| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dyskinesia in cerebral palsy (DCP) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Dyskinesia in cerebral palsy (DCP) |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068804 |
| E.1.2 | Term | Athetoid cerebral palsy |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| 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 in children and adolescents with DCP. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to evaluate the efficacy of long-term therapy with TEV-50717 in reducing the severity of DCP. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients who have completed Study TV50717-CNS-30080 have already met the criteria below:
a. Patient has completed week 16 of Study TV50717-CNS-30080.
b. Patient weighs at least 12 kg 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 patients provides assent (in accordance to 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 at day 1) and for 30 days after last dose of TEV-50717.
|
|
| E.4 | Principal 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: (i) intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought; (ii) suicidal preparatory acts or behaviour.
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 for dystonia or chorea within the specified exclusionary windows from sreening or day 1 (whichever comes first) of this study: (a) within 30 days: tetrabenazine or valbenazine; (b) within 21 days: reserpine; (c) 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.
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: (a) 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; (b) 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 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, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V™).
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 of the Protocol 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The safety measures/endpoints are as follows:
- adverse events
- vital signs
- children’s C-SSRS (Columbia-Suicide Severity Rating Scale)
- electrocardiogram (ECG) parameters
- clinical laboratory parameters (hematology, serum chemistry, and urinalysis)
- ESRS (Extrapyramidal Symptom Rating Scale - subscales I and II)
- CBCL (Child Behavior Checklist)
- ESS (Epworth Sleepiness Scale) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 1 to each visit the assessments are performed/scale is administered until W55 (End of Study). Children C-SSRS and ESS are in addition assessed at Screening. |
|
| E.5.2 | Secondary end point(s) |
Efficacy measures/endpoints are as follows:
- MD-CRS part I total score (centrally read)
- MD-CRS part II total score (centrally read)
- MD-CRS (Movement Disorder-Childhood Rating Scale) part I total score (physician rated)
- MD-CRS (Movement Disorder-Childhood Rating Scale) part II (physician rated)
- MD-CRS Global Index (calculated from MD-CRS part I and II total scores)
- CaGI-I (Caregiver Global Impression of Improvement) (global, caregiver rated)
- CGI-I (Clinical Global Impression of Improvement) (global, physician rated)
- CGI-S (Clinical Global Impression of Severity) (global, physician rated)
- PEDI-CAT (Pediatric Evaluation Disability Inventory-Computer Adapted Test) (activities of daily living, caregiver completed, content-balanced version)
- UHDRS-TMC (centrally read)
- UHDRS-TMD (centrally read)
- UHDRS-TMS (Unified Huntington’s Disease Rating Scale-Total Motor Score) (physician rated)
- UHDRS-TMC (Unified Huntington's Disease Rating Scale-Total Maximal
Chorea) (physician rated)
-UHDRS-TMD (Unified Huntington's Disease Rating Scale-Total Maximal
Dystonia) (physician rated)
- COPM (Canadian Occupational Performance Measure) (physician rated)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 1/week 1/week 14 to each visit the scale is administered until W53-54-55 (depending on the scale). |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Israel |
| United States |
| Poland |
| Spain |
| Italy |
| Denmark |
| Russian Federation |
| Ukraine |
| United Kingdom |
|
| 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
|
The end of study is defined as the date of the week 55 follow-up telephone contact of the last participant.
Justification: Week 55 is a telephone contact for safety assessments that occurs about 2 weeks after stopping deutetrabenazine. As the patient will have already been assessed by a face-to-face visit on Week 54 after 1 week washout, there is no need for an additional face-to face visit at Week 55. |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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