n ge) fr o m baseli ne t o eac h visit  will be 
s u m marize d usi n g patie nt c o u nts f or all t he la b orat or y tests as a p plica ble. O nl y patie nts wit h 
b ot h baseli ne a n d p ost -baseli ne assess me nts will be s u m marize d i n t he s hift ta bles.  
O nl y ce ntral la b orat or y assess me nts will be s u m marize d; l ocal la b orat or y asse ss me nts will be 
liste d. V al ues bel o w t he l o wer li mit of q ua ntificati o n or a b o ve t he u p per li mit of q ua ntificati o n 
will be assesse d  o n a cas e -b y -case basis  if prese nt i n t he data a n d disc usse d i n t he fi nal bli n de d 
statistical data re vie w m eeti n g.  
8. 6.  
P h ysic al E x a mi n ati o ns   
P h ysical e x a mi nati o ns  will be perf or me d at t he ti me p oi nts detaile d i n Ta ble 4 a n d Ta ble 5  of t h e 
st u d y pr ot oc ol. P h ysical e x a mi nati o ns will n ot be s u m marize d. A n y f i n di n g will be liste d. 
W ei g ht, hei g ht a n d B MI will be assesse d as a part of t he vital si g ns  ( Secti o n 8. 8 ). 
8. 7.  
Ne ur ol o gic al E x a mi n ati o ns   
Ne ur ol o gical e x a mi nati o ns will be perf or me d at t he ti me p oi nts detaile d i n Ta ble 4 a n d  T a ble 5 
of t he st u d y pr ot oc ol. Ne ur ol o gic al e x a mi nati o ns will n ot be s u m marize d. A n y fi n di n g will be 
liste d.  
8. 8.  
Vit al Si g ns   
Vital si g ns ( bl o o d press ure [ B P; s yst olic/ diast olic], res pirat or y rate, b o d y te m perat ure, a n d p ulse)  
will be meas ure d at t he ti me p oi nts detaile d i n  Ta ble 2  a n d Ta ble 3 . 
V ital si g ns val ues a n d c h a n ges fr o m bas eli ne t o eac h visit will be s u m marize d usi n g d escri pti ve 
statistics.  
Ort h ostatic s yst olic a n d diast olic B P a n d p ulse will be calc ul ate d as s u pi ne or se mi erect/seate d 
meas ure me nt mi n us  sta n di n g meas ure me nt a n d v al ues a n d c h a n ges fr o m baseli ne t o eac h visit 
will  be s u m mariz e d usi n g des cri pti ve statistics .  
Ort h ostatic h y p ot e nsi o n ( deter mi ne d b y B P  meas ure me nts o nl y ; p ositi ve val ue i n case of 
a b n or malit y) is defi ne d as ha vi n g eit her a ≥2 0 m m H g re d ucti o n fr o m s u pi ne t o sta n di n g p ositi o n 
i n s yst olic bl o o d press ure ( S B P) or ≥1 0-m m H g re d ucti o n fr o m s u pi ne t o sta n di n g p ositi o n i n 
d iast olic bl o o d press ure ( D B P) or b ot h. Ort h ostati c tac h ycar dia is defi ne d as p ulse i ncreas e ≥2 0 
b p m fr o m s u pi ne t o sta n di n g p ositi o n.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 4  
S u m maries of p ote ntiall y cli nicall y si g nifica nt a b n or mal val ues will i ncl u de all p ost -baseli ne  
val ues (i ncl u di n g sc he d ul e d , u nsc he d ule d, a n d wit h dra wal  visits). T he i nci d e nce of p ot e ntiall y  
cli nicall y si g nifica nt a b n or mal val ues will be s u m marize d usi n g descri pti ve statistics  wit h t he 
criteria s pecifie d i n  Ta bl e 8 . 
Ta ble 8  s pecifi es t he crit eria f or i d e ntif yi n g vital si g ns as p ote ntiall y cli nicall y si gnifi ca nt 
a b n or mal  val ues .  
T a ble 8 : 
Criteri a f or P ote nti all y Cli nic all y Si g nific a nt Vit al Si g ns   
Vit al Si g n ( u nit)  
A ge  
P ot e nti all y Cli nic all y 
Si g nific a nt  L o w Criteri o n 
v al ue  
P ote nti all y Cli nic all y 
Si g nific a nt Hi g h Criteri o n 
v al ue  
S B P (s u pi ne ) ( m m H g) 
6 -1 2  
Val ue ≤7 0 a n d ≥2 0 decrease fr o m 
baseli ne  
Val ue ≥1 2 0 a n d  
≥2 0 i ncrease fr o m baseli ne  
 
1 3 -1 8  
Val ue ≤ 9 0 a n d  
≥2 0 decrease fr o m baseli ne  
Val ue ≥1 3 5 a n d  
≥2 0 i ncrease fr o m baseli ne 
D B P (s u pi ne ) ( m m H g) 
6 -1 2  
Val ue ≤4 0 a n d  
≥1 5 decrease fr o m baseli ne  
Val ue ≥8 0 a n d  
≥1 5 i ncrease fr o m baseli ne  
 
1 3 -1 8  
Val ue ≤5 0 a n d  
≥1 5 decrease fr o m baseli ne  
Val ue ≥9 0 a n d  
≥1 5 i ncrease fr o m baseli ne  
P ulse rate (s u pi ne ) 
( b p m) 
6 -1 0  
Val ue ≤6 0 a n d  
≥1 5 decrease fr o m baseli ne  
Val ue ≥1 3 5 a n d  
≥1 5 i ncrease fr o m baseli ne  
 
1 1 -1 8  
Val ue ≤5 0 a n d  
≥1 5 decrease fr o m baseli ne  
Val ue ≥1 2 0 a n d  
≥1 5 i ncrease fr o m baseli ne  
S B P ort h ostatic criteria 
( m m H g) 
~  
≥2 0 decrease fr o m s u pi ne t o 
sta n di n g p ositi o n 
N A  
D B P ort h ostatic criteria 
( m m H g) 
~  
≥1 0 decrease fr o m s u pi ne t o 
sta n di n g p ositi o n 
N A  
P ulse rate ort h ostatic 
criteria ( b p m) 
~  
N A  
≥2 0 i ncrease fr o m s u pi ne t o 
sta n di n g p ositi o n 
T e m perat ure (˚ C)  
~  
N A  
Val ue ≥3 8. 3° C a n d ≥0. 8° C 
i ncrease fr o m baseli ne  
T he B MI will be c o m p ute d si milarl y t o descri pti o n i n Secti o n  5. 3  at p ost -baseli ne  visits usi n g  
wei g ht at visit a n d last a vaila ble hei g ht meas ure me nt.  
I n a d diti o n, n or mal a ge a n d se x-base d z -sc ores a n d perce ntiles f or B MI will be deter mi ne d usi n g 
t he W H O gr o wt h c harts. A ge a n d se x-base d B MI cate g ories i n cl u de: U n der wei g ht ( < 5 
perce ntile), N or mal ( ≥ 5 - < 8 5 perce ntile), O ver wei g ht ( ≥ 8 5 - < 9 5 perce ntile), O b ese ( ≥ 9 5 
perce ntile).  
Descri pti ve statistics f or wei g ht , h ei g ht a n d B MI will be pr o vi de d.  Data will be liste d.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 5  
F or C O VI D -1 9 u p dates, vital Si g ns are o pti o nal at wee k 3 a n d wee k 1 4, m a n dat or y at Wee k 7, 
ma n dat or y at W ee k 2 7 a n d at wee k 4 0 if n ot d o ne at t h e res pecti ve pre vi o us visit a n d ma n dat or y 
at wee k 5 3/ E T a n d wee k 5 4. Vital Si g ns ca n be m eas ure d at h o me, at a l o cal p har mac y or b y t he 
h o me n ursi n g.  
Ort h ostatic bl o o d press ur e a n d p ulse are o pti o nal.  
8. 9.  
Electr oc ar di o gr a p h y   
A 1 2 -lea d E C G will be rec or de d at t he ti me p oi nts detaile d i n Ta ble 4 a n d Ta ble 5  of t he st u d y 
pr ot oc ol. All E C Gs will be perf or me d after at least 5 mi n utes rest i n a s u pi ne or se mi-s u pi ne 
p ositi o n. A q ualifie d p h ysicia n at a ce ntral dia g n ostic ce nter will be i nter preti n g t he E C G.  A 
ce ntral E C G Sta n dar d 1 2 -lea d E C G will rec or d heart rate ( H R), P R i nter val (Ti me fr o m t he 
be gi n ni n g of t he P  w a ve t o t he be gi n ni n g of t he Q R S c o m ple x i n electr ocar di o gra m), R R i nter val 
(Ti me bet wee n t he start of o ne R wa ve a n d t he start of t he ne xt R wa ve i n t he E C G ), Q T i nter val, 
Fri deri cia’s c orrecte d Q T i nter val ( Q Tc F), a n d Q R S d urati o n  (Gra p hical deflecti o ns 
c orres p o n di n g t o ve ntri c ular de p olariz ati o n i n a t y pical electr o car di o gra m ). 
All E C G res ults o utsi de of t he refere nce ra n ges will be j u d ge d b y t he i n vesti gat or as b el o n gi n g t o 
o ne of t he f oll o wi n g cate g ories:  
•  a b n or mal a n d n ot cli nicall y si g nifica nt  
•  a b n or mal a n d cli nic all y si g nifica nt  
If an a b n or mal  p ost -baseli ne Q Tc F val ue > 5 0 0 ms ec or c h a n ge fr o m baseli ne  > 6 0 msec is f o u n d, 
t he i n vesti gat or m ust f urt her e val u ate Q T c F b ase d o n pr ot oc ol secti o n 7. 9.  
S hifts ( n or mal a n d a b n or mal) fr o m baseli ne t o o v erall res ult i nter pretati o n  a n d eac h visit wil l be 
s u m marize d usi n g patie nt c o u nts f or t he ce ntrall y-rea d i nter pretati o n. F or o verall res ult 
i nter pretati o n t he w orst p ost -baseli ne  fi n di n g f or t he patie nt (t he a b n or mal fi n di n g if t here are 
b ot h n or mal a n d a b n or m al fi n di n gs) will be use d i n t he s u m marie s. S u m mar y statistics f or E C G 
varia bles val u es will be prese nte d. Act ual val ues a n d c ha n ges fr o m baseli ne t o eac h visit  will be 
s u m marize d usi n g descri pti ve statistics. 
Q Tc F v al ues will be classi fie d as ha vi n g Q Tc pr ol o n gati o n if a n y of t he f oll o wi n g c o n diti o ns are 
met .  
•  C o nfir me d Q Tc F > 4 5 0 msec  
•  C o nfir me d Q Tc F > 4 8 0 msec  
•  C o nfir me d Q Tc F > 5 0 0 msec  
•  I n crease fr o m baseli ne Q Tc F > 6 0 msec 
•  I n crease fr o m baseli ne c o nfir me d Q Tc F >  6 0 msec  
T he c o nfir me d Q Tc F is defi ne d as t he a vera ge of u p t o 3 sta n dar d E C G val ues at a visit, or a 
si n gle s u m mar y E C G. If t here are m ore t h a n 3 sta n dar d or m ore t ha n o ne s u m mar y E C G at a 
visit, t he n use t he last E C Gs f or t he c o nfir me d Q T c F.  
T he n u m ber a n d p erce nta ge of patie nt s wit h Q Tc pr ol o n gati o n will be s u m marized o verall,  a n d 
b y visit.   
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 6  
T he i nci de nce of p ote ntiall y cli nicall y si g nifi ca nt a b n or mal val ues f or E C G varia bles will be 
s u m marize d usi n g descri pti ve statistics wit h t he criteria prese nt e d i n Ta ble 9 . T he s u m mar y will 
be c o m plete d b y a ge gr o u ps ( 6 t o < 8 years, 8 t o < 1 2 years, 1 2  t o < 1 6 years , a n d ≥1 6 years) , 
a n d o verall .  
T a ble 9 :  
P ote nti all y Cli nic all y Si g nific a nt V al ues f or E C G V ari a bles  b y A ge   
E C G p ar a meter ( u nit)  a  
A ge ( ye ars ol d)  
P ote nti all y Cli nic all y 
Si g nific a nt  L o w  
P ote nti all y Cli nic all y 
Si g nific a nt  Hi g h  
H eart R ate ( b p m) 
6 t o < 8  
< 6 5  
> 1 1 5  
8 t o < 1 2  
< 5 5  
> 1 1 0  
1 2 t o < 1 6  
< 5 0  
> 1 0 5  
≥1 6  
< 5 0  
> 1 0 0  
P R i nter val ( msec)  
6 t o < 8  
-- 
> 1 6 0  
8 t o < 1 2  
-- 
> 1 7 5  
1 2 t o < 1 6  
-- 
> 1 8 0  
≥1 6  
-- 
> 2 0 0  
Q R S i nter val ( msec)  
6 t o < 8  
-- 
> 1 0 0  
8 t o < 1 2  
-- 
> 1 0 5  
1 2 t o < 1 6  
-- 
> 1 1 0  
≥1 6  
-- 
> 1 2 0  
a b p m = b eats per mi n ute; H R = h eart rate; P R i nter val = Ti me fr o m t he be gi n ni n g of t he P wa ve t o t he be gi n ni n g of 
t he Q R S c o m ple x i n electr ocar di o gra m; R R i nter val = Ti me bet wee n t he start of o ne R wa ve a n d t he start of t he 
ne xt R wa ve i n t he E C G; Q R S d urati o n = Gra p hical deflecti o ns c orres p o n di n g t o ve ntric ular de p olarizati o n i n a 
t y pical electr ocar di o gra m 
8. 1 0.  
C o nc o mit a nt Me dic ati o ns or T her a pies   
C o nc o mita nt t hera p ies a n d me dicati o ns , i ncl u di n g me dicati o ns t hat are ta ke n o n a n as nee de d 
basis  a n d occasi o nal t hera pies , will be m o nit ore d d uri n g t he st u d y. Details of pr o hi bite d 
me dicati o ns ma y b e f o u n d i n Secti o n  8. 1 0  of t he st u d y pr ot oc ol. All c o nc o mita nt me dicati o ns 
will be c o de d usi n g t h e W H O Dr u g.  
T he i nci de nce of c o n c o mita nt t hera pies a n d me dicati o ns will be s u m marize d usi n g descri pti ve 
statistics b y t h era p e utic class cate g or y, preferre d b ase na me a n d preferre d t er m.  Patie nts are 
c o u nte d o nl y o n ce i n e ac h t hera pe utic class , o nce i n eac h preferre d b ase na me a n d o nl y o n ce i n 
eac h preferre d ter m c ate g or y.  C o nc o mita nt  t hera pi es a n d me dicati o ns will i ncl u de all 
me dicati o ns ta ke n after t he first a d mi nistrati o n of t he I M P u p t o t he e n d of st u d y as defi ne d i n 
t he st u d y pr ot oc ol .  
I n or der t o det er mi ne w h et her a me di cati o n is c o n c o mita nt, partial start dat es wit h missi n g da y 
a n d/ or m o nt h will be i m p ute d wit h t he first da y of t he m o nt h/first m o nt h of t he year, res pecti vel y 
a n d partial e n d d ates wit h missi n g da y a n d/ or m o nt h will be i m p ute d wit h t he 2 8 t h da y of  t he 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 7  
m o nt h/last m o nt h of t he year res pecti vel y. I m p ut e d dates will be use d f or calc ulati o ns o nl y, 
act ual dates will be liste d.  
Pr o hi bite d me dicati o ns t hat are ass ociate d wit h Q Tc pr ol o n gati o n a n d pr o hi bite d a nti ps yc h otic 
dr u gs are liste d i n A p pe n di x H, Ta ble s 1 1  a n d 1 2 , of t he st u d y pr ot oc ol , res pectf ull y. A n y 
i nci de nce of t h ese pr o hi bite d me dicati o ns will be liste d  se paratel y. 
8. 1 1.  
C hil dre n’s C ol u m bi a -S uici de Se verit y R ati n g Sc ale   
T he fre q u e nc y a n d se verit y of s uici dal i deati o n or be ha vi or acc or di n g t o t he c hil dre n’s C -S S R S 
q uesti o n naire will be prese nte d f or all patie nts a ge ≥1 2 years b y visit . A s hift ta ble t o e xa mi ne 
c ha n ges i n c hil dre n’s C -S S R S cate g ories fr o m  baseli ne /scree ni n g ( usi n g t h e lifeti me versi o n of 
t he q uesti o ns), c o m pare d t o t he w orst ( hi g h est) cat e g or y d uri n g t he treat me nt peri o d will be 
prese nte d  b y all patie nts a n d o verall .  
Patie nts will be place d i nt o cate g ories f or s uici dal i deati o n a n d s uici dal be h a vi or base d o n t heir 
res p o nses t o vari o us q uesti o ns. T he s uici dal i deati o n cate g ories will be deter mi ne d  b y t he 
f oll o wi n g 5 q uesti o ns. 
T a ble  1 0 : 
S uici d al I de ati o n C ate g or y   
T y pe  
C ate g or y  
S uici dal I deati o n  
( 0) N o ne –  if res p o nse is N o t o Q uesti o ns 1 a n d 2  
( 1) Wis h t o be Dea d –  if res p o nse t o Q uesti o n 1 is Yes a n d res p o nses t o 
Q uesti o ns 2 -5 are N o.  
( 2) N o n-S pecific Acti ve S uici dal T h o u g hts –  if res p o nse t o Q uesti o n 2 is Yes 
a n d res p o nse t o Q uesti o ns 3 -5 are N o.  
( 3) Acti ve S uici dal I deati o n wit h A n y Met h o ds ( N ot Pla n) wit h o ut I nte nt t o Act 
–  if res p o nse t o q uesti o n 3 is Yes a n d res p o nse t o q uesti o ns 4 a n d 5 are N o.  
( 4) Acti ve S uici dal I deati o n wit h S o me Inte nt t o Act, wit h o ut S pecific Pla n –  if 
res p o nse t o Q uesti o n 4 is Yes a n d res p o nse t o Q uesti o n 5 is N o.  
( 5) Acti ve S uici dal I deati o n wit h S pecific Pla n a n d I nte nt –  if res p o nse t o 
Q uesti o n 5 is Yes.  
F or s uici dal be h a vi or, t he f oll o wi n g cate g ories will b e use d. T he cate g ories will be deter mi ne d 
base d o n t he res p o nse t o t he q uesti o ns .  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 8  
T a ble  1 1 : 
S uici d al Be h a vi or C ate g or y   
T y pe  
C ate g or y  
S uici dal Be ha vi or  
( 6) Pre parat or y Acts or Be ha vi or –  if res p o nse t o Pre parat or y Acts a n d 
Be ha vi or is Yes a n d res p o nses t o Act ual Atte m pt, I nterr u pte d Atte m pt, A b orte d 
Atte m pt, a n d C o m plete d S uici de are N o  
( 7) A b orte d Atte m pt –  if res p o nse t o A b orte d Atte m pt is Yes a n d res p o nses t o 
Act ual Atte m pt, I nterr u pte d Atte m pt, a n d C o m plete d S uici de are N o.  
( 8) I nterr u pte d Atte m pt –  if res p o nse t o I nterr u pte d Atte m pt is Yes a n d 
res p o nse t o Act ual Atte m pt, a n d C o m plete d S uici de are N o. 
( 9) Act ual Atte m pt –  if res p o nse t o Act ual Atte m pt is Yes a n d C o m plete d 
S uici de is N o.  
( 1 0) C o m plete d S uici de - if res p o nse t o C o m plete d S uici de is Yes 
( 0) N o ne –  if res p o nses t o all t he a b o ve q uesti o ns are N o. 
S uici dal i deati o n or be ha vi or will be deri ve d as t h e hi g h est s uici dal i deati o n or be ha vi or s c ore at 
t he visit. Sc ore of 0 re prese nt “N o S uici dal I deati o n/ Be ha vi or ”.  
T he fre q u e nc y a n d perce nta ge of s uici dal i deati o n, s uici dal be ha vi or, s uici dal i deati o n or 
be ha vi or, a n d s elf-i nj uri o us be ha vi or wit h o ut s uici dal i nte nt will be s u m mari ze d b y treat me nt 
a n d o verall , a n d visit.  
8. 1 2.  
C hil d Be h a vi or C hec klist f or A ges 6 -1 8 ( C B C L)   
T he C B C L assess es be ha vi oral a n d e m oti o nal stat us i n c hil dre n a ges 6 t hr o u g h 1 8 years of a ge as 
re p orte d b y t he p are nt/care gi ver (Ac he n b ac h a n d R uffle 2 0 0 0 ; Ac he n b ac h 2 0 0 5 ). T he f ull C B C L 
has 2  parts, a C o m pete n ce Scale ( Parts I t o VII) a n d a S y n dr o m e Scale ( b e h a vi oral ite ms).   
8. 1 2. 1.  
C o m pete nce Sc ale   
T he C o m pete nce Scale ( Parts I t o VII) assesses v ari o us acti vities , i nter pers o nal relati o ns hi ps, a n d 
aca d e mic perf or ma nce.  C o m pete nce assess me nt  will be perf or me d  at scree ni n g or da y 1  visit a n d 
at t he 5 3/ E T visit . 
T he c o m pete n ce scale is di vi de d i nt o 3 s u bscales  –  see Ta ble 1 2 . 
T a ble 1 2 : 
C B C L  C o m pete nce Sc ale   
Acti vities  
S oci al  
Sc h o ol  
I. A. n u m ber of s p orts 
I. B. Mea n part/s kills 
II. A. n u m ber of acti vities 
II. B. Mea n part/s kills 
I V. A. n u m ber of j o bs 
I V. B. Mea n j o b q ualit y  
III. A. n u m ber of or ga nizati o ns 
III. B. Mea n P artici pati o n 
V. 1 n u m ber of frie n ds  
V. 2 Fre q ue nc y of c o ntact  
VI. A. Be ha vi or wit h ot hers  
VI. B. Be ha vi or al o ne  
VII. 1. Mea n perf or ma nce  
VII. 2. S pecial class  
VII. 3. Re peate d gra de  
VII. 4. Sc h o ol pr o ble ms  
T otal sc ore a n d c ha n ge fr o m baseli ne f or eac h s u bscale se p aratel y a n d a t ot al sc ore a n d c ha n ge 
fr o m baseli ne f or all ite ms will be s u m marize d f or eac h ti me p oi nt usi n g d es cri pti ve statistics f or 
c o nti n u o us varia bles . T ot al sc ores are r o u n de d t o nearest 0. 5 . 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
4 9  
Sc ores per ite m are calc ulate d as f oll o w s i n Ta ble 1 3 : 
T a ble 1 3 : 
C B C L C o m pete nce Sc ale Sc ori n g   
S u bsc ale  
Ite m 
Sc ori n g  
Acti vities  I. A. n u m ber of 
s p orts 
c o u nt t he n u m ber of s p orts . 
I. B. Mea n part/s kills 
mea n of u p t o 6 rates, 2 f or eac h s p ort acti vit y. W here  ' bel o w a vera ge' or ’ Less 
t ha n a vera ge’ = 0, ' A vera ge' = 1, 'a b o ve a vera ge' or ‘ M ore t ha n a vera ge’ = 2. 
II. A. n u m ber of 
acti vities  
c o u nt t he n u m ber of acti vities.  
II. B. Mea n part/s kills mea n of u p t o 6 rates, 2 f or eac h acti vit y. W here  ' bel o w a ver a ge' or ’ Less t ha n 
a vera ge’ = 0, ' A vera ge' = 1, 'a b o ve a vera ge' or ‘ M ore t ha n a vera ge’ = 2 . 
I V. A. n u m ber of 
j o bs 
c o u nt t he n u m ber of j o bs. 
I V. B. Mea n j o b 
q ualit y  
mea n of u p t o 3 rates, 1 f or eac h j o b. W here: ' bel o w a vera ge' = 0, ' A vera ge' = 1, 
'a b o ve a vera ge’' = 2. 
S ocial  
III. A. n u m ber of 
or ga nizati o ns  
c o u nt t he n u m ber of or ga nizati o ns.  
III. B. Mea n 
P artici pati o n  
mea n of u p t o 3 rates, 1 f or eac h or ga nizati o n. W here: ' Less acti ve' = 0, 
' A vera ge' = 1, ‘ M ore acti ve' = 2. 
V. 1 n u m ber of 
frie n ds 
N o ne’ = 0, ' 1' = 1, ' 2 or 3' = 2, ' 4 or m ore' = 3.  
V. 2 Fre q ue nc y of 
c o ntact  
' Less t ha n 1' = 0, ' 1 or 2' = 1, ' 3 or m ore' = 2.  
VI. A. B e ha vi or wit h 
ot hers  
mea n of ite ms a -c. W here: ' W orse' = 0, ' A vera ge' = 1, ' Better' = 2.  
VI. B. B e ha vi or al o ne  rate f or ite m d. W here: ' W orse' = 0, ' A vera ge' = 1, ' Better' = 2. 
Sc h o ol  
VII. 1. Mea n 
perf or ma nce  
Mea n of u p t o 7 perf or ma nce ite ms. W here 'faili n g' = 0, ' bel o w a vera ge' = 1, 
'a vera ge' = 2,'a b o ve a vera ge' = 3. 
VII. 2. S pecial class  
' Yes =' 0', ' N o =' 1'. 
VII. 3. Re p eate d 
gra d e  
' Yes =' 0', ' N o =' 1'. 
VII. 4. Sc h o ol 
pr o ble ms  
' Yes =' 0', ' N o =' 1'. 
V al ues of ' D o n ot k n o w' , ' N ot a p plica ble', or ' Has n o br ot hers or sisters' will b e i g n ore d f or mea n 
calc ulati o ns a n d l o gicall y s ki p pe d ite ms will be i m p ute d as 0 or n o ne.  
A s u bscale sc ore is c alc ulate d as t he s u m of t he ite m sc ores a n d t he t otal sc ore is calc ul ate d as 
t he s u m of the s u bscale s c ores. If o ne or m ore s u bscale sc ores are missi n g, t he t otal sc ore will n ot 
be calc ul ate d.  
If 1  ite m fr o m a cti vities a n d s ocial s u bscales has a missi n g val ue, t he mea n of t he ot her ite ms of 
t hat s u bscale is s u bstit ute d f or t hat ite m. If m ore t h a n 1  ite m is missi n g fr o m eit her of t hese 
scales or a n y ite m is missi n g fr o m t he s c h o ol scale, t he res pecti ve scale is n ot t o be sc ore d. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 0  
R es ults will be liste d. 
8. 1 2. 2.  
S y n dr o me Sc ale   
T he S y n dr o m e Scale c o m prises 1 1 3  q uesti o ns relate d t o pr o ble m be ha vi ors. S y n dr o me 
assess me nt will be perf or me d at da y 1, a n d at wee ks 3, 7, 1 4, 2 7 , 4 0, a n d 5 4/f oll o w -u p visits.  
F or eac h ite m, t he pare nt/care gi ver will circle ‘0 ’ if t he ite m is n ot tr ue of t heir c hil d, ‘1 ’ if t he 
ite m is s o me w hat or s o meti mes tr ue, a n d ‘2 ’ if t he ite m is ver y tr u e or ofte n tr ue. 
T he S y n dr o m e scale is di vi de d i nt o 8 s u bscales  –  see Ta ble 1 4 . 
V V- 0 0 4 7 3 0 5 6 v 2. 0


U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 1  
 
T a ble 1 4 : 
C B C L S y n dr o me Sc ale   
A n xi o us  / De presse d  
Wit h dr a w n  / 
De presse d  
S o m atic  C o m pl ai nts  
S oci al  Pr o ble ms  
T h o u g ht  Pr o ble ms  
1 4. Cries  
3 0. Fears Sc h o ol  
3 2. P erfect  
3 5. W ort hless  
5 0. Fearf ul  
7 1. Self C o nsc  
1 1 2. W orr ies 
2 9. Fears  
3 1. Fear D o B a d  
3 3. U nl o ve d  
4 5. Ner v o us   
5 2. G uilt y  
9 1. T hi n ks S uici de  
5. E nj o ys Little  
4 2. Rat her Be Al o ne  
6 5. W o n't T al k  
6 9. Secreti ve  
7 5. S h y  
1 0 2. Lac ks E ner g y  
1 0 3. Sa d  
1 1 1. Wit h dra w n  
4 7. Ni g ht mares  
4 9. C o nsti pate d  
5 1. Dizz y  
5 4. Tire d  
5 6a -g .P h ysical 
Pr o ble ms wit h o ut 
k n o w n me dical ca use a   
1 1. De p e n de nt  
1 2. L o nel y  
2 5. N ot Get Al o n g 
2 7.J eal o us  
3 4. O ut T o Get  
3 6. Acci de nts  
3 8. T ease d  
4 8. N ot Li ke d  
6 2. Cl u ms y  
6 4. Prefer Y o u n g 
7 9. S peec h Pr o b  
9. Mi n d Off  
4 0. Hears T hi n gs  
5 8. Pic ks S k i n 
6 0. Se x P arts M  
7 0. Sees T hi n gs  
8 3. St ores U p  
8 5. Stra n geI deas 
1 0 0. Slee p Pr o b  
1 8. Har ms Self  
4 6. T witc hes  
5 9. Se x P arts P   
6 6. Re p eats Acts  
7 6. Slee ps Less  
8 4. Stra n ge B e ha v  
9 2. Slee p W al k  
R ule -B re a ki n g  B e h a vi or  
Atte nti o n 
Pr o ble ms  
A g gressi ve Be h a vi or  
Ot her Pr o ble ms  
2. Alc o h ol  
2 8. Brea ks R ules  
4 3. Lies C heats  
6 7. R u n A wa y  
7 3. Se x Pr o bs  
8 2. Steals Ot her  
9 6. T hi n ks Se x  
1 0 1. Tr ua nt  
1 0 6. Va n dalis m  
2 6. Lac ks G uilt   
3 9. B a d Frie n ds  
6 3. Prefer Ol der  
7 2. Sets Fires  
8 1. Steals H o me  
9 0. S wears  
9 9. T o bacc o  
1 0 5. Uses Dr u gs   
1. Acts Y o u n g  
4. Fails T o Fi ni s h 
8. C o nce ntrate  
1 0. Sit Still  
1 3. C o nf use d  
1 7. Da y drea m s 
4 1.I m p ulsi ve  
6 1. P o or Sc h o o l 
7 8.I natte nti ve  
8 0. Stares  
3. Ar g ues  
1 9. De m Atte n  
2 1. Destr o y Ot her  
2 3. Dis o be y Sc hl   
5 7. Attac ks   
8 6. St u b b or n 8 8. S ul ks  
9 4. T eases  
9 7. T hreate n  
1 6. Mea n   
2 0. Destr o y O w n  
2 2. Dis o be y H o me  
3 7 . Fi ghts  
6 8. Screa ms  
8 7. M o o d C ha n g  
8 9. S us pici o us  
9 5. T e m per  
1 0 4. L o u d  
6. B M O ut  
1 5. Cr uel A ni mal  
4 4. Bite Nail  
5 5. O ver wei g ht  
7 4. S h o ws Off  
9 3. T al k M uc h  
1 0 7. Wets Self  
1 0 9. W hi ni n g  
1 1 3. Ot her Pr o b b   
7. Bra gs  
2 4. N o Eat W ell  
5 3. O vereat  
5 6 h. Ot her P h ys  
7 7. Slee ps M ore  
9 8. T h u m b S uc k  
1 0 8. Wets Be d  
1 1 0. Wis h O p p Se x  
a Ite m 5 6 sta n ds f or “ P h ysical Pr o ble ms wit h o ut k n o w n me dical ca use: ot her” a n d ma y n ot be fille d i n b y t he res p o n der.  
b Si milarl y, ite m 1 1 3 t hat sta n ds f or “ A n y pr o ble ms t hat wer e n ot liste d a b o ve” ma y be missi n g, f or t he sa me reas o n. 
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 2  
T otal sc ore f or eac h s u bs cale se p arat el y, t otal sc ore f or all ite ms, c ha n ge fr o m baseli ne f or t he 
t otal sc ore f or eac h s u bsc ale se paratel y a n d c ha n ge fr o m baseli ne f or t otal sc ore f or all ite ms will 
be s u m mariz e d f or eac h ti me p oi nt usi n g descri pti ve statistics f or c o nti n u o us varia bles . 
T otal sc ore is c alc ulate d as t h e s u m of ite ms sc ores.  
If m ore t ha n 2 0 ite ms ha ve missi n g val ues, e x cl u di n g ite ms 5 6 h a n d 1 1 3, w hic h ma y be left 
bla n k b y str u ct ure (s ee T a ble 1 4  f or d etails), t he n n o sc ores will be pr o vi de d. F or calc ulati n g 
s u bscale sc ores, if o ne or m ore ite ms, e x cl u di n g ite ms 5 6 h a n d 1 1 3, are missi n g  i n a s u bscale, t he 
s u bscale sc ore will n ot be calc ul ate d.  
Data will be liste d.  
8. 1 3.  
E p w ort h Slee pi ness Sc ale   
T he E p w ort h Slee pi ness Scale (E S S ) is a self-a d mi nistere d q uesti o n naire c o m p ose d of 8 
q uesti o ns t hat pr o vi de a meas ure of a patie nt’s ge neral le vel of da yti me sle e pi ness (J o h ns 1 9 9 1). 
T he E S S is a d mi nistrate d at scree ni n g  a n d/ or da y 1 visit, a n d a d mi nistere d at  wee k s 3, 7, 1 4, 2 7 , 
4 0, 5 3/ E T, a n d 5 4/f oll o w -u p visits.  
T he E S S is c o m p ose d of 8 ite ms. T he res p o n ders are as k e d t o rate t h eir c h a nces  of falli n g aslee p  
w hile e n ga ge d at 8 differe nt acti vities, o n a 4 -p oi nt scale ( 0 -3). T heref ore, t he t otal sc ore ca n 
ra n ge fr o m 0 t o 2 4. 
If at least 1 ite m has a missi n g val ue, t he n t h e e ntire q uesti o n naire is n ot vali d. 
T otal sc ore  of t h e 8 ite ms  a n d t otal sc ores c h a n ge fr o m baseli ne will be s u m marize d b y ti me 
p oi nt, usi n g descri pti ve statistics.  I n t he case of b ot h care gi ver a n d self-a d mi nistere d versi o ns of 
t he E S S are pres e nte d at t he sa me visit, care gi v er versi o n will be use d f or p atie nts w h o are 6 t o 
1 2 years ol d a n d s elf -a d mi nistere d versi o n will be use d f or p atie nts 1 3 years of a ge a n d ol der.  
T otal sc ore is c alc ulate d as t he s u m of ite m sc ores.  
Data will be liste d.  
8. 1 4.  
E xtr a p yr a mi d al S y m pt o m R ati n g Sc ale   
T he E xtra p yra mi dal S y m pt o m Rati n g Scale ( E S R S)  c o nsist s of  2 s u bscales, E S R S I a n d E S R S 
II.  
E S R S I a n d I I are a d mi nistrate d at t he bas eli ne/ da y 1 visit a n d a d mi nistere d at wee k s 3, 7, 1 4, 2 7, 
4 0, 5 3/ E T, a n d 5 4/f oll o w -u p visits.  
8. 1 4. 1.  
E S R S I   
T he first s u bscale ( E S R S I) is a 7 ite m s u bjecti ve q uesti o n naire t o e val u ate p ar ki ns o n is m, 
akat hisia, d yst o nia a n d d ys ki nesia. T h e E S R S I is sc ore d o n f or p oi nt scale ( 0 =a bse nt, 1 = Mil d, 
2 = M o derat e, Se vere = 3) f or eac h ite m.  
T otal sc ore will be t he s u m of t he 7 ite ms . Missi n g ite m will be re place d b y t he a vera ge of t h e 
re mai ni n g resp o nses wit hi n eac h ite m .  
T otal sc ore a n d t otal s c ores c ha n ge fr o m bas eli ne will be s u m marize d b y ti me p oi nt, usi n g 
descri pti ve statistics . 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 3  
Data will be liste d.  
8. 1 4. 2.  
E S R S II   
T he sec o n d s u bsc ale ( E S R S II) is a 1 7 -ite m q uesti o n naire t o e val u ate p ar ki ns o n is m a n d 
akat hisia.  
E S R S II c o nsists of t he f oll o wi n g parts:  
1.  Tre m or: sc ore d o n a 7-p oi nt ite m scale f or 8 parts of t he b o d y. F or eac h part of t he b o d y, 
fre q ue n c y a n d a m plit u de are sel ecte d, assi g ni n g eac h o ne of t he 8 ite ms a s c ore fr o m 
0 = n o ne t o 6 =se v ere. T h eref ore, t he t otal sc ore f or tre m or ca n ra n ge d fr o m 0 t o 4 8.  
2.  Bra d y ki n esia: sc ore d o n a 7 -p oi nt ite m scale ( 0 -6).  
3.  Gait a n d P ost ure: sc ore d o n a 7 -p oi nt ite m scale ( 0 -6).  
4.  P ost ural sta bilit y: sc ore d o n a 7 -p oi nt ite m  scale ( 0-6).  
5.  Ri gi dit y: sc ore d o n a 7 -p oi nt ite m scale ( 0 -6) f or 4 parts of t he b o d y. T heref ore, t h e t otal 
sc ore f or ri gi dit y ca n ra n ge d fr o m 0 t o 2 4.  
6.  E x pressi ve a ut o matic m o ve me nts: sc ore d o n a 7 -p oi nt ite m scale ( 0 -6).  
7.  A kat hisia: sc ore d o n a 7 -p oi nt ite m scale ( 0 -6).  
T he t otal sc ore of t he 1 7 ite ms ca n ra n ge d fr o m 0 t o 1 0 2.  
T otal sc ore will be t he s u m of t he 1 7 ite ms. Missi n g ite m will be re pl ace d b y t he a vera ge of t h e 
re mai ni n g res p o nses wit hi n eac h ite m.  
T otal sc ore a n d t otal s c ores c ha n ge fr o m bas eli ne will be s u m marize d b y ti me p oi nt, usi n g 
descri pti ve statistics f or c o nti n u o us varia bles.  
Data will be liste d.  
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 4  
9.  
T O L E R A BI LI T Y V A RI A B L E S A N D A N A L Y SI S   
If m ore t ha n 1 5 % of t he patie nts  wit h dra w fr o m t he st u d y b ef ore t he e n d of t he treat me nt peri o d, 
t he n u m ber of da ys u ntil st u d y disc o nti n uati o n will be a nal yz e d usi n g Ka pl a n-Meier 
met h o d ol o g y wit h  t he I T T a nal ysis set. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 5  
1 0.  
S T A TI S TI C A L S O F T W A R E   
All data listi n gs, s u m maries, a n d statistical a nal ys es will be ge nerate d usi n g S A S ® versi o n 9. 4 or 
later. 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 6  
1 1.  
C H A N G E S T O A N A L Y S E S S P E CI FI E D I N T H E S T U D Y 
P R O T O C O L   
N ot a p plica ble.  
 
 
V V- 0 0 4 7 3 0 5 6 v 2. 0


 
U nc o ntr olle d St u d y – D ys ki nesia i n Cere bral Pals y  
Statistical A nal ysis Pla n  
St u d y T V 5 0 7 1 7 -C N S -3 0 0 8 1  
5 7  
1 2.  
R E F E R E N C E S   
Ac he n bac h T M. A d va n ci n g ass ess me nt of c hil dre n a n d a d olesce nts: c o m me ntar y o n e vi de nce -
base d assess me nt of c hil d a n d a d olesce nt dis or ders. J Cli n C hil d A d olesc Ps yc h ol 
2 0 0 5; 3 4: 5 4 1 -7.  
Ac he n bac h T M, a n d R uffle T M. T he C hil d Be h a vi or C hec klist a n d Relate d F or ms f or  Ass essi n g 
Be ha vi oral/ E m oti o nal Pr o ble ms a n d C o m pete ncies. Pe di atrics i n Re vie w. 2 0 0 0; 2 1( 1): 2 6 5 -2 7 1.  
J o h ns M W. A ne w met h o d f or meas uri n g d a yti m e slee pi ness: t he E p w ort h Slee pi ness Scale. 
Slee p 1 9 9 1; 1 4: 5 0 -5 5.  
P E DI -C A T ( Versi o n 1. 3. 6 ) De vel o p me nt, Sta n dar dizati o n a n d A d mi nistrati o n Ma n ual , Tr ustees 
of B ost o n U ni versi t y, u n der lice nse t o C R Ecare, L L C, 2 0 1 1. 
Ha user R A , G or d o n M F, Miz u n o Y, P oe we W, Bar o ne P, Sc ha pira  A H , et al Mi ni mal cli nicall y 
i m p orta nt differe n ce i n P ar ki ns o n's disease as assesse d i n pi v otal trials of pra mi pe x ole e xte n de d 
releas e. Par ki ns o n's disease 2 0 1 4, 4 6 7 1 3 1 . htt ps:// d oi. or g/ 1 0. 1 1 5 5/ 2 0 1 4/ 4 6 7 1 3 1 
Ha user R A, Bar ka y H, Wil hel m A, Wie ma n M, Sa v ola J -M, G or d o n M F. Mi ni mal cli nicall y 
i m p orta nt c ha n ge i n a b n or mal i n v ol u ntar y m o v e me nt scale sc ore i n tar di v e d ys ki nesia as 
assesse d i n pi v otal trials of de ut etra b e nazi ne. Par ki ns o nis m Relat Dis or d 2 0 2 2; 9 7: 4 7 -5 1.  
V V- 0 0 4 7 3 0 5 6 v 2. 0