| 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 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 provided 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 beta-human chorionic gonadotropin (β HCG) test at baseline or are sterile. Definitions of sterile are 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 the 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. |
|
| 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.
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 first dose:
- 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 H, table 9) 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 Attention Deficit Hyperactivity Disorder (ADHD), dosing has been stable for at least 2 weeks before screening, and no changes to dose or frequency are anticipated during the course of the study.
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, and no changes to dose or frequency are anticipated during the course of the study.
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 regardless of indication 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. 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 the screening visit.
l. 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.
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 a 12-lead electrocardiogram (ECG) at screening, or requires treatment with drugs known to prolong the QT interval.
n. Patient has a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure.
o. 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 screening
- alkaline phosphatase (ALP) or total bilirubin >2 × ULN at screening
Note: Patients with Gilbert’s syndrome are eligible to participate if approved by the medical monitor.
Note: Patients with abnormalities in 2 or more of the following clinical laboratory parameters must be approved for enrollment by the medical monitor: AST, ALT, ALP, and total bilirubin.
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 baseline visit.
r. Patient has a known allergy to any of the components of the IMP product.
u. Patient has a history of or acknowledges alcohol-related disorder in the previous 12 months, as defined in the DSM-V™.
Please refer to the protocol for the full list of exclusion criteria |
|
| 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)
In addition to routine monitoring of adverse events, clinical laboratory parameters, 12-lead ECGs and safety scales, an independent Data Monitoring Committee will monitor safety during the conduct of the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 8
For secondary safety endpoints.
- from screening in clinical laboratory parameters
- from baseline in the rest of safety endpoints (vital signs, CDI-2; Parent and Self-report Profiles, ECG parameters and clinically significant abnormal findings)
- safety monitoring during the conduct of the study (by IDMC) |
|
| 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) | 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 |
| Canada |
| 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 | 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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