Clinical Trial Results:
A Multicenter, Open-label, Pilot Study of TAK-935 (OV935) in Patients With 15Q Duplication Syndrome or CDKL5 Deficiency Disorder (ARCADE Study)
Summary
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EudraCT number |
2022-001315-44 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
31 Jul 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jul 2022
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First version publication date |
15 Jul 2022
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Other versions |
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 |
TAK-935-18-002 (OV935)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03694275 | ||
WHO universal trial number (UTN) |
U1111-1219-5787 | ||
Sponsors
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Sponsor organisation name |
Takeda
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Sponsor organisation address |
95 Hayden Avenue, Lexington, MA, United States, 02421
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Public contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, TrialDisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002572-PIP01-19 | ||
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 |
31 Jul 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jul 2020
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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 main objective of the trial was to investigate the effect of TAK-935 (soticlestat) on the frequency of motor seizures for participants with 15q duplication syndrome (Dup15q) or cyclin-dependent kinase-like 5 deficiency disorder (CDD) during the Maintenance Period.
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Protection of trial subjects |
Study participants were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Sep 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 20
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Worldwide total number of subjects |
20
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EEA total number of subjects |
0
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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) |
9
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Adolescents (12-17 years) |
9
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Adults (18-64 years) |
2
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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 took part in the study at 8 investigative sites in the United States from 10 September 2018 to 31 July 2020. | ||||||||||||||||||
Pre-assignment
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Screening details |
Participants with a diagnosis of Dup15q or CDD were enroled in 2 cohorts to receive treatment with TAK-935 for up to 20 weeks Treatment Period (8-week Dose Optimisation Period and 12-week Maintenance Period). | ||||||||||||||||||
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 |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Soticlestat Dup15q | ||||||||||||||||||
Arm description |
Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup15q weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Soticlestat
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Investigational medicinal product code |
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Other name |
TAK-935
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
TAK-935 tablets
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Arm title
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Soticlestat CDD | ||||||||||||||||||
Arm description |
Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Soticlestat
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Investigational medicinal product code |
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Other name |
TAK-935
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
TAK-935 tablets
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Baseline characteristics reporting groups
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Reporting group title |
Soticlestat Dup15q
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Reporting group description |
Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup15q weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Soticlestat CDD
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Reporting group description |
Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Soticlestat Dup15q
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Reporting group description |
Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup15q weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||
Reporting group title |
Soticlestat CDD
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Reporting group description |
Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. |
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End point title |
Percent Change from Baseline in Motor Seizure Frequency per 28 Days During the Maintenance Period [1] | ||||||||||||
End point description |
Seizure frequency per 28 days was defined as total number of Seizures reported during the period divided by number of days with no missing seizure count during the period multiplied by 28. Percent Change from Baseline was defined as (frequency of seizures per 28 days during Maintenance Period – frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100. Positive percent change from Baseline indicates seizure increase and negative percent change from Baseline indicates seizure decrease. Modified Intent-to-Treat (mITT) Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are the number of participants with data available for analyses.
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End point type |
Primary
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End point timeframe |
Maintenance Period: Weeks 9 to 20
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics was planned to be reported for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Percent Change from Baseline in Motor Seizure Frequency per 28 Days During the Treatment Period | ||||||||||||
End point description |
Seizure frequency per 28 days was defined as total number of Seizures reported during the period divided by number of days with no missing seizure count during the period multiplied by 28. Percent Change from Baseline was defined as (frequency of seizures per 28 days during the treatment period – frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100. Positive percent change from Baseline indicates seizure increase and negative percent change from Baseline indicates seizure decrease. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period.
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End point type |
Secondary
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End point timeframe |
Treatment Period: Weeks 0 to 20
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No statistical analyses for this end point |
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End point title |
Percentage of Participants Considered as Treatment Responders During the Maintenance Period | |||||||||||||||||||||||||||
End point description |
Responders were defined as having over 50% motor seizure reduction compared to Baseline. Percent reduction from Baseline (%) was defined as [(Maintenance Period motor Seizure Frequency -Baseline Period motor Seizure Frequency) divided by Baseline motor Seizure Frequency] multiplied by 100. Data is reported as reduction of 25%, 50%, 75% and 100% or more in motor seizures from Baseline. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Maintenance Period: Weeks 9 to 20
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No statistical analyses for this end point |
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End point title |
Percent Change from Baseline in Frequency of Motor Seizures Longer Than 5 Minutes in Participants with CDD [2] | ||||||||
End point description |
Seizure frequency was defined as total number of Seizures reported during the period divided by number of days with no missing seizure count during the period. Percent Change from Baseline was defined as (frequency of seizures during Treatment period –frequency of seizures at Baseline) divided by frequency of seizures at Baseline multiplied by 100. Positive percent change from Baseline indicates seizure increase and negative percent change from Baseline indicates seizure decrease. The data is reported only for CDD participants. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are all participants whose analyses were conducted using observed values and no imputation was done for missing data.
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End point type |
Secondary
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End point timeframe |
Treatment Period: Weeks 0 to 20
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive statistics was planned to be reported for this endpoint. |
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No statistical analyses for this end point |
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End point title |
Proportion of Motor Seizure-free Days in Participants During the Maintenance Period | ||||||||||||
End point description |
Seizure-free days was defined as number of days with zero motor seizure during the period the Maintenance Period divided by number of days participant was in the Maintenance Period. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Maintenance Period: Weeks 9 to 20
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Clinician's Global Impression of Severity (CGI-S) Responses of Investigator | ||||||||||||||||||
End point description |
The CGI-S focuses on clinician's observations of the participant’s cognitive, functional, and behavioral performance since the beginning of the study. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses where, 1= normal, not at all ill, 2= borderline mentally ill, 3= mildly ill, 4= moderately ill, 5= markedly ill, 6= severely ill and 7=amongst the most extremely ill participants. Negative change from Baseline indicates improvement. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. 'n'= number analysed is the number of participants with data available for analyses at the given timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 20
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Clinical Global Impression of Change (CGI-C) Responses as per the Investigator Reported Impression | |||||||||||||||||||||||||||
End point description |
CGI-C treatment response ratings should take account of both therapeutic efficacy and treatment-related AEs. Each component of the CGI is rated separately; the instrument does not yield a global score. The CGI-C is rated on a 5-point scale, where, 0 = marked improvement and no side-effects, 1 = marked improvement and minimal side-effects, 2 = no change, 3 = minimal improvement and marked side-effects and 4 = unchanged or worse and side effects outweigh the therapeutic effect. Lower scores indicated improvement. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Week 20
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Care Clinical Global Impression of Change (CGI-C) Responses of Parent/Family | |||||||||||||||||||||||||||||||||
End point description |
CGI-C treatment response ratings should take account of both therapeutic efficacy and treatment-related AEs. Each component of the CGI is rated separately; the instrument does not yield a global score. The CGI-C is rated on a 7-point scale where, 1 = very much improved, 2 = much improved, 3 = slightly improved, 4= no change, 5= slightly worse, 6= much worse and 7= very much worse and marked side-effects. Lower scores indicated improvement. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed are the number of participants with data available for analyses.
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End point type |
Secondary
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End point timeframe |
Week 20
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No statistical analyses for this end point |
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End point title |
Change from Baseline of Plasma 24S-hydroxycholesterol (24HC) Levels | ||||||||||||||||||
End point description |
mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period. Overall subjects analysed is the number of participants with data available for analyses. 'n'=number analysed is the number of participants with data available for analyses at the given timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 20
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No statistical analyses for this end point |
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End point title |
Change from Baseline in Seizure Frequency in Participants Treated with TAK-935 as an Adjunctive Therapy | ||||||||||||||||||
End point description |
Seizure Frequency per 28 days was defined as total number of Seizures reported during the period divided by number of days with no missing seizure during the
period seizures were assessed multiplied by 28. Positive change from Baseline indicates seizure increase and negative change from Baseline indicates seizure decrease. mITT Analysis Set included all participants who have received at least 1 dose of study drug and have been assessed for at least 1 day in the Treatment Period.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 20
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From the first dose to 30 days post-last dose of study treatment (Up to 24 weeks)
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Adverse event reporting additional description |
At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
Soticlestat Dup15q
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Reporting group description |
Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup15q weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Soticlestat CDD
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Reporting group description |
Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing <60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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31 Jan 2019 |
The changes implemented based on Amendment 1 were: -Revised study design. -Updated name of titration period to Dose Optimization Period due to change in the length of the treatment period. -Revised the primary and secondary objectives/endpoints. -Added secondary objectives/endpoints. -Revised exploratory objectives. -One exploratory objective/endpoint was added. -Study visits were changed to reflect the revised study design. -Timepoints for collection of samples for pharmacokinetic analysis were clarified. -The age for participation was increased to 35 years. -Route of administration was expanded to include G-tube/PEG tube/J-tube at all sites except those in China. -Perampanel was added as a prohibited medication. -The use of traditional Chinese medicines was clarified. -Clarified and revised inclusion and exclusion criteria. -An optional severity assessment for cyclin-dependent kinase-like 5 (CDKL5) deficiency syndrome was added. -Handling of missed doses was clarified. -Requirement was added to discontinue a patient if he/she exhibits signs of suicidal ideation. -Cytochrome P450 (CYP) 46A1 mutation analysis was removed and replaced with optional blood sample storage for exploratory research. |
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31 Jan 2019 |
-Two additional timepoints were added for collection of plasma 24HC. -Amount of blood samples was changed to reflect additional visits. -Change in dose during the study was clarified. -Weight-based dosing was updated to reflect the administration of 100 mg tablets. -Use of an electroencephalogram (EEG) charter was removed. -An additional electrocardiogram (ECG) assessment was added. -Clarification was added for rolling over from the antecedent trial to the open-label extension. -Oxcarbazepine was added to the assay for concomitant antiepileptic drugs (AEDs). -An analysis population (Efficacy Analysis Population) was added. -Statistical analyses were revised. -Confidentiality of participant information was clarified. -The length of time participants must avoid pregnancy, donation of ova, and sperm donation after the last dose of study drug was clarified and instructions were included if urine cannot be collected at Visit 2. -End of study definition was added. -Description of the dosing card was added. |
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20 Nov 2019 |
The changes implemented based on Amendment 2 were: -Modified inclusion/exclusion criteria to increase the age for participation in the trial to 55 years old and expand the inclusion criteria to allow participants with a diagnosis of interstitial Dup15q. -Corrected an inadvertent error in the way the secondary endpoints CGI-S, CGI-C, and Care-CGI-C were defined, from “percent change” to “change”. -Added that Jejunostomy tube (J-tube) may be considered based on approval from Medical Monitor and Sponsor. -Allowed ad hoc analyses throughout the trial. -Added an additional subgroup in the treatment responder analysis (≥75% reduction in motor seizure frequency). -Made corrections in schedule of assessment table including, 1.Separated out CGI-S from CGI-C; 2.Removed collection seizure diary checks on Day 8, Day 22, Day 57, Day 113. -Removed the exploratory endpoint of EEG parameters in participants with Dup15q. -Removed the optional blood sample for research analysis. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |