| 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 the study is to evaluate the efficacy of fixed doses of TEV 50717 to reduce motor and phonic tics associated with Tourette Syndrome |
|
| E.2.2 | Secondary objectives of the trial |
| A secondary objective is to evaluate the safety and tolerability of TEV-50717 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Patient is 12 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-5) diagnostic criteria for TS and, in the opinion of the investigator,
patient, and parent/legal guardian, 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 parent/legal guardian 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 parent/legal guardian 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 parent/legal guardian provided written informed consent according to local regulations (eg, the patient has provided written assent and/or co-consent, as appropriate).
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. Definition of sterile is given in Appendix E.
k. Females who are postmenarchal or ≥12 years of age whose male partners are
potentially fertile (ie, no vasectomy) must use highly effective birth control methods for the duration of the study (ie, starting at screening) and for 30 days or 5 half-lives, whichever is longer after last dose of IMP. Further details are included in Appendix E.
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.
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| E.4 | Principal exclusion criteria |
a. Patient has a neurologic disorder other than TS that could obscure the evaluation of tics.
b. The patient’s predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder.
c. Patient has clinically significant obsessive-compulsive disorder (OCD) at baseline that, in the opinion of the investigator, is the primary cause of impairment.
d. Patient has clinically significant depression at screening or baseline.
Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose for at least 6 weeks before baseline (see Table 9 for prohibited antidepressants).
e. Patient has a history of suicidal intent or related behaviors within 2 years of
screening:
- previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought
- previous suicidal preparatory acts or behavior
f. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
g. Patient has a first-degree relative who has completed suicide.
h. Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
i. Patient has a DSM diagnosis based on the Mini International Neuropsychiatric
Interview For Children and Adolescents Inventory at screening that, in the opinion of the investigator, makes the patient unsuitable for the study.
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 following specified exclusionary windows of screening:
- within 3 months: depot neuroleptics, botulinum toxin, or tetrabenazine
- within 21 days: reserpine
- within 14 days: neuroleptics (oral), typical and atypical antipsychotics
(see Appendix H, Table 9), metoclopramide, levodopa, and dopamine agonists
Note: Use of benzodiazepines is allowed if primary use is not for tics and
dosing has been stable for at least 4 weeks before screening.
Note: Use of topiramate (up to 200 mg/day) is allowed if dosing has been
stable for at least 4 weeks before screening.
Note: Use of guanfacine or clonidine is allowed if dosing has been stable for
at least 4 weeks before screening.
l. Patient has received treatment with depot antipsychotics within 3 months prior to prescreening.
m. Patient has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation within 4 weeks of the screening visit for reduction of tics.
n. Patient has a QTcF value >450 msec (males) or >460 msec (females), or >480 msec with right bundle branch block) on a 12-lead electrocardiogram (ECG) at screening, or requires treatment with drugs known to prolong the QT interval (see Appendix H Table 10 for a complete list of prohibited QT-prolonging drugs).
o. Patient has a history of torsades de pointes, congenital long QT syndrome,
bradyarrhythmias, or uncompensated heart failure.
p. Patient has any value above the normal range for hepatic or renal function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, or creatinine.
q. Patient has a known allergy to any of the components of the IMP product.
r. Patient has participated in an investigational drug or device study and received IMP/intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
s. Patient is a pregnant or lactating female, or plans to become pregnant during the study.
t. Patient has a history of or acknowledges alcohol-related disorder in the previous 12 months, as defined in the DSM-5.
u. Patient has a positive urine drug screen test result or is unable to refrain from
substance abuse throughout the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS) from baseline to week 8 between high-dose TEV 50717 treated patients and placebo-treated patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1.change in the TS-CGI score from baseline to week 8 between high-dose TEV-50717 treated patients and placebo treated patients
2.change in the TTS of the YGTSS from baseline to week 8 for low dose TEV 50717 and placebo will be tested
3.change in the TS-CGI score from baseline to week 8 between low dose TEV-50717 treated patients and placebo treated patients
4.change in the Tourette Syndrome-Patient Global Impression of Impact (TS-PGII) score from baseline to week 8 between high-dose TEV-50717-treated patients and placebo-treated patients
5.change in the TS-PGII score from baseline to week 8 between low-dose TEV-50717-treated patients and placebo-treated patients
6.change in the Child and Adolescent Gilles de la Tourette Syndrome – Quality of Life- scale (C&A-GTS-QOL) activities of daily living (ADL) subscale from baseline to week 8 between high-dose TEV 50717 treated patients and placebo treated patients
7.change in the C&A-GTS-QOL ADL subscale from baseline to week 8 between low-dose TEV 50717 treated patients and placebo treated patients
The safety endpoints are as follows:
•incidence of adverse events
•observed values and changes from baseline in vital signs
•observed values and change from baseline in the Children’s Depression Inventory Second Edition (CDI-2; Parent and Self-report Profiles)
•observed values in the children’s Columbia Suicide Severity Rating Scale (C-SSRS)
•observed values and changes from baseline in electrocardiogram (ECG) parameters and shifts from baseline for clinically significant abnormal findings
•observed values and changes from screening in clinical laboratory parameters (hematology, chemistry, and urinalysis)
|
|
| 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 | No |
| 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) | 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 | 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 | 3 |
| 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 | 35 |
| 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 |
| Colombia |
| France |
| Hungary |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Sweden |
| Ukraine |
| 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 study is defined as the date of the week 10 telephone contact with the last participant. |
|
| 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 | 0 |
| 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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