| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Tics associated with Tourette Syndrome(TS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tics associated with Tourette Syndrome(TS) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| 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 efficacy of TEV 50717 to reduce motor and phonic tics associated with TS. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to evaluate the safety and tolerability of titration and maintenance therapy with TEV-50717. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Patient is 6 to 16 years of age, inclusive, at baseline.
b. Patient weighs at least 44 pounds (20 kg) at baseline.
c. Patient meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V™) diagnostic criteria for TS and, in the opinion of the investigator, patient, and caregiver/adult, the patient’s active tics are causing distress or impairment.
d. Patient has a TTS of 20 or higher on the YGTSS at screening and baseline.
e. Patient is able to swallow study medication whole.
f. Patient and caregiver/adult are willing to adhere to the medication regimen and to comply with all study procedures.
g. Patient is in good general health, as indicated by medical and psychiatric history as well as physical and neurological examination.
h. In the investigator’s opinion, the patient and caregiver/adult have the ability to understand the nature of the study and its procedures, and the patient is expected to complete the study as designed.
i. Patient and caregiver/adult provide written informed consent/assent, depending on the child’s age, as appropriate, according to local regulations.
j. Females who are postmenarchal or ≥12 years of age may be included only if they have a negative β-HCG test at baseline or are sterile.
k. Females who are postmenarchal or ≥12 years of age whose male partners are potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study (ie, starting at screening) and for 30 days or 5 half-lives, whichever is longer after the last dose of IMP.
l. The patient must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
a. Patient has a neurologic disorder other than TS that could obscure evaluation of tics.
b. Patient’s predominant movement disorder is stereotypy (coordinated movements that repeat continually & identically) associated with autism spectrum disorder.
c. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
d. Patient has clinically significant depression at screening or baseline.
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 w before screening.
e. Patient has a history of suicidal intent or related behaviors within 2 years of screening:
-previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at time of suicidal thought
-previous suicidal preparatory acts or behavior
f. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
g. Patient has a first-degree relative who has completed suicide.
h. Patient has clinically significant OCD at baseline that, in opinion of investigator, is prim cause of impairment.
i. Patient has received CBIT for TS or CBT for OCD within 4 w of screening.
j. Patient has received any of following concomitant medications for tics within specified exclusionary windows of first dose:
-within 3 m: Depot neuroleptics, botulinum toxin, or tetrabenazine
-within 4 w: cannabidiol oil & valbenazine
-within 21 d: Reserpine
-within 14 days: Neuroleptics (oral), typical & atypical antipsychotics (see Appendix A), metoclopramide, levodopa, & dopamine agonists
Note: Use of stimulant medications, incl amphetamine, methylphenidate, &lisdexamfetamine, is allowed if prim use is for treatment of ADHD &dosing has been stable for at least 2 w bef screening &no changes to dose or frequency are anticipated during course of study.
Note: Use of atomoxetine is allowed if prim use is for treatment of ADHD &dosing has been stable for at least 4 w before screening &no changes to dose or frequency are anticipated during course of study.
Note: Use of benzodiazepines is allowed if prim use is not for tics, &dosing has been stable for at least 4 w before screening.
Note: Use of topiramate (up to 200 mg/day) is allowed if dosing has been stable for at least 4 w before screening.
Note: Use of guanfacine or clonidine is allowed regardless of indication (ie, if prescribed for tics or Tourette syndrome) if dosing has been stable for at least 4 w before screening &no changes to dose or frequency are anticipated during course of study. If discontinuation of either medication is anticipated due to ineffectiveness, poor tolerability, or patient/caregiver preference, discontinuation should occur 4 or more weeks prior to screening visit.
k. Patient has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for reduction of tics within 4 w of screening visit.
l. Patient has an unstable or serious medical illness at screening or baseline
m. Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval value >450 msec (males) or >460 msec (females) or >480msec (with right bundle branch block) on 12-lead ECG at screening, OR requires treatment with drugs known to prolong QT interval (see Appendix A, Table 10 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 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 medical monitor.
Note: Patients with abnormalities in 2 or more of following clinical laboratory parameters must be approved for enrollment by medical monitor: AST, ALT, ALP, & Tbil.
p. Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5 × ULN at screening.
q. Patient has received a MAOI within 14 days of baseline visit.
r. Patient has a known allergy to any of the components of IMP.
s. Patient has participated in an investigational drug or device study & received IMP/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
t. Patient is a pregnant or lactating female, or plans to become pregnant during study.
u. Patient has a history of or acknowledges alcohol-related disorder in previous 12 m, as defined in the DSM-V™.
v. Patient has a positive UDS test result, or is unable to refrain from substance abuse throughout study.
w. Patient has a DSM diagnosis based on MINI Kid modules performed at screening that, in opinion of investigator, makes patient unsuitable for study.
|
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from baseline to week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Change in the Tourette Syndrome-Clinical Global Impression (TS-CGI) score from baseline to week 12
2. Change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from baseline to week 12
3. Change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life (C&A-GTS-QOL) activities of daily living (ADL) subscale score from baseline to week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 24 |
| 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 |
| Canada |
| Denmark |
| Russian Federation |
| Serbia |
| Spain |
| United States |
|
| 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
|
| End of the trial is the last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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