Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Study of TEV-50717 (Deutetrabenazine) for the Treatment of Dyskinesia in Cerebral Palsy in Children and Adolescents
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Summary
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EudraCT number |
2018-003742-17 |
Trial protocol |
GB DK PL ES IT |
Global end of trial date |
21 Jul 2022
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Results information
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Results version number |
v2(current) |
This version publication date |
27 Oct 2023
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First version publication date |
07 Feb 2023
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TV50717-CNS-30080
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products, R&D Inc.
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Sponsor organisation address |
145 Brandywine Parkway, West Chester, United States, 19380
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, USMedInfo@tevapharm.com
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, USMedInfo@tevapharm.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Nov 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Jul 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Jul 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Aug 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 8
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Country: Number of subjects enrolled |
Ukraine: 14
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Country: Number of subjects enrolled |
Russian Federation: 12
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Country: Number of subjects enrolled |
Poland: 8
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Israel: 2
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Denmark: 2
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Worldwide total number of subjects |
63
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EEA total number of subjects |
22
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
37
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Adolescents (12-17 years) |
23
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Adults (18-64 years) |
3
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants received oral tablets once daily for up to 15 weeks (7 weeks dose titration and 8 weeks maintenance). From Week 1 through Week 7, the dose of TEV-50717 was adjusted as determined by the investigator. After titration, participants continued to receive their maintenance dose over the next 8 weeks. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
63 participants with Dyskinesia in Cerebral Palsy (DCP) were randomized (41 participants in the TEV-50717 group and 22 participants in the placebo group). | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Placebo administered as oral tablets once daily for up to 15 weeks. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo
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Arm title
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TEV-50717 | ||||||||||||||||||||||||||||||
Arm description |
TEV-50717 administered as oral tablets once daily for up to 15 weeks (7 weeks dose titration and 8 weeks maintenance). From Week 1 through Week 7, the dose of TEV-50717 was adjusted according to the titrations scheme (based on body weight and CYP2D6 impairment status at baseline) to identify a dose level that optimally reduced dyskinesia (as determined by the investigator, as indicated by a reduction in the ClinRO of the assessment of the CGI-I) and was well tolerated. After titration, participants continued to receive their maintenance dose over the next 8 weeks. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Deutetrabenazine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Dosage ranging from 6 mg to 48 mg
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered as oral tablets once daily for up to 15 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEV-50717
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Reporting group description |
TEV-50717 administered as oral tablets once daily for up to 15 weeks (7 weeks dose titration and 8 weeks maintenance). From Week 1 through Week 7, the dose of TEV-50717 was adjusted according to the titrations scheme (based on body weight and CYP2D6 impairment status at baseline) to identify a dose level that optimally reduced dyskinesia (as determined by the investigator, as indicated by a reduction in the ClinRO of the assessment of the CGI-I) and was well tolerated. After titration, participants continued to receive their maintenance dose over the next 8 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo administered as oral tablets once daily for up to 15 weeks. | ||
Reporting group title |
TEV-50717
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Reporting group description |
TEV-50717 administered as oral tablets once daily for up to 15 weeks (7 weeks dose titration and 8 weeks maintenance). From Week 1 through Week 7, the dose of TEV-50717 was adjusted according to the titrations scheme (based on body weight and CYP2D6 impairment status at baseline) to identify a dose level that optimally reduced dyskinesia (as determined by the investigator, as indicated by a reduction in the ClinRO of the assessment of the CGI-I) and was well tolerated. After titration, participants continued to receive their maintenance dose over the next 8 weeks. | ||
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End point title |
Change From Baseline in the Movement Disorder-Childhood Rating Scale (MD-CRS) Part II Total Score (Movement Disorder Severity, Centrally Read) at Week 15 | ||||||||||||
End point description |
MD-CRS part II evaluates the severity of movement disorder in a scale of 0 to 4 in 7 body regions, all areas in which dyskinesia can be seen. In rating the movement disorder, 0 refers to absence of a movement disorder and 4 refers to a situation where movement disorder is present during all the tasks for the region examined and/or involves 3 or more of other regions, making completion impossible. The 7 body regions are (i) eye and periorbital region, (ii) face, (iii) tongue and perioral region, (iv) neck, (v) trunk, (vi) upper limb, and (vii) lower limb. Total score was obtained by summing the individual items scores and ranges from 0 (absent of a movement disorder) to 28 (marked/prolonged movement disorder), with higher scores indicating more movement disorder. Least square (LS) mean and standard error (SE) was calculated using a mixed-model repeated-measure (MMRM). mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Primary
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End point timeframe |
Baseline, Week 15
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Statistical analysis title |
LS mean of the change in MDCRS part II total score | ||||||||||||
Statistical analysis description |
The LS mean of the change in MDCRS part II total score from baseline to Week 15 was compared (TEV-50717 arm versus placebo) using a 1-sided test for superiority at a nominal significance level of α=0.025.
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Comparison groups |
Placebo v TEV-50717
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Number of subjects included in analysis |
61
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.335 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-1.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.49 | ||||||||||||
upper limit |
1.19 | ||||||||||||
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End point title |
Change From Baseline in the MD-CRS Part I Total Score (General Assessment, Centrally Read) at Week 15 | ||||||||||||
End point description |
The MD-CRS part I evaluates the impact of dyskinesia in cerebral palsy (DCP) on the activities of the participant and provides a general assessment of the movement disorder of motor function (7 items), oral/verbal function (3 items), self-care (3 items), and attention/alertness (2 items) on a scale of 0 (present) to 4 (absent). All items were scored by the rater in the clinic and were centrally read based on video recording. The total score was obtained by summing the individual items scores and ranges from 0 (marked/prolonged disorder) to 60 (absent of a disorder), with higher scores indicating lesser disorder. he mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Caregiver Global Impression of Improvement (CaGI-I) Scale Score (Global, Caregiver Rated) at Week 15 | ||||||||||||
End point description |
The CaGI-I is single item questionnaire to assess the caregiver’s impression of improvement in dyskinesia symptoms after initiating therapy. The scale is a caregiver-reported outcome that aims to evaluate all aspects of participants’ health and determine if there has been an overall improvement or not in dyskinesia symptoms. The caregiver selected the 1 response from the response options that gave the most accurate description of change in dyskinesia symptoms of the participant they cared for from the beginning of the study: 1=very much improved (since the initiation of treatment); 2=much improved; 3=minimally improved; 4=no change from baseline (symptoms remain essentially unchanged); 5=minimally worse; 6=much worse; 7=very much worse (since the initiation of treatment). The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Secondary
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End point timeframe |
Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Global Impression of Improvement (CGI-I) Scale Score (Global, Physician Rated) at Week 15 | ||||||||||||
End point description |
CGI-I is a clinician-reported outcome that uses a 7-point Likert scale to compare participant’s condition at the visit to the baseline condition: 1=very much improved (nearly all better; good level of functioning; minimal symptoms); 2=much improved (notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain); 3=minimally improved (slightly better with little or no clinically meaningful reduction of symptoms; represents very little change in basic clinical status, level of care, or functional capacity); 4=no change from baseline (symptoms remain unchanged); 5=minimally worse (slightly worse but may not be clinically meaningful); 6=much worse (clinically significant increase in symptoms and diminished functioning); 7=very much worse (severe exacerbation of symptoms and loss of functioning). The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Secondary
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End point timeframe |
Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Unified Huntington’s Disease Rating Scale-Total Maximal Dystonia (UHDRS-TMD) Score (Centrally Read) at Week 15 | ||||||||||||
End point description |
The UHDRS-TMD is part of the UHDRS-TMS assessment and assesses the severity of dystonia in the 5 body parts: trunk and the 4 extremities (right and left upper extremities, right and left lower extremities). Each part was rated from 0 (absent) to 4 (prolonged). The central rating was done for all participants, based on the videos collected for the central rating of MD-CRS. The TMD score was obtained by adding up each of the separate scores and ranged from 0 (absent) to 20 (marked/prolonged), with higher scores indicating the worse symptoms. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Unified Huntington’s Disease Rating Scale-Total Maximal Chorea (UHDRS-TMC) Score (Centrally Read) at Week 15 | ||||||||||||
End point description |
The UHDRS-TMC is part of the Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS) assessment and assesses the severity of chorea in the 7 body parts: face, mouth, trunk, and the 4 extremities (right and left upper extremities, right and left lower extremities). Each part was rated from 0 (absent) to 4 (prolonged). The central rating was done for all participants, based on the videos collected for the central rating of MD-CRS. The TMC score was obtained by adding up each of the separate scores and ranged from 0 (absent) to 28 (marked/prolonged), with higher scores indicating the worse symptoms. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in MD-CRS Global Index Score (Calculated From MD-CRS Parts I and II Total Scores, Centrally Read) at Week 15 | ||||||||||||
End point description |
MD-CRS Global Index consolidates the information from MD-CRS parts I and II using the method of weighted means of the 2 normalized indexes obtained from each part. Standardized/normalized score for each item of MD-CRS parts I and II with value X calculated using formula: Xst = X – Xmin divided by Xmax – Xmin, where Xmax is the maximum value, and Xmin is the minimum value for the score, or 4 and 0 respectively. Normalized index, MD-CRS parts I or II, Index I or II, calculated as the mean value of Xst. MD-CRS Global index = n1 * index 1 + n2 * index 2 divided by n1 + n2, where n1 and n2 are the numbers of items in MD-CRS parts I and II respectively. The minimum score is 0 (better) and the maximum score is 1 (worse). A higher score indicates more severe movement disorder. mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in MD-CRS Global Index Score (Calculated From MD-CRS Parts I and II Total Scores, Physician Rated) at Week 15 | ||||||||||||
End point description |
MD-CRS Global Index consolidates the information from MD-CRS parts I and II using the method of weighted means of 2 normalized indexes obtained from each part. Standardized/normalized score for each item of MD-CRS parts I and II with value X calculated using formula: Xst = X – Xmin divided by Xmax – Xmin, where Xmax is the maximum value, and Xmin is the minimum value for the score, or 4 and 0 respectively. Normalized index, MD-CRS parts I or II, Index I or II, calculated as the mean value of Xst. MD-CRS Global index = n1 * index 1 + n2 * index 2 divided by n1 + n2, where n1 and n2 are the numbers of items in MD-CRS parts I and II respectively. Minimum score is 0 (better) and the maximum score is 1 (worse). A higher score indicates more severe movement disorder. mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in the MD-CRS Part I Total Score (General Assessment, Physician Rated) at Week 15 | ||||||||||||
End point description |
The MD-CRS part I evaluates the impact of DCP on the activities of the participant and provides a general assessment of the movement disorder of motor function (7 items), oral/verbal function (3 items), self-care (3 items), and attention/alertness (2 items) on a scale of 0 (present) to 4 (absent). All items were scored by the investigational center physician. The total score was obtained by summing the individual items scores and ranges from 0 (marked/prolonged movement disorder) to 60 (absent of a movement disorder), with higher scores indicating lesser movement disorder. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in the MD-CRS Part II Total Score (General Assessment, Physician Rated) at Week 15 | ||||||||||||
End point description |
MD-CRS part II evaluates the severity of movement disorder in a scale of 0 to 4 in 7 body regions, all areas in which dyskinesia can be seen. In rating the movement disorder, 0 refers to absence of a movement disorder and 4 refers to a situation where movement disorder is present during all of the tasks for the region examined and/or involves 3 or more of the other regions, making completion impossible. The 7 body regions are (i) eye and periorbital region, (ii) face, (iii) tongue and perioral region, (iv) neck, (v) trunk, (vi) upper limb, and (vii) lower limb. Total score was obtained by summing the individual items scores and ranges from 0 (absent of a movement disorder) to 28 (marked/prolonged movement disorder), with higher scores indicating more movement disorder. mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in UHDRS-TMS Score (Physician Rated) at Week 15 | ||||||||||||
End point description |
The UHDRS comprises a broad assessment of features associated with Huntington’s disease (HD). It is a research tool that has been developed to provide a uniform assessment of the clinical features and course of HD. The Total Motor Score assessment of the UHDRS (UHDRS-TMS) comprises 15 items and assesses eye movements, speech, alternating hand movements, dystonia, chorea, and gait. The UHDRS-TMS was calculated as the sum of the 31 motor assessments; each of which ranged between 0 (absent) to 4 (worst). All items were scored by the investigational center physician. TMS score is a sum of individual scores ranging from 0 (normal motor function) to 124 (severely impaired motor function), with lower scores indicating better motor function. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in UHDRS-TMC Score (Physician Rated) at Week 15 | ||||||||||||
End point description |
The UHDRS-TMC is part of the UHDRS-TMS assessment and assesses the severity of chorea in the 7 body parts: face, mouth, trunk, and the 4 extremities (right and left upper extremities, right and left lower extremities). Each part was rated from 0 (absent) to 4 (prolonged). All items were scored by the investigational center physician. The TMC score was obtained by adding up each of the separate scores and ranged from 0 (absent) to 28 (marked/prolonged), with higher scores indicating the worse symptoms. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in UHDRS-TMD Score (Physician Rated) at Week 15 | ||||||||||||
End point description |
The UHDRS-TMD is part of the UHDRS-TMS assessment and assesses the severity of dystonia in the 5 body parts: trunk and the 4 extremities (right and left upper extremities, right and left lower extremities). Each part was rated from 0 (absent) to 4 (prolonged). All items were scored by the investigational center physician. The TMD score was obtained by adding up each of the separate scores and ranged from 0 (absent) to 20 (marked/prolonged), with higher scores indicating the worse symptoms. The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Pediatric Evaluation Disability Inventory-Computer Adapted Test (PEDI-CAT) Score (Activities of Daily Living [ADL], Caregiver Completed, Content-Balanced Version) at Week 15 | ||||||||||||
End point description |
PEDI-CAT measures function in 4 domains: Daily Activities; Mobility; Social/Cognitive, and Responsibility. A total of approximately 30 items were administered. PEDI-CAT software utilizes Item Response Theory statistical models to estimate a child’s abilities from a minimal number of the most relevant items or from a set number of items within each domain. The CAT program then displays the results: normative standard scores, scaled scores and SE. Scaled score is reported in this endpoint. Scaled scores are based on an estimate of the placement of an individual child along the hierarchical scale within each domain. PEDI-CAT scaled scores are currently on a 20 (lesser improvement) to 80 (more improvement) scale metric. Higher scores indicate greater improvement in functional skills. mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Clinical Global Impression of Severity (CGI-S) Scale Score (Global, Physician Rated) at Week 15 | ||||||||||||
End point description |
CGI-S uses a 7-point Likert scale to assess dyskinesia severity as follows: 1=normal (not at all ill, symptoms of disorder not present past 7 days); 2=borderline (subtle or suspected pathology); 3=mild (clearly established symptoms with minimal, if any, distress or difficulty in social and/or occupational function); 4=moderate (overt symptoms causing noticeable, but modest, functional impairment or distress; symptom level may warrant medication); 5=marked (intrusive symptoms that distinctly impair social/occupational function or cause intrusive levels of distress); 6=severe (disruptive symptoms, behavior and function are frequently influenced by symptoms, may require assistance from others); 7=extreme (symptoms drastically interferes in many life functions; may be hospitalized). mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Patient Global Impression of Improvement (PGI-I) Scale Score (Global, Participant/Caregiver) at Week 15 | ||||||||||||
End point description |
The PGI-I is single item questionnaire to assess the participant’s impression of improvement in dyskinesia symptoms after initiating therapy. The scale is a participant-reported outcome that aims to evaluate all aspects of participants’ health and determine if there has been an overall improvement or not in dyskinesia symptoms. The participant selected the 1 response from the visual response options (“emojis”) that gave the most accurate description of his/her state of health and overall status: 1=much improved (since the initiation of treatment); 2=somewhat improved; 3=no change; 4=somewhat worse; 5=much worse (since the initiation of treatment). The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline in the CP Module of the Pediatric Quality of Life Inventory (PedsQL) Total Score (Quality of Life [QoL], Participant/Caregiver) at Week 15 | ||||||||||||||||||
End point description |
The 35-item PedsQL 3.0 CP module encompasses 7 scales: Daily Activities (9 items); School Activities (4 items); Movement and Balance (5 items); Pain and Hurt (4 items); Fatigue (4 items); Eating Activities (5 items); and Speech and Communication (4 items). A 5-point response scale is utilized across child self-report and parent proxy report: 0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem. Items are reverse scored and linearly transformed to a 0–100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better quality of life. Total score = sum of 35 items divided by the number of items answered. Change from baseline scores can range from -100 to 100. mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Overall number of participants analyzed = participants evaluable for this endpoint. ‘n' = participants evaluable for specified category.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||
End point title |
Number of Participants with CGI-I Response | |||||||||
End point description |
CGI-I response was defined as participants who were described as “Much Improved” or “Very Much Improved” in the CGI-I score. CGI-I uses a 7-point Likert scale to compare participant’s condition at the visit to the baseline condition as follows: 1=very much improved (nearly all better; good level of functioning); 2=much improved (notably better with significant reduction of symptoms; increase in the level of functioning); 3=minimally improved (slightly better with little or no clinically meaningful reduction of symptoms); 4=no change from baseline (symptoms remain unchanged); 5=minimally worse (slightly worse but may not be clinically meaningful); 6=much worse (clinically significant increase in symptoms and diminished functioning); 7=very much worse (severe exacerbation of symptoms). mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Week 15
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Participants with CGI-S Response | |||||||||
End point description |
CGI-S response was defined as participants who had a reduction of ≥1 point in the CGI-S score. CGI-S uses a 7-point Likert scale to assess dyskinesia severity as follows: 1=normal (not at all ill, symptoms of disorder not present past 7 days); 2=borderline (subtle or suspected pathology); 3=mild (clearly established symptoms with minimal, if any, distress or difficulty in social and/or occupational function); 4=moderate (overt symptoms causing noticeable, but modest, functional impairment or distress); 5=marked (intrusive symptoms that distinctly impair social/occupational function or cause intrusive levels of distress); 6=severe (disruptive symptoms, behavior and function are frequently influenced by symptoms); 7=extreme (symptoms drastically interferes in many life functions). mITT analysis set: all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Week 15
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Participants with PGI-I Response | |||||||||
End point description |
PGI-I response was defined as participants who were described as “Much Improved” or “Somewhat Improved” in the PGI-I score. PGI-I is single item questionnaire to assess the participant’s impression of improvement in dyskinesia symptoms after initiating therapy. The scale is a participant-reported outcome that aims to evaluate all aspects of participants’ health and determine if there has been an overall improvement or not in dyskinesia symptoms. The participant selected the 1 response from the visual response options (“emojis”) that gave the most accurate description of his/her state of health and overall status: 1=much improved (since the initiation of treatment); 2=somewhat improved; 3=no change; 4=somewhat worse; 5=much worse (since the initiation of treatment). The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Week 15
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Participants With Adverse Events (AEs) | |||||||||
End point description |
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. Safety analysis set included all randomized participants who received at least 1 dose of study drug.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Baseline up to Week 17
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||
End point title |
Number of Participants with CaGI-I Response | |||||||||
End point description |
CaGI-I response was defined as participants who were described by the caregiver as “Much Improved” or “Very Much Improved” in the CaGI-I score. The scale is a caregiver-reported outcome that aims to evaluate all aspects of participants’ health and determine if there has been an overall improvement or not in dyskinesia symptoms. The caregiver selected 1 response from the response options that gave the most accurate description of change in dyskinesia symptoms of the participant they cared for from the beginning of study: 1=very much improved (since the initiation of treatment); 2=much improved; 3=minimally improved; 4=no change from baseline (symptoms remain essentially unchanged); 5=minimally worse; 6=much worse; 7=very much worse (since the initiation of treatment). The mITT analysis set included all randomized participants with at least 1 postbaseline centrally read MD-CRS part II assessment. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Week 15
|
|||||||||
|
||||||||||
| No statistical analyses for this end point | ||||||||||
|
||||||||||||||||||||||
End point title |
Number of Participants With Shift From Baseline to Week 15 in Electrocardiogram (ECG) Findings | |||||||||||||||||||||
End point description |
ECG parameters included: Heart rate, PR interval, QRS interval, RR interval, QT interval, and QT interval corrected using the Fridericia formula (QTcF). Shifts represented as Baseline - Week 15 value (last observed postbaseline value). Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline to Week 15
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Extrapyramidal Symptom Rating Scale (ESRS) Subscale I Total Score at Week 15 | ||||||||||||
End point description |
The ESRS subscale I is a 7-item subjective questionnaire to evaluate parkinsonism, akathisia, dystonia and dyskinesia. The ESRS I is scored on 4-point scale (0=absent, 1=Mild, 2=Moderate, 3=Severe) for each item. The evaluation takes into account the verbal report of the participant on 1) the frequency and duration of the symptom during the day, 2) the number of days the symptom was present during the last week, and 3) the subjective evaluation of the intensity of the symptom by the participant. Total score was the sum of the 7 items which ranges from 0 (absent) to 28 (severe). Higher scores indicate greater severity of disorder. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Child Behavior Checklist (CBCL) Syndrome Total Score at Week 15 | ||||||||||||
End point description |
The full CBCL has two parts, a Competence Scale (Parts I to VII) and a Syndrome Scale (behavioral items). The Syndrome Scale comprises 113 questions related to problem behaviors. For each item, the responses are recorded on a scale: 0 = Not True; 1 = Somewhat or Sometimes True; 2 = Very True or Often True. The problem behaviors are scored on the following 8 empirically based syndromes: anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior. CBCL syndrome total score ranged from 0 (no problem) to 226 (lesser problem), was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Child Behavior Checklist (CBCL) Competence Total Score at Week 15 | ||||||||||||
End point description |
The full CBCL has two parts, a Competence Scale (Parts I to VII) and a Syndrome Scale (behavioral items). The Competence Scale (Parts I to VII) assesses various activities (for example, sports, hobbies, games, organizations, clubs, teams, groups, jobs, and chores), interpersonal relationships, and academic performance. The checklists having 120 questions consist of a number of statements about the child's behavior and responses which are recorded on a scale: 0 = Not True; 1 = Somewhat or Sometimes True; 2 = Very True or Often True. CBCL competence total score ranged from 0 (no problem) to 240 (lesser problem), was calculated by adding individual score of each domain. Higher scores indicate greater problems in child behavior. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Extrapyramidal Symptom Rating Scale (ESRS) Subscale II Total Score at Week 15 | ||||||||||||
End point description |
The ESRS subscale II is a 17-item questionnaire to evaluate parkinsonism and akathisia. The ESRS II consists of the following parts: tremor (0 [none]–48 [severe]), gait and posture (0 [none]–6 [severe]), postural stability (0 [none]-6 [severe]), rigidity (0 [none]–24 [severe]), expressive automatic movements (0 [none]–6 [severe]), bradykinesia (0 [none]-6 [severe]), and akathisia (0 [none]–6 [severe]). Total score was the sum of the 17 items which from ranges from 0 (absent) to 102 (severe). Higher scores indicate greater severity of disorder. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
End point title |
Number of Participants With Columbia-Suicide Severity Rating Scale (C-SSRS) Outcomes (Suicidal Ideation and Suicidal Behavior) at Week 15 | |||||||||||||||
End point description |
Participants were placed into categories for suicidal ideation and suicidal behavior based on their responses to various questions. For suicidal ideation, following categories were used: None; Wish to be dead; Non-specific active suicidal thoughts; Any methods (not plan) without intent to act; Some intent to act, without specific plan; and Specific plan and intent. For suicidal behavior, following categories were used: None; Preparatory acts or behavior; Aborted attempt; Interrupted attempt; Actual attempt; and Suicide. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Week 15
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Week 15 | ||||||||||||
End point description |
The ESS is a self-administered questionnaire composed of 8 questions that provide a measure of a participant’s general level of daytime sleepiness. The ESS is composed of 8 items. The responders were asked to rate their chances of falling asleep while engaged at 8 different activities, on a 4-point scale: 0 = would never fall asleep; 1=slight chance of falling asleep; 2=moderate chance of falling asleep; 3=high chance of falling asleep. Total score was calculated as the sum of 8 item scores which ranges from 0 (never) to 24 (high chance of falling asleep). Higher scores indicate high chances of falling asleep. Safety analysis set included all randomized participants who received at least 1 dose of study drug. Here, overall number of participants analyzed = participants evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 15
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline up to Week 17
|
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
|
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|
Reporting groups
|
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Reporting group title |
TEV-50717
|
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Reporting group description |
TEV-50717 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
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Reporting group description |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
20 Dec 2018 |
Updates to scales |
||
17 Oct 2019 |
Clarify inclusion/exclusion criteria |
||
08 Jun 2020 |
COVID-19 updates |
||
09 Mar 2021 |
Clarify inclusion/exclusion criteria |
||
24 Mar 2022 |
Adjust sample size |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
