Clinical Trial Results:
A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults with Dravet Syndrome (Cohort 2)
Summary
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EudraCT number |
2016-000474-38 |
Trial protocol |
NL DE GB ES |
Global end of trial date |
05 Jun 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jun 2022
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First version publication date |
23 Jun 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 |
ZX008-1504
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02926898 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Zogenix International Limited
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Sponsor organisation address |
Siena Court, Broadway, Maidenhead, United Kingdom, SL6 1NJ
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Public contact |
Zogenix International Limited, Zogenix International Limited, Zogenixeu@druginfo.com
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Scientific contact |
Zogenix International Limited, Zogenix International Limited, Zogenixeu@druginfo.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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
02 Jul 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Jun 2018
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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 demonstrate that fenfluramine hydrochloride was superior to placebo for the treatment of Dravet syndrome in children and young adults stabilized on a STP regimen based on the change in convulsive seizure frequency (CSF) from Baseline to the combined Titration and Maintenance Periods (T+M period)
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Protection of trial subjects |
The study procedures set out in the protocol were designed to ensure that the Sponsor and the Investigators abided by the principles of the current International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guideline on the conduct, evaluation and documentation of this study, as described in ICH Topic E6 Guideline. The study was also carried out according to all applicable international and national regulatory requirements. The Sponsor ensured that all ethical and legal requirements were met before the first subject was enrolled into the study.
The Investigator was responsible for obtaining a subject’s informed consent to participate in the study. A Subject Information Sheet and study master ICFs, including a subject ICF (for adult subjects), subject assent form (for subjects under the age of consent), and an ICF for the parent/caregiver, were prepared by the Sponsor according to the provisions of ICH GCP and local legal requirements.
For pediatric subjects (<18 years of age), or young adult subjects (18 years of age) unable to provide consent due to intellectual disability, the written informed consent of a legally acceptable representative was required. Pediatric and young adult subjects who could understand the nature, scope, and possible consequences of the study must also have given their assent, orally and/or in writing via the assent document, as appropriate.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jan 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
2 Years | ||
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 |
Spain: 10
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
United States: 22
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Country: Number of subjects enrolled |
Canada: 7
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Country: Number of subjects enrolled |
France: 23
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Country: Number of subjects enrolled |
Germany: 3
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Country: Number of subjects enrolled |
Netherlands: 10
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Worldwide total number of subjects |
87
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EEA total number of subjects |
58
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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) |
57
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Adolescents (12-17 years) |
28
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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 |
A total of 28 study sites in Canada, France, Germany, the Netherlands, Spain, the United Kingdom, and the United States enrolled participants for Study 1504 Cohort 2. | ||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 115 subjects were screened for eligibility to participate in Study 1504 Cohort 2. Of these, 87 subjects were enrolled and randomized. | ||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study Period (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, Monitor, Carer | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Matching fenfluramine placebo was supplied as an oral solution.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||
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 |
Upon completion of the 6-week Baseline Period, subjects received fenfluramine hydrochloride (at a dose of 0.5 mg/kg/day; maximum dose of 20 mg/day). All subjects were titrated to their randomized dose during the Titration Period. The duration of the titration period was 21 days.
Following titration, subjects continued treatment at their assigned dose of fenfluramine 0.5 mg/kg/day over a 12-week Maintenance Period. The total treatment time from the beginning of the Titration Period through the end of the maintenance period was a maximum of 15 weeks.
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Arm title
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Cohort 2: Placebo | ||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||
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 |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Upon completion of the 6-week Baseline Period, subjects received placebo, volume matched to the 0.4 mg/kg/day dose level. To maintain the blinded aspect of the study, subjects titrated the placebo dose over 21 days and remained at this dose for the 12-week Maintenance Period.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
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Reporting group description |
Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2: Placebo
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Reporting group description |
Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
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Reporting group description |
Subjects received fenfluramine hydrochloride 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum stiripentol (STP) plus clobazam (CLB) and/or valproic acid (VPA). Study medication was administered twice daily (BID) in equally divided doses with food. | ||
Reporting group title |
Cohort 2: Placebo
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Reporting group description |
Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to a standard-of-care regimen that included STP at a minimum plus CLB and/or VPA. Placebo was administered twice daily (BID) in equally divided doses with food. |
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End point title |
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period | ||||||||||||
End point description |
Baseline-adjusted in CSF (mean number of convulsive seizures per 28 days) from Baseline to the T + M Period in ZX008 0.5 mg/kg/day vs placebo. Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
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End point type |
Primary
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End point timeframe |
15 weeks (combined Titration + Maintenance Period)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day v Cohort 2: Placebo
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [1] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
percent difference | ||||||||||||
Point estimate |
-54
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-67.2 | ||||||||||||
upper limit |
-35.6 | ||||||||||||
Notes [1] - ANCOVA model with treatment group (ZX008 or placebo) and age group (< 6 years, ≥ 6 years) as factors, and with log baseline frequency as a covariate, and log CSF as the outcome variable. |
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End point title |
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period | ||||||||||||
End point description |
Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups. Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
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End point type |
Secondary
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End point timeframe |
15 weeks (combined Titration + Maintenance Period)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day v Cohort 2: Placebo
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [2] | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Confidence interval |
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Notes [2] - A logistic regression model using a categorical response variable as a function of Treatment group, Baseline seizure frequency, and age group. |
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End point title |
Longest Convulsive Seizure-Free Interval (Days) | ||||||||||||
End point description |
Comparison of the duration of the longest convulsive seizure–free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups. Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
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End point type |
Secondary
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End point timeframe |
15 weeks (combined Titration + Maintenance Period)
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Cohort 2: Placebo v Cohort 2: fenfluramine hydrochloride 0.5 mg/kg/day
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Number of subjects included in analysis |
87
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.004 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
The period of observation for Adverse Events extended from the time the subject gave informed consent until the end of the Follow-up Visit (up to Day 120 [Visit 13]).
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Assessment type |
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 |
Cohort 2: fenfluramine 0.5 mg/kg/day
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Reporting group description |
Subjects received fenfluramine 0.5 mg/kg/day (maximum dose of 20 mg/day) added to a standard-of-care regimen that included at a minimum STP plus CLB and/or VPA. Study medication was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2: Placebo
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Reporting group description |
Subjects received placebo, volume matched to the 0.5 mg/kg/day dose level, added to standard-of-care treatment that included STP. Study medication was administered twice daily (BID) in equally divided doses with food. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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25 May 2016 |
- Addition of chest x-ray prior to and after 13 weeks of treatment with study medication (France and The Netherlands)
- Addition of 24-month cardiac safety follow-up for subjects who have completed more than 13 weeks of double-blind or open-label treatment with study medication (France,
The Netherlands, and Germany)
- Updated prohibited medication/food section to include the prohibition of alcohol
- Added new section of transition for subjects who will enter the open-label extension study, including updates as appropriate in inclusion/exclusion criteria, study design, study visits, blood volumes to be taken, statistical methods, etc.
- Increased the number of sites and countries
- Clarified the use of midazolam and diazepam as rescue medication did not require Medical Monitor approval prior to use
- Clarified that QOLCE was to be administered to all children
- Clarified seizure type definitions
-The participating countries were expanded to include Canada and Germany |
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30 Sep 2016 |
- The participating countries were expanded to include Belgium, Italy, Spain, and United States
- The number of participating sites was updated.
- The required number of seizures during the Baseline period was corrected due to a typographical error.
- The Screening was extended to 21 days
- Corrections were made to state that ECGs were to be read centrally
- SAE reporting process was updated |
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13 Dec 2016 |
Clarifications and changes were made to the various sections of the protocol based on the selected dose of ZX008 0.5 mg/kg/day, maximum 20 mg/day for Cohort 2, including the Schedule of Assessments, risk-benefit rationale, and description of the primary outcome. |
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02 Feb 2018 |
- Sample size was updated (sample size had been expanded to include approximately 90 subjects)
- Updates were made to statistical analysis and efficacy objectives to align with the SAP.
- The AESI list was updated to 1) remove cardiovascular/respiratory items, including discontinuation of the reporting of ECHOs with trace mitral regurgitation as AESIs;
2) remove serotonin syndrome; 3) remove hallucinations, psychosis, euphoria, mood disorders; 4) remove galactorrhea, gynecomastia, priapism; and 5) remove fasting serum
blood glucose ≥2×ULN |
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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 |