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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02682927




Registration number
NCT02682927
Ethics application status
Date submitted
5/02/2016
Date registered
17/02/2016
Date last updated
28/09/2023

Titles & IDs
Public title
A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
Scientific title
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
Secondary ID [1] 0 0
ZX008-1502
Secondary ID [2] 0 0
ZX008-1501
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dravet Syndrome 0 0
Seizure Disorder 0 0
Condition category
Condition code
Neurological 0 0 0 0
Epilepsy
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - ZX008 (Fenfluramine Hydrochloride)
Treatment: Drugs - Matching Placebo

Experimental: ZX008 - 0.8 mg/kg/day - ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.

Experimental: ZX008 - 0.2 mg/kg/day - ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.

Placebo comparator: Matching Placebo - Placebo will be administered twice a day (BID) in equally divided doses with food.


Treatment: Drugs: ZX008 (Fenfluramine Hydrochloride)
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet.

Treatment: Drugs: Matching Placebo
Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo
Timepoint [1] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [1] 0 0
Change From Baseline in the Mean Convulsive Seizures Frequency to the Combined Titration and Maintenance Period (T+M) in Participants Receiving ZX008 0.2 mg/kg/Day Compared to Placebo
Timepoint [1] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [2] 0 0
Percentage of Participants Who Achieved Greater Than or Equal to 25% (=25%) Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
Timepoint [2] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [3] 0 0
Percentage of Participants Who Achieved a =50% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
Timepoint [3] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [4] 0 0
Percentage of Participants Who Achieved a =75% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
Timepoint [4] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [5] 0 0
Percentage of Participants Who Achieved a 100% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period
Timepoint [5] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [6] 0 0
Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Timepoint [6] 0 0
During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary outcome [7] 0 0
Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Timepoint [7] 0 0
During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary outcome [8] 0 0
Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [8] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [9] 0 0
Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [9] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [10] 0 0
Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Timepoint [10] 0 0
From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcome [11] 0 0
Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study
Timepoint [11] 0 0
During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary outcome [12] 0 0
Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Timepoint [12] 0 0
During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary outcome [13] 0 0
Distribution of Duration of Convulsive Seizures (in Percentage) in Each ZX008 Treatment Arm Compared to Placebo at Baseline and During the Titration and Maintenance Period
Timepoint [13] 0 0
At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
Secondary outcome [14] 0 0
Percentage of Participants With Clinical Global Impression - Improvement (CGI-I) Rating Score, as Assessed by the Principal Investigator in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [14] 0 0
At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
Secondary outcome [15] 0 0
Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [15] 0 0
At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
Secondary outcome [16] 0 0
Change From Baseline to Day 99 in the Quality of Life in Childhood Epilepsy (QOLCE) Score to Measure Quality of Life in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [16] 0 0
From Baseline to Day 99
Secondary outcome [17] 0 0
Change From Baseline to Day 99 in the Overall Quality of Life Score From the Pediatric Quality of Life Inventory™ (PedsQL) Score in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [17] 0 0
From Baseline to Day 99
Secondary outcome [18] 0 0
Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [18] 0 0
From Baseline to Day 99
Secondary outcome [19] 0 0
Quality of Life (QoL) of the Parent/Caregiver Using the EQ- 5D-5L Scale in Each ZX008 Treatment Arm Compared to Placebo at Baseline and Day 99
Timepoint [19] 0 0
At Baseline and Day 99
Secondary outcome [20] 0 0
Change From Baseline to Day 99 in Affective Symptoms of the Parent/Caregiver Using the Hospital Anxiety and Depression Scale (HADS) in Each ZX008 Treatment Arm Compared to Placebo
Timepoint [20] 0 0
From Baseline to Day 99
Secondary outcome [21] 0 0
Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State
Timepoint [21] 0 0
At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary outcome [22] 0 0
Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State
Timepoint [22] 0 0
At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary outcome [23] 0 0
Time to Maximum Concentration [Tmax] of ZX008 at Steady State
Timepoint [23] 0 0
At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary outcome [24] 0 0
Elimination Half-life [t1/2 Beta] of ZX008 at Steady State
Timepoint [24] 0 0
At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Eligibility
Key inclusion criteria
Key

* Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the Screening Visit.
* Clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
* Must have a minimum # of convulsive seizures per 4-week period for past 12 weeks prior to screening.
* All medications or interventions for epilepsy must be stable for at least 4 weeks prior to screening and expected to remain stable throughout the study.
* No cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or physical examination.
* Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.

Key
Minimum age
2 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Pulmonary arterial hypertension.
* Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke.
* Current or past history of glaucoma.
* Moderate or severe hepatic impairment.
* Receiving concomitant therapy with: anorectic agents; monoamine-oxidase inhibitors; medications that act via serotonin including serotonin reuptake inhibitors; atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine.
* Currently receiving or has received stiripentol in the past 21 days prior to Screening.
* Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days.
* Positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test at the Screening Visit.
* A clinically significant medical condition,that would interfere with study participation, collection of study data, or pose a risk to the subject.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
15/01/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
29/07/2020
Sample size
Target
Accrual to date
Final
262
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Melbourne Brain Centre Austin Hospital - Melbourne
Recruitment hospital [2] 0 0
Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
The Children's Hospital Westmead Dept. of Neurology and Neurosurgery - Westmead
Recruitment postcode(s) [1] 0 0
- Melbourne
Recruitment postcode(s) [2] 0 0
- South Brisbane
Recruitment postcode(s) [3] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Massachusetts
Country [8] 0 0
United States of America
State/province [8] 0 0
Minnesota
Country [9] 0 0
United States of America
State/province [9] 0 0
New Jersey
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Utah
Country [13] 0 0
United States of America
State/province [13] 0 0
Washington
Country [14] 0 0
Belgium
State/province [14] 0 0
Antwerp
Country [15] 0 0
Canada
State/province [15] 0 0
British Columbia
Country [16] 0 0
Canada
State/province [16] 0 0
Montréal
Country [17] 0 0
Denmark
State/province [17] 0 0
Dianalund
Country [18] 0 0
France
State/province [18] 0 0
Paris
Country [19] 0 0
Germany
State/province [19] 0 0
Berlin
Country [20] 0 0
Germany
State/province [20] 0 0
Bielefeld
Country [21] 0 0
Germany
State/province [21] 0 0
Freiburg
Country [22] 0 0
Germany
State/province [22] 0 0
Jena
Country [23] 0 0
Germany
State/province [23] 0 0
Kiel
Country [24] 0 0
Germany
State/province [24] 0 0
Radeberg
Country [25] 0 0
Germany
State/province [25] 0 0
Tübingen
Country [26] 0 0
Germany
State/province [26] 0 0
Vogtareuth
Country [27] 0 0
Italy
State/province [27] 0 0
Firenze
Country [28] 0 0
Italy
State/province [28] 0 0
Genova
Country [29] 0 0
Italy
State/province [29] 0 0
Mantova
Country [30] 0 0
Italy
State/province [30] 0 0
Milano
Country [31] 0 0
Italy
State/province [31] 0 0
Roma
Country [32] 0 0
Italy
State/province [32] 0 0
Verona
Country [33] 0 0
Japan
State/province [33] 0 0
Okayama
Country [34] 0 0
Japan
State/province [34] 0 0
Saitama
Country [35] 0 0
Japan
State/province [35] 0 0
Shizuoka
Country [36] 0 0
Japan
State/province [36] 0 0
Tokyo
Country [37] 0 0
Spain
State/province [37] 0 0
Barcelona
Country [38] 0 0
Spain
State/province [38] 0 0
Madrid
Country [39] 0 0
Spain
State/province [39] 0 0
Pamplona
Country [40] 0 0
United Kingdom
State/province [40] 0 0
Birmingham
Country [41] 0 0
United Kingdom
State/province [41] 0 0
Glasgow
Country [42] 0 0
United Kingdom
State/province [42] 0 0
Liverpool
Country [43] 0 0
United Kingdom
State/province [43] 0 0
London
Country [44] 0 0
United Kingdom
State/province [44] 0 0
Sheffield

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Study 1 and Study 3 are the prospective, merged analyses of 2 identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and pharmacokinetics of ZX008 when used as adjunctive therapy in pediatric and young adult subjects with Dravet syndrome. Study 1501 and Study 1502 were conducted in parallel; Study 1501 was conducted at approximately 30 study sites in North America; Study 1502 was conducted at approximately 30 study sites in Europe, Asia and Australia. Upon completion of the Baseline Period after initial Screening and Baseline charting of seizure frequency, subjects who qualified for the studies were randomized (1:1:1) in a double-blind manner to receive either 1 of 2 doses of ZX008 (0.2 mg/kg/day or 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization was stratified by age group (\< 6 years, =6 to 18 years) to achieve balance across treatment arms, with the target of 25% of subjects in each age group. All subjects were titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects continued treatment at their randomly assigned dose over a 12-week Maintenance Period. Subjects exiting the study underwent a 2-week taper, unless they enrolled in a follow-on study. Subjects were followed for post-study safety monitoring.
Trial website
https://clinicaltrials.gov/study/NCT02682927
Trial related presentations / publications
Sullivan J, Lagae L, Cross JH, Devinsky O, Guerrini R, Knupp KG, Laux L, Nikanorova M, Polster T, Talwar D, Ceulemans B, Nabbout R, Farfel GM, Galer BS, Gammaitoni AR, Lock M, Agarwal A, Scheffer IE; FAiRE DS Study Group. Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial. Epilepsia. 2023 Oct;64(10):2653-2666. doi: 10.1111/epi.17737. Epub 2023 Aug 17.
Cross JH, Galer BS, Gil-Nagel A, Devinsky O, Ceulemans B, Lagae L, Schoonjans AS, Donner E, Wirrell E, Kothare S, Agarwal A, Lock M, Gammaitoni AR. Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome. Seizure. 2021 Dec;93:154-159. doi: 10.1016/j.seizure.2021.10.024. Epub 2021 Nov 2.
Sullivan J, Specchio N, Devinsky O, Auvin S, Perry MS, Strzelczyk A, Gil-Nagel A, Dai D, Galer BS, Gammaitoni AR. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis. Epilepsia. 2022 Jan;63(1):130-138. doi: 10.1111/epi.17106. Epub 2021 Oct 22.
Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019 Dec 21;394(10216):2243-2254. doi: 10.1016/S0140-6736(19)32500-0. Epub 2019 Dec 17.
Sullivan J, Perry MS, Wheless JW, Galer B, Gammaitoni A. Fenfluramine responder analyses and numbers needed to treat: Translating epilepsy trial data into clinical practice. Eur J Paediatr Neurol. 2021 Mar;31:10-14. doi: 10.1016/j.ejpn.2021.01.005. Epub 2021 Jan 22.
Public notes

Contacts
Principal investigator
Name 0 0
UCB Cares
Address 0 0
001 844 599 2273
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02682927