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A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome

Primary Purpose

Dravet Syndrome, Seizure Disorder

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

ZX008 (Fenfluramine Hydrochloride)

Matching Placebo

About this trial

This is an interventional treatment trial for Dravet Syndrome focused on measuring seizure, tonic-atonic, clonic, epilepsy, myoclonic, encephalopathy

Eligibility Criteria

2 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria:

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 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.

Sites / Locations

Phoenix Children's
Center for Neurosciences - Tucson
Rady Children's Hospital San Diego
University of California San Francisco
The Children's Hospital Colorado
NW FL Clinical Research Group, LLC
Miami Children's Hospital Brain Institute
Neurology and Epilepsy Research Center
Panda Neurology
Children's Hospital of Chicago
Massachusetts General Hospital
Boston Children's Hospital
Mayo Clinic
Saint Barnabas Medical Center
Children's Hospital of Philadelphia
Cook Children's Medical Center
University of Utah
Seattle Children's Hospital
MultiCare Institute for Research & Innovation
Melbourne Brain Centre Austin Hospital
Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital
The Children's Hospital Westmead Dept. of Neurology and Neurosurgery
Universitair Ziekenhuis Antwerpen
British Columbia Children's Hospital BCCH
Centre Hospitalier Universitaire Sainte-Justine
Danish National Epilepsy Centre
French Ref centre Necker Hospital Paris
Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche
Krankenhaus Mara Epilepsie-Zentrum Bethel
Epilepsiezentrum Freiburg
Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie
Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel
Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH
Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III
Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie
AOU Anna Meyer
Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia
A.O Carlo Poma
Instituto Neurologica Carlo Besta
Ospedale Fatebenefratelli e Oftalmico
U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS
Ospedal Policlinico Giambattista Rossi diBorga Roma
Okayama University Hospital
Saitama Children's Medical Center
National Epilepsy Center Shizuoka Institute
Tokyo Women's Medical University Hospital
Hospital Sant Joande Déu
Hospital Ruber Internacional Primera Planta Servicio de Neurologia
Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria
Birmingham Children Hospital
Institute of Neurosciences Queens Elizabeth University Hospital
Alder Hey Hospital
Evelina Hospital
Great Ormonnd Street Hospital for Children NHS Foundation Trust
Sheffield Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

ZX008 - 0.8 mg/kg/day

ZX008 - 0.2 mg/kg/day

Matching Placebo

Arm Description

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 will be administered twice a day (BID) in equally divided doses with food.

Outcomes

Primary Outcome Measures

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

Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.

Secondary Outcome Measures

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

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

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 25% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

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

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 50% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

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

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 75% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

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

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 100% reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

The longest interval between convulsive seizures was calculated over the entire Titration and Maintenance Period and was derived as the maximum of the number of days between consecutive convulsive seizures.

Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

A convulsive seizure free day was defined as a day for which diary data are available and no convulsive seizures were reported. Convulsive seizure free days were taken from the electronic diary data.

Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The number of non-convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day non-convulsive seizure frequency.

Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Total seizure frequency were defined as the combination of convulsive and non-convulsive seizures. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). Non-convulsive seizures included focal without clear observable motor signs, absence or atypical absence, myoclonic and atonic. The seizure frequency was based on electronic diary data obtained for each participant. The number of all seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day convulsive or non-convulsive seizure frequency.

Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Rescue medication was administered according to each participant's usual or prescribed regimen consisting of 1 or more medications. The usage of rescue medication (number of days and number of medications used per seizure episode) was based on electronic diary data obtained for each participant. The number of days rescue medication was taken (normalized to 28 days) was calculated for each participant. Multiple medications taken on the same day were counted once for that day.

Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study

Participants who utilized medical center care to treat a seizure during the study were reported.

Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

The participants who either had SE episode recorded as an adverse event (AE) during treatment or a seizure greater than 10 minutes were reported for each treatment group. Additionally, a single participant who may had more than one episode of SE, and an episode of SE recorded as both an AE and as a seizure longer than 10 minutes was counted as a single event.

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

Duration of single convulsive seizures during the Baseline and the duration over the Titration and Maintenance Period were reported by treatment group using categories as <2 minutes, 2 to 10 minutes and > 10 minutes as collected in the seizure diary.

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

CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse. The Principal Investigator rated their global impression of the participant's condition during the study.

Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo

CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse. The Parent/Caregiver rated their global impression of the participant's condition during the study.

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

QOLCE is a low-burden parent/caregiver completed assessment that evaluates how epilepsy affects day-to day functioning of the participant in various life areas, including physical activities, well being, cognition, social activities, behavior, and general health. QOLCE scores items on 16 subscales with possible 5-point response for each, where scores of 5 was best possible response and 1 was worst possible response. Item scores were then transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100. A score for each participant for each subscale was calculated by averaging that participant's responses to each item in the subscale. Subscale scores per participant were averaged to obtain an overall QoL score for each participant. Higher the subscale and overall QoL scores, better the response.

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

The Pediatric Quality of Life Inventory (PedsQL) is a pediatric modular measure of health related quality of life (QoL) completed by the parent/caregiver on behalf of the participant. It consisted of 23 items across 4 core scales that measure physical (8 items), emotional, social, and school functioning (5 items each). Each of the responses to the 23 items is initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Scores are linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores correspond to better health-related QoL. The Overall Quality of Life is the average of all the items over the number of items answered on all the Scales.

Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo

The PedsQL Family Impact measured the impact of pediatric chronic health conditions on parents and the family by measuring parent self-reported physical, emotional, social, and cognitive functioning, communication, worry, and family daily activities and relationships. There are a total of 36 items in the PedsQL: 6 items for Physical Functioning, 5 items each for Emotional Functioning, Cognitive Functioning and Worry, 4 for Social Functioning, 3 for Communication, 3 questions for Daily Activities, and 5 for Family Relationships. Each of the responses are initially scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always) and then linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores mean better health-related QoL.

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

The EuroQOL-5 Dimensions-5 Levels scale produced by European QOL Group (EQ-5D-5L) health questionnaire is a health-related QOL instrument with 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The 5 dimensions of EQ-5D-5L health questionnaire were assessed on a Likert scale with 5 possible levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The categories "slight problems", "moderate problems", "severe problems" and "extreme problems" are collapsed into one response category "problems. The QOL of the parent/caregiver was assessed and percentage of participants was reported for each item.

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

The HADS is a tool that was validated to assess presence of anxiety or depression in an outpatient non-psychiatric population. The HADS a 14-item scale that generates ordinal data for 2 dimensions: 1) Anxiety (7 items), and 2) Depression (7 items). Each item has 4 possible answers rated 0 to 3, of which 0 = No distress and 3 = worst distress. All answers to the items for a dimension with their respective rating are added resulting in a range for each dimension from 0-21, out of which of 0-7 = normal; 8-10=borderline abnormal; 11-21=abnormal. Scores for the entire scale (emotional distress) range from 0 to 42, with higher scores indicating more distress.

Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State

Cmax is the maximum observed concentration determined directly from the concentration-time profile.

Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State

AUC0-24 is the area under the concentration time curve from time zero to 24 hours.

Time to Maximum Concentration [Tmax] of ZX008 at Steady State

Tmax is the time to maximum concentration at steady state.

Elimination Half-life [t1/2 Beta] of ZX008 at Steady State

t1/2 beta is the elimination half-life.

Full Information

NCT ID

NCT02682927

First Posted

February 5, 2016

Last Updated

September 20, 2023

Sponsor

Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02682927

Brief Title

A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

January 15, 2016 (Actual)

Primary Completion Date

July 29, 2020 (Actual)

Study Completion Date

July 29, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dravet Syndrome, Seizure Disorder

Keywords

seizure, tonic-atonic, clonic, epilepsy, myoclonic, encephalopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

262 (Actual)

8. Arms, Groups, and Interventions

Arm Title

ZX008 - 0.8 mg/kg/day

Arm Type

Experimental

Arm Description

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.

Arm Title

ZX008 - 0.2 mg/kg/day

Arm Type

Experimental

Arm Description

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.

Arm Title

Matching Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

ZX008 (Fenfluramine Hydrochloride)

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Matching Placebo

Intervention Description

Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

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

Description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 50% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

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

Description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 75% or greater reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

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

Description

Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). A responder was a participant who experienced a 100% reduction in convulsive seizure frequency per 28 days during Titration and Maintenance Period.

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Description

Time Frame

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Title

Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Description

A convulsive seizure free day was defined as a day for which diary data are available and no convulsive seizures were reported. Convulsive seizure free days were taken from the electronic diary data.

Time Frame

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Title

Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Description

Time Frame

From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Title

Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study

Description

Participants who utilized medical center care to treat a seizure during the study were reported.

Time Frame

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Title

Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period

Description

Time Frame

During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)

Title

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

Description

Time Frame

At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)

Title

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

Description

Time Frame

At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

Title

Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo

Description

CGI-I scale measures improvement in the participant's clinical status from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse. The Parent/Caregiver rated their global impression of the participant's condition during the study.

Time Frame

At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)

Title

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

Description

Time Frame

From Baseline to Day 99

Title

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

Description

Time Frame

From Baseline to Day 99

Title

Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo

Description

Time Frame

From Baseline to Day 99

Title

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

Description

Time Frame

At Baseline and Day 99

Title

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

Description

Time Frame

From Baseline to Day 99

Title

Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State

Description

Cmax is the maximum observed concentration determined directly from the concentration-time profile.

Time Frame

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Title

Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State

Description

AUC0-24 is the area under the concentration time curve from time zero to 24 hours.

Time Frame

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Title

Time to Maximum Concentration [Tmax] of ZX008 at Steady State

Description

Tmax is the time to maximum concentration at steady state.

Time Frame

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

Title

Elimination Half-life [t1/2 Beta] of ZX008 at Steady State

Description

t1/2 beta is the elimination half-life.

Time Frame

At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria: 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 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

UCB Cares

Organizational Affiliation

001 844 599 2273

Official's Role

Study Director

Facility Information:

Facility Name

Phoenix Children's

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85016

Country

United States

Facility Name

Center for Neurosciences - Tucson

City

Tucson

State/Province

Arizona

ZIP/Postal Code

85718

Country

United States

Facility Name

Rady Children's Hospital San Diego

City

San Diego

State/Province

California

ZIP/Postal Code

92123

Country

United States

Facility Name

University of California San Francisco

City

San Francisco

State/Province

California

ZIP/Postal Code

94143

Country

United States

Facility Name

The Children's Hospital Colorado

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

NW FL Clinical Research Group, LLC

City

Gulf Breeze

State/Province

Florida

ZIP/Postal Code

32561

Country

United States

Facility Name

Miami Children's Hospital Brain Institute

City

Miami

State/Province

Florida

ZIP/Postal Code

33155

Country

United States

Facility Name

Neurology and Epilepsy Research Center

City

Orlando

State/Province

Florida

ZIP/Postal Code

32819

Country

United States

Facility Name

Panda Neurology

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30328

Country

United States

Facility Name

Children's Hospital of Chicago

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Boston Children's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02467

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Facility Name

Saint Barnabas Medical Center

City

Livingston

State/Province

New Jersey

ZIP/Postal Code

07039

Country

United States

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Cook Children's Medical Center

City

Fort Worth

State/Province

Texas

ZIP/Postal Code

76087

Country

United States

Facility Name

University of Utah

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84113

Country

United States

Facility Name

Seattle Children's Hospital

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

Facility Name

MultiCare Institute for Research & Innovation

City

Tacoma

State/Province

Washington

ZIP/Postal Code

98405

Country

United States

Facility Name

Melbourne Brain Centre Austin Hospital

City

Melbourne

Country

Australia

Facility Name

Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital

City

South Brisbane

Country

Australia

Facility Name

The Children's Hospital Westmead Dept. of Neurology and Neurosurgery

City

Westmead

Country

Australia

Facility Name

Universitair Ziekenhuis Antwerpen

City

Antwerp

Country

Belgium

Facility Name

British Columbia Children's Hospital BCCH

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V6H3V4

Country

Canada

Facility Name

Centre Hospitalier Universitaire Sainte-Justine

City

Montréal

ZIP/Postal Code

H3T 1C5

Country

Canada

Facility Name

Danish National Epilepsy Centre

City

Dianalund

Country

Denmark

Facility Name

French Ref centre Necker Hospital Paris

City

Paris

Country

France

Facility Name

Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche

City

Berlin

Country

Germany

Facility Name

Krankenhaus Mara Epilepsie-Zentrum Bethel

City

Bielefeld

Country

Germany

Facility Name

Epilepsiezentrum Freiburg

City

Freiburg

Country

Germany

Facility Name

Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie

City

Jena

Country

Germany

Facility Name

Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel

City

Kiel

Country

Germany

Facility Name

Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH

City

Radeberg

Country

Germany

Facility Name

Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III

City

Tübingen

Country

Germany

Facility Name

Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie

City

Vogtareuth

Country

Germany

Facility Name

AOU Anna Meyer

City

Firenze

ZIP/Postal Code

50139

Country

Italy

Facility Name

Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia

City

Genova

Country

Italy

Facility Name

A.O Carlo Poma

City

Mantova

ZIP/Postal Code

46100

Country

Italy

Facility Name

Instituto Neurologica Carlo Besta

City

Milano

ZIP/Postal Code

20133

Country

Italy

Facility Name

Ospedale Fatebenefratelli e Oftalmico

City

Milano

Country

Italy

Facility Name

U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS

City

Roma

ZIP/Postal Code

00165

Country

Italy

Facility Name

Ospedal Policlinico Giambattista Rossi diBorga Roma

City

Verona

ZIP/Postal Code

37134

Country

Italy

Facility Name

Okayama University Hospital

City

Okayama-shi

State/Province

Okayama

Country

Japan

Facility Name

Saitama Children's Medical Center

City

Saitama-shi

State/Province

Saitama

Country

Japan

Facility Name

National Epilepsy Center Shizuoka Institute

City

Shizuoka-city

State/Province

Shizuoka

Country

Japan

Facility Name

Tokyo Women's Medical University Hospital

City

Shinjuku-ku

State/Province

Tokyo

Country

Japan

Facility Name

Hospital Sant Joande Déu

City

Barcelona

Country

Spain

Facility Name

Hospital Ruber Internacional Primera Planta Servicio de Neurologia

City

Madrid

Country

Spain

Facility Name

Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria

City

Pamplona

Country

Spain

Facility Name

Birmingham Children Hospital

City

Birmingham

Country

United Kingdom

Facility Name

Institute of Neurosciences Queens Elizabeth University Hospital

City

Glasgow

Country

United Kingdom

Facility Name

Alder Hey Hospital

City

Liverpool

Country

United Kingdom

Facility Name

Evelina Hospital

City

London

Country

United Kingdom

Facility Name

Great Ormonnd Street Hospital for Children NHS Foundation Trust

City

London

Country

United Kingdom

Facility Name

Sheffield Children's Hospital

City

Sheffield

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

37543865

Citation

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.

Results Reference

result

PubMed Identifier

34768178

Citation

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.

Results Reference

derived

PubMed Identifier

34676542

Citation

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.

Results Reference

derived

PubMed Identifier

31862249

Citation

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.

Results Reference

derived

PubMed Identifier

33540241

Citation

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.

Results Reference

derived

Learn more about this trial

A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome

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