| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Tics associated with Tourette Syndrome(TS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Tics associated with Tourette Syndrome(TS) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10044127 |
| E.1.2 | Term | Tourette's syndrome |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018269 |
| E.1.2 | Term | Gilles de la Tourette syndrome |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the safety and tolerability of long-term therapy with TEV-50717. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study are:
•to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the severity of TS tics
•to confirm long-term maintenance of effect by means of a double-blind, placebo-controlled, randomized drug withdrawal period after 28 weeks of open-label treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Patient is younger than 18 years of age on day 1.
b. Patient weighs at least 44 pounds (20 kg) on day 1.
c. Patient is able to swallow IMP whole.
d. Patient and caregiver/adult are willing to adhere to IMP regimen and comply with all study procedures.
e. Patient is in good general health, as indicated by medical and psychiatric history as well as physical and neurological examination.
f. In the investigator’s opinion, the patient and caregiver/adult have the ability to understand the nature of the study and its procedures, and the patient is expected to complete the study as designed.
g. Patient and caregiver/adult provide written informed consent/assent, depending on the child’s age, as appropriate, according to local regulations.
h. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative β-HCG test on day 1 or are sterile. Definitions of sterile are given in Appendix L.
i. Females who are postmenarchal or ≥12 years of age whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study (ie, starting at screening) and for 30 days or 5 half lives, whichever is longer after last dose of IMP. Further details are included in Appendix L.
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| E.4 | Principal exclusion criteria |
a. Patient is 18 years of age or older.
b. Patient has a neurologic disorder other than TS that could obscure the evaluation of tics.
c. The patient’s predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder.
d. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
e. Patient has clinically significant depression at screening or day 1.
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 weeks before screening.
f. Patient has a history of suicidal intent or related behaviors within 2 years of screening:
previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought
previous suicidal preparatory acts or behavior
g. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
h. Patient has a first-degree relative who has completed suicide.
i. Patient has clinically significant OCD on day 1 that, in the opinion of the investigator, is the primary cause of impairment.
j. Patient has received comprehensive behavioral intervention for tics for TS or cognitive behavioral therapy for OCD within 4 weeks of screening.
k. Patient has received any of the following concomitant medications for tics within the specified exclusionary windows of screening prior to dosing for washout:
within 3 months: depot neuroleptics, botulinum toxin, or tetrabenazine
within 4 weeks: cannabidiol oil and Valbenazine
within 21 days: reserpine
within 14 days: neuroleptics (oral), typical and atypical antipsychotics (see Appendix A, Table 7), metoclopramide, levodopa, and dopamine agonists
Note: Use of stimulant medications, including amphetamine, methylphenidate, and lisdexamfetamine, is allowed if primary use is for the treatment of ADHD and dosing has been stable for at least 2 weeks before screening.
Note: Use of atomoxetine is allowed if the primary use is for the treatment of ADHD, dosing has been stable for at least 4 weeks before screening.
Note: Use of benzodiazepines is allowed if the primary use is not for tics and dosing has been stable for at least 4 weeks before screening.
Note: Use of topiramate (up to 200 mg/day) is allowed if the dosing has been stable for at least 4 weeks before screening.
Note: Use of guanfacine or clonidine is allowed regardless of indication (ie, if prescribed for tics or Tourette syndrome) if the dosing has been stable for at least 4 weeks before screening and no changes to dose or frequency are anticipated during the course of the study.
l. Patient has an unstable or serious medical illness at screening or day 1.
m. Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval value >450 msec (males) or >460 msec (females) or >480 msec (with right bundle branch block) on 12-lead ECG at screening. Patient requires treatment with drugs known to prolong the QT interval (see Appendix A Table 8 for a complete list of prohibited QT-prolonging drugs).
n. Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure.
o. Patient has evidence of hepatic impairment, as indicated by:
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × the upper limit of the normal range (ULN) at screening
alkaline phosphatase (ALP) or total bilirubin (Tbil) >2 × ULN at screening
Note: Patients with Gilbert’s Syndrome are eligible to participate if approved by the medical monitor.
Note: Patients with abnormalities in 2 or more of the following clinical laboratory parameters must be approved for enrollment by the medical monitor: AST, ALT, ALP, and Tbil.
p. Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5 × ULN at screening.
q. Patient has received a monoamine oxidase inhibitor within 14 days of the day 1 visit.
r. Patient has a known allergy to any of the components of the IMP.
s. Patient has participated in an investigational drug or device study (with the exception of Study SD 809 C 17 or Study TV50717-CNS 30046 or Study TV50717-CNS 30060) and received IMP/intervention within 30 days.
t. The patient is a pregnant or lactating female, or has plans to become pregnant during the study.
u. Patient has a history of or acknowledges alcohol-related disorder in the previous 12 months, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-V™).
v. Patient has a positive UDS test result or is unable to refrain from substance abuse throughout the study.
w. Patient has a DSM diagnosis based on the MINI Kid modules performed at screening that, in the opinion of the investigator, makes the patient unsuitable for the study
For complete wording refer to Protocol Amdt 4.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints Part A:
•incidence of adverse events
•observed values and changes from day 1 in vital signs
•observed values and changes from day 1 in the Children’s Depression Inventory, Second Edition (CDI 2; Parent and Self-report versions)
•observed values in the Children’s Columbia-Suicide Severity Rating Scale (C-SSRS)
•observed values in electrocardiogram (ECG) parameters and shifts from day 1 for clinically significant abnormal findings
•observed values and changes from day 1 in clinical laboratory parameters (hematology, serum chemistry, and urinalysis)
The following safety endpoints will be assessed in Part B (Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal):
•incidence of adverse events
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Baseline to Week 54
Part B: week 28 to Week 30 |
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| E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
Part A (Day 1, Titration, and Maintenance):
•change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from day 1 to each visit in which the scale is administered
•change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from day 1 to each visit in which the scale is administered
•change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from day 1 to each visit in which the scale is administered
•change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS QOL) activities of daily living (ADL) subscale score from day 1 to each visit in which the scale is administered
Part B (Blinded, Randomized Drug Withdrawal Period and Titration Post-Drug Withdrawal):
•change in the TTS of the YGTSS from week 28 to week 30
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints
Part A: day 1 to each visit in which the scale is administered
Part B: week 28 to week 30 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Study Includes a Double-Blind, Placebo-Controlled, Randomized Withdrawal Period between week 28-30 |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Colombia |
| Denmark |
| France |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Sweden |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of study is defined as the date of the week 56 visit of the last participant |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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