Clinical Trial Results:
An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome
Summary
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EudraCT number |
2016-002804-14 |
Trial protocol |
GB BE DE IT DK ES FR |
Global end of trial date |
27 Jan 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Aug 2023
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First version publication date |
12 Aug 2023
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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 |
ZX008-1503
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02823145 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Zogenix International Limited (a wholly owned subsidiary of Zogenix, Inc.)
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Sponsor organisation address |
5959 Horton Street, Emeryville, United States, CA 94608
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Public contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Scientific contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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-001990-PIP01-16 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Apr 2023
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Jan 2023
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Jan 2023
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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 |
To assess the long-term safety and tolerability of ZX008
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Protection of trial subjects |
During the conduct of the study all participants were closely monitored.
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Background therapy |
Background therapy as permitted in the protocol. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
08 Jun 2016
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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 Kingdom: 27
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Country: Number of subjects enrolled |
United States: 145
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Country: Number of subjects enrolled |
Australia: 15
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Country: Number of subjects enrolled |
Belgium: 9
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Country: Number of subjects enrolled |
Canada: 14
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Country: Number of subjects enrolled |
Denmark: 10
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Country: Number of subjects enrolled |
France: 35
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Country: Number of subjects enrolled |
Germany: 39
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Country: Number of subjects enrolled |
Italy: 29
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Country: Number of subjects enrolled |
Japan: 13
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Country: Number of subjects enrolled |
Netherlands: 10
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Country: Number of subjects enrolled |
Spain: 29
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Worldwide total number of subjects |
375
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EEA total number of subjects |
161
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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) |
233
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Adolescents (12-17 years) |
100
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Adults (18-64 years) |
42
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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 |
The study started to enroll participants in Jul 2016 and concluded in Jan 2023. Participants who completed 14 weeks treatment in any of the core studies ZX008-1501/ZX008-1502 (NCT02682927), or ZX008-1504 (NCT02926898) Cohort 2, or completed ZX008-1504 Cohort 1 study, and de novo participants were eligible to participate in this study. | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The Participant Flow refers to the Safety (SAF) Population. | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Enrollment
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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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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Not Treated | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participant (de novo) signed the informed consent form (ICF) but never received any study medication during the study. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Any ZX008 Open Label Dose | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fenfluramine hydrochloride
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Investigational medicinal product code |
ZX008
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received ZX008 0.2 mg/kg/day to maximum of 30 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 42 months.
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Period 2
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Period 2 title |
Treatment
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Is this the baseline period? |
Yes [1] | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||
Arms
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Arm title
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Any ZX008 Open Label Dose | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fenfluramine hydrochloride
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Investigational medicinal product code |
ZX008
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Other name |
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Participants received ZX008 0.2 mg/kg/day to maximum of 30 mg/kg/day as an oral solution, bid, in equally divided doses with food for up to approximately 42 months.
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Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: As pre-specified in the SAP, participant Demographics and Baseline Characteristics were summarized for the safety population. In Period 1, no participant received study medication therefore, Period 2 is considered as Baseline Period. |
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Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 1 participant enrolled but discontinued the study without receiving study medication and Demographics were planned for participants who received at least one dose of ZX008 during OLE. |
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Baseline characteristics reporting groups
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Reporting group title |
Any ZX008 Open Label Dose
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Reporting group description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Not Treated
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Reporting group description |
Participant (de novo) signed the informed consent form (ICF) but never received any study medication during the study. | ||
Reporting group title |
Any ZX008 Open Label Dose
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Reporting group description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | ||
Reporting group title |
Any ZX008 Open Label Dose
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Reporting group description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. |
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End point title |
Percentage of participants with treatment-emergent adverse events (TEAEs) leading to withdrawal from investigational medicinal product (IMP) during the OLE Treatment Period [1] | ||||||||
End point description |
A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
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End point type |
Primary
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End point timeframe |
From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
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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: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with treatment-emergent adverse events (TEAEs) during the Open-label extension (OLE) Treatment Period [2] | ||||||||
End point description |
Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
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End point type |
Primary
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End point timeframe |
From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
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Notes [2] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with Serious treatment-emergent adverse events (TEAEs) during the OLE Treatment Period [3] | ||||||||
End point description |
Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion. Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
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End point type |
Primary
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End point timeframe |
From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
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Notes [3] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Convulsive Seizure Frequency (CSF) per 28 days during the OLE Treatment Period (to Month 36) | ||||||||||||||||||||||||||||||||||||
End point description |
Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where,i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, 'n' signifies participants who were evaluable at specified time points.
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End point type |
Secondary
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End point timeframe |
At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36
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No statistical analyses for this end point |
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End point title |
Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period | ||||||||
End point description |
Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo subjects (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. Modified Intent-to-Treat (mITT) population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
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End point type |
Secondary
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End point timeframe |
From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
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No statistical analyses for this end point |
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End point title |
Change From Baseline (Core) in Convulsive Seizure Frequency per 28 days from Month 2 to EOS (Month 42) in the OLE Treatment Period | ||||||||
End point description |
Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment.
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End point type |
Secondary
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End point timeframe |
From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
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No statistical analyses for this end point |
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End point title |
Convulsive Seizure Frequency (CSF) by Mean Daily Dose during the overall OLE Treatment Period | ||||||||||||||
End point description |
Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to <0.4 mg/kg), medium (0.4 to <0.6 mg/kg), and high dose (>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, 'n' represents the number of participants categorized by mean daily dose.
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End point type |
Secondary
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End point timeframe |
From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
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No statistical analyses for this end point |
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End point title |
Percentage of participants With Changes in antiepileptic drug (AED) medications during first 6 months of OLE Treatment Period | ||||||||||||||||||||
End point description |
Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported. mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
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End point type |
Secondary
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End point timeframe |
At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period
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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 Day 1 up to 42 months
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Adverse event reporting additional description |
A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. The Safety (SAF) population was the set of all enrolled subjects who received at least one dose of ZX008 during the OLE. As pre-specified in the SAP, safety analyses were performed on the SAF Population.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Any ZX008 Open Label Dose
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Reporting group description |
Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 May 2016 |
Amendment 1.2-Important clarifications and changes were made to the protocol and included the following:
• Addition of Study 1504 as a core study contributing subjects to this study, including updates/additions as appropriate in exploratory objectives, planned number of subjects/study centers, inclusion/exclusion criteria, study design, treatment
administration, prohibited concomitant medication, study visits, assessments specific to Study 1504 subjects only, statistical methods, etc. • Clarified the use of concomitant AED treatments
• Clarified the dose adjustment parameters in the first month of the study • Updated risk-benefit for the study
• Updated prohibited medication/food section to include the prohibition of alcohol • Clarified how ongoing AEs from the core studies were to be handled in this study |
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01 Nov 2016 |
Amendment 2.0- Clarifications and changes were made to the protocol, including changes requested based on feedback received from the United States Food and Drug Administration, and included the
following: • Added the criteria for dose adjustments outside the protocol-specified range for safety and/or efficacy
• Clarified the criteria on inclusion for subjects who did not complete the 12-week Maintenance period of the core study
• Added Pediatric Quality of Life Inventory (PedsQL) Family Impact module as an effectiveness endpoint • Reproduction requirements were updated and clarified • Clarified the transition from the core study to the OLE study • Clarified the timing of the echocardiogram (ECHO) - moved from Week 6 to Month 1 • Clarified the timing of the cardiac follow-up visits
• Added guidance consistent with the Seattle Children’s Research Foundation for volume of blood collected from children
• Severity of valve regurgitation (tricuspid or pulmonary) was changed • Clarified the process for SAE reporting • Added the requirement for pharmacokinetic (PK) as soon as feasible after an SAE |
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05 May 2017 |
Amendment 3.0- Clarifications and changes were made to the protocol, and included the following: • Extend the study duration to 2 years (24 months) • Clarified the methodology sections regarding dosing for subjects who entered the open label extension trial from core studies and increased the study duration to
24 months • Updated the Risk Benefit Assessment with regards to ZX008 doses administered in the core studies
• Increased number of subjects expected to enroll in the study
• Clarified the timing for cardiac follow up visits and increased study duration to 2 years (24 months) • Updated the study drug doses for open-label Treatment period • Added visit windows for year 2 visits and clarified timing of the cardiac follow up
visits in Table 6 “Time Windows for Assessments”
• Clarified the timing and observation period for reporting of AEs
• Clarified the process for SAE reporting |
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02 Feb 2018 |
Amendment 4.0- Clarifications and changes were made to the protocol, and included the following:
• Updated number of enrolled subjects to 340 from the core studies and up to 50 subjects who did not participate in the core studies (de novo) • Included eligibility criteria for de novo subjects aged > 18 to 35 years of age; provided summary of eligibility, clarified language, for de novo adult subjects
• Adjusted duration of study to approximately 36 months • Updated rationale to provide risk-benefit assessment that included results from Study 1. • Clarified that seizure comparisons would include the time when dose was stable • Included clinical data results from double-blind, controlled study (Study 1) • Clarified dose changes for subjects receiving and not receiving stiripentol • Corrected procedures for postdose Visit 13
• Clarified cardiac follow-up visits • Updated estimated blood volume to be collected • Clarified age range for PedsQL
• Clarified how to code and report SAEs • Clarified ECHO reading severity (trace and mild) and oversight based on patient age |
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03 Aug 2020 |
Amendment 5.0- Clarifications and changes were made to the protocol, and included the following:
• Included study conduct information for the COVID-19 pandemic • Updated background information related to existing treatments for Dravet and
additional clinical and pre-clinical study data available in the updated ZX008 Investigator’s Brochure (IB) • Updated language for subjects transitioning to another extension study or to commercial drug • Updated number of study centers to include Japan |
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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 |