| 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) |
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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 |
|
| 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 the study is to evaluate the efficacy of TEV-50717 to reduce the severity of dyskinetic involuntary movements associated with CP. |
|
| E.2.2 | Secondary objectives of the trial |
A secondary objective is to evaluate the specific efficacy parameters of TEV-50717 beyond the measure of the primary objective.
A secondary objective of the study is to evaluate the safety and tolerability of TEV-50717. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is 6 through 18 years of age (inclusive) at baseline.
2.Patient weighs at least 26 pounds (12 kg) at baseline.
3.Patient has had CP symptoms since infancy (≤2 years), and CP is judged by the investigator to be of a nonprogressive nature (Monbaliu et al 2017, Wimalasundera et al 2016).
4.Patient has a diagnosis of DCP according to the Surveillance of Cerebral Palsy in Europe criteria (Cans 2000).
5.Patient has an MD-CRD part II total score of ≥10 at the baseline visit, based on investigator scoring of chorea.
6.Patient’s symptoms are causing functional problems determined by a Clinical Global Impression of Severity (CGI-S) score of 4 or greater based on investigator scoring.
7.Choreiform is the predominant (ie, the main cause of impairment or distress) movement disorder as assessed at screening.
8.Patient is able to swallow study medication whole.
9.Patient and caregiver are willing to adhere to the medication regimen and to comply with all study procedures.
10.Patient is in good general health, as indicated by medical and psychiatric history, as well as physical and neurological examination.
11.In the investigator’s opinion, the patient and caregiver have the ability to understand the nature of the study and its procedures, and the patient is expected to complete the study as designed.
12. For a patient who is a minor, the parent(s)/legal guardian(s) provide written informed consent, and the patient provides assent (in accordance with local regulations). Adult patients provide their own written informed consent (in accordance with local regulations).
13. Caregiver provide written informed consent after being assigned the role by an adult patient, or if this role is delegated by the parent/legal guardian of a patient who is minor.
14. 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, premenarchal, and postmenarchal are given in Appendix F.
15. 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 after the last dose of IMP. Further details are included in Appendix F of the protocol. |
|
| E.4 | Principal exclusion criteria |
1.a. Patient has a predominant movement disorder other than dyskinesia.
b. Patient’s predominant motor symptoms are dystonic.
c. Patient’s predominant motor symptoms are spastic.
d. Patient has another other movement disorder that could impair the motor assessment in the MD-CRS part II.
e. Patient has choreiform movement disorder that has not been consistent throughout the life of the patient.
2.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 screening.
3.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
4.Patient has a history of a previous actual, interrupted, or aborted suicide attempt.
5.Patient has a first-degree relative who has completed suicide.
6.Patient who is currently receiving or who, in the last 4 months before screening, 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, and if they are expected to continue this stable regimen of BoNT injections for the duration of this study. The patient is expected to continue on this stable regimen of BoNT injections on a regularly scheduled interval every 3 months for the duration of this study. The injection for spasticity or dystonia must be in a muscular region that is separate from the main areas affected by choreiform movement disorder.
Note: Patients who received BoNT injections more than 4 months before screening and who do not plan to continue these injections may be considered for this study.
7.Patient has received any of the following concomitant medications for dystonia or chorea within the specified exclusionary windows of screening:
Within 3 months: depot neuroleptics
Within 30 days: tetrabenazine, deutetrabenazine, or valbenazine
Within 21 days: reserpine
Within 14 days: neuroleptics (oral), typical and atypical antipsychotics (see Appendix H), metoclopramide, levodopa, dopamine agonists, and MAOIs
Note: Use of benzodiazepines, muscle relaxants, trihexyphenidyl, baclofen (oral and intrathecal), gabapentin, and levetiracetam is allowed if the 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.
8.Patient has received treatment with stem cells, deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation for treatment of abnormal movements or CP within 6 months of the screening visit, or the patient is not in a stable clinical condition.
9.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.
10.Patient has a severe mental disability or an unstable or serious medical illness (eg, epilepsy) at screening or baseline that, in the opinion of the investigator, could jeopardize or would compromise the patient’s ability to participate in this study.
11.Patient has a QT interval corrected for heart rate using Fridericia’s formula (QTcF) value >450 msec on 12-lead ECG at screening.
12.Patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, other cardiac arrhythmias, or uncompensated heart failure.
13. Patient has evidence of diminished hepatic function, 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.
14. Patient has evidence of clinically significant renal impairment, indicated by a serum creatinine >1.5 × ULN at screening.
15. Patient has a known allergy to any of the components of the IMP.
16. Patient has participated in an investigational drug or device study and received IMP/intervention within 30 days or 5 drug half-lives of screening, whichever is longer.
17. Patient is pregnant or breastfeeding.
For additional exclusion criteria and details of the above-mentioned exclusion criteria, please refer to the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline to week 15 in the MD-CRS part II total score (movement disorder severity, centrally read) (TEV-50717 versus placebo). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints (TEV-50717 versus placebo) are the following:
•MD-CRS part I total score (general assessment, centrally read) change from baseline to week 15
•CaGI-I Scale (global, caregiver rated) at week 15
•CGI-I Scale (global, physician rated) at week 15
Other efficacy measures and endpoints (TEV-50717 versus placebo) include the following:
•MD-CRS Global Index (calculated from MD CRS parts I and II total scores)
•UHDRS-TMS
•UHDRS-TMC
•UHDRS-TMD
•PEDI-CAT (ADL, caregiver completed, content-balanced version)
•The CP module of the PedsQL (QoL, patient/caregiver)
•PGI-I Scale (global, patient/caregiver)
•CGI-S Scale (global, physician rated)
•CaGI-I response, defined as patients who are described by the caregiver as “Much Improved” or “Very Much Improved” in the CaGI-I score
•CGI-I response, defined as patients who are described as “Much Improved” or “Very Much Improved” in the CGI-I score
•CGI-S response, defined as patients who have a reduction of ≥1 point in the CGI-S score
•PGI-I response, defined as patients who are described as “Much Improved” or “Somewhat Improved” in the PGI-I score
The safety variables include adverse events (and the number of patients who withdraw from the study due to adverse events), vital signs, laboratory tests (hematology, chemistry, and urinalysis), ECG measurements, CBCL, ESRS, ESS, and the children’s C-SSRS. |
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| 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 | 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 | 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
|
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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