E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Dyskinesia in cerebral palsy (DCP) |
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E.1.1.1 | Medical condition in easily understood language |
Dyskinesia in cerebral palsy (DCP) |
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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 | 20.1 |
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 |
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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. |
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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. |
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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:
1. Patient is of an eligible age from parent Study TV50717-CNS-30080.
2. Patient weighs at least 12 kg on day 1 of this study.
3. Patient is able to swallow TEV-50717 tablet whole.
4. Patient and caregiver/adult are willing to adhere to TEV-50717 regimen and comply with all study procedures.
5. Patient is in good general health, as indicated by medical and psychiatric history and physical and neurological examination.
6. 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.
7. Patient and caregiver/adult provide written informed consent/assent, depending on the child’s age, as appropriate, according to local regulations.
8. 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.
9. 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.
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E.4 | Principal exclusion criteria |
Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
1. Patient has a predominant movement disorder other than dyskinesia.
2. Patient’s predominant motor symptoms are dystonic.
3. Patient’s predominant motor symptoms are spastic.
4. Patient has another movement disorder that could impair the motor assessment in the MD-CRS part II.
5. Patient has clinically significant depression at day 1 of this study. Note: Patients receiving antidepressant therapy may be enrolled if on a stable dose.
6. Patient has a history of suicidal intent or related behaviors: (a) previous intent to act on suicidal ideation with a specific plan, irrespective of level of ambivalence, at the time of suicidal thought; (b) previous suicidal preparatory acts or behaviour.
7. Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
8. Patient has a first-degree relative who has completed suicide.
9. Patient who is currently receiving or who has received botulinum neurotoxin (BoNT) in an investigational clinical trial.
Note: Patients may be included in the study if they have at least 2 treatments of Food and Drug Administration-approved BoNT at a regular interval (eg, every 3 to 4 months), in reasonably stable dosages and locations (subject to investigator’s judgement) to treat lower limb spasticity or dystonia.
10. Patient has received any of the following concomitant medications for dystonia or chorea within the specified exclusionary windows of day 1 of this study: (a) within 3 months: depot neuroleptics; (b) within 30 days: tetrabenazine or valbenazine; (c) within 21 days: reserpine; (d) within 14 days: neuroleptics (oral), typical and atypical antipsychotics, metoclopramide, levodopa, dopamine agonists, and monoamine oxidase inhibitors.
11. Patient has received treatment with stem cells, deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for treatment of abnormal movements or CP, or the patient is not in a stable clinical condition.
12. Patient has recent surgical procedure 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.
13. 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.
14. Patient has a QT interval (QTc) corrected for heart rate using Fridericia’s formula (QTcF) value >450 msec on 12-lead ECG at day 1 of this study.
15. Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.
16. 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 day 1 of this study; (b) alkaline phosphatase (ALP) or total bilirubin (Tbil) >2×ULN at day 1 of this study. 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.
17. Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5×ULN at day 1 of this study.
18. Patient has a known allergy to any of the components of TEV-50717.
19. 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.
20. Patient is pregnant or breastfeeding.
21. 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™).
22. 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) |
Safety measures/endpoints:
- Incidence of adverse events
- Observed values and changes in vital signs from day 1 to each visit in which vital signs are assessed
- Observed values and changes in children’s C-SSRS (Columbia-Suicide Severity Rating Scale) from day 1 to each visit in which the scale is administered
- Observed values in electrocardiogram (ECG) parameters and shifts for clinically significant abnormal findings from day 1 to each visit in which the ECG test is performed
- Observed values and changes in clinical laboratory parameters (hematology, serum chemistry and urinalysis) from day 1 to each visit in which the laboratory parameters are assessed
- Observed values and changes in ESRS (Extrapyramidal Symptom Rating Scale - subscales I and II) from day 1 to each visit in which the scale is administered
- Observed values and changes in CBCL (Child Behavior Checklist) from day 1 to each visit in which the scale is administered
- Observed values and changes in ESS (Epworth Sleepiness Scale) from day 1 to each visit in which the scale is administered. |
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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). |
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E.5.2 | Secondary end point(s) |
Efficacy measures/endpoints:
- Change in the total score of MD-CRS (Movement Disorder-Childhood Rating Scale) part I from day 1 to each visit in which the scale is administered
- Change in the total score of MD-CRS (Movement Disorder-Childhood Rating Scale) part II from day 1 to each visit in which the scale is administered
- Change in the MD-CRS Global Index (calculated from MD-CRS part I and II total scores) from day 1 to each visit in which MD-CRS part I and II are administered
- Change in the Ca-GI-I (Caregiver Global Impression of Improvement) score from week 14 to each visit in which the scale is administered
- Change in the CGI-I (Clinical Global Impression of Improvement) score from week 1 to each visit in which the scale is administered
- Change in the CGI-S (Clinical Global Impression of Severity) score from day 1 to each visit in which the scale is administered
- Change in the PEDI-CAT (Pediatric Evaluation Disability Inventory-Computer Adapted Test) score from day 1 to each visit in which the scale is administered
- Change in the UHDRS-TMS (Unified Huntington’s Disease Rating Scale-Total Motor Score) score from day 1 to each visit in which the scale is administered
- Change in the COPM (Canadian Occupational Performance Measure) score from day 1 to each visit in which the scale is administered
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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). |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Belgium |
Canada |
Denmark |
Israel |
Italy |
Poland |
Russian Federation |
Spain |
Ukraine |
United Kingdom |
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 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. |
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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 | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |