Dravet SyndromePhase 3NCT02682927
A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome
A Phase 3 study testing ZX008 (Fenfluramine Hydrochloride) in people with Dravet Syndrome and Seizure Disorder, run by Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. at 55 sites in 11 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Dravet Syndrome, Seizure Disorder
- What is being tested?
- ZX008 (Fenfluramine Hydrochloride)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 262 participants
- Where
- 55 sitesin 11 countries
- Study dates
- 15 Jan 2016to 29 Jul 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
55 sites in 11 countries.
55 sites in 11 countries
United States19 sites
Panda Neurology
Atlanta, Georgia, 30328
The Children's Hospital Colorado
Aurora, Colorado, 80045
Massachusetts General Hospital
Boston, Massachusetts, 02114
Boston Children's Hospital
Boston, Massachusetts, 02467
Children's Hospital of Chicago
Chicago, Illinois, 60611
Cook Children's Medical Center
Fort Worth, Texas, 76087
NW FL Clinical Research Group, LLC
Gulf Breeze, Florida, 32561
Saint Barnabas Medical Center
Livingston, New Jersey, 07039
Miami Children's Hospital Brain Institute
Miami, Florida, 33155
Neurology and Epilepsy Research Center
Orlando, Florida, 32819
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Phoenix Children's
Phoenix, Arizona, 85016
Mayo Clinic
Rochester, Minnesota, 55905
University of Utah
Salt Lake City, Utah, 84113
Rady Children's Hospital San Diego
San Diego, California, 92123
University of California San Francisco
San Francisco, California, 94143
Seattle Children's Hospital
Seattle, Washington, 98105
MultiCare Institute for Research & Innovation
Tacoma, Washington, 98405
Center for Neurosciences - Tucson
Tucson, Arizona, 85718
Germany8 sites
Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche
Berlin
Krankenhaus Mara Epilepsie-Zentrum Bethel
Bielefeld
Epilepsiezentrum Freiburg
Freiburg im Breisgau
Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie
Jena
Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel
Kiel
Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH
Radeberg
Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III
Tübingen
Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie
Vogtareuth
Italy7 sites
AOU Anna Meyer
Florence, 50139
Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia
Genova
A.O Carlo Poma
Mantua, 46100
Instituto Neurologica Carlo Besta
Milan, 20133
Ospedale Fatebenefratelli e Oftalmico
Milan
U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS
Roma, 00165
Ospedal Policlinico Giambattista Rossi diBorga Roma
Verona, 37134
United Kingdom6 sites
Birmingham Children Hospital
Birmingham
Institute of Neurosciences Queens Elizabeth University Hospital
Glasgow
Alder Hey Hospital
Liverpool
Evelina Hospital
London
Great Ormonnd Street Hospital for Children NHS Foundation Trust
London
Sheffield Children's Hospital
Sheffield
Japan4 sites
Okayama University Hospital
Okayama, Okayama-ken
Saitama Children's Medical Center
Saitama-shi, Saitama
Tokyo Women's Medical University Hospital
Shinjuku-ku, Tokyo
National Epilepsy Center Shizuoka Institute
Shizuoka, Shizuoka
Australia3 sites
Melbourne Brain Centre Austin Hospital
Melbourne
Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital
South Brisbane
The Children's Hospital Westmead Dept. of Neurology and Neurosurgery
Westmead
Spain3 sites
Hospital Sant Joande Déu
Barcelona
Hospital Ruber Internacional Primera Planta Servicio de Neurologia
Madrid
Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria
Pamplona
Canada2 sites
Centre Hospitalier Universitaire Sainte-Justine
Montreal, H3T 1C5
British Columbia Children's Hospital BCCH
Vancouver, British Columbia, V6H3V4
About this study
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 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.
- Conditions
- Dravet Syndrome, Seizure Disorder
- Being tested
- ZX008 (Fenfluramine Hydrochloride), Matching Placebo
- Keywords
- seizure, tonic-atonic, clonic, epilepsy, myoclonic, encephalopathy
- Medical subject headings
- Epilepsies, Myoclonic, Epilepsy, Seizures, Brain Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZX008 (Fenfluramine Hydrochloride)Drug
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.
Matching PlaceboDrug
Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.
| Study group | Role | What they receive |
|---|---|---|
| ZX008 - 0.8 mg/kg/day | Experimental | 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. Receives: Drug: ZX008 (Fenfluramine Hydrochloride) |
| ZX008 - 0.2 mg/kg/day | Experimental | 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. Receives: Drug: ZX008 (Fenfluramine Hydrochloride) |
| Matching Placebo | Placebo comparator | Placebo will be administered twice a day (BID) in equally divided doses with food. Receives: Drug: Matching Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcomes (24)
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
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
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.
Measured: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
Measured: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
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.
Measured: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
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.
Measured: At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
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.
Measured: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
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.
Measured: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
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.
Measured: From Baseline to Day 99
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.
Measured: From Baseline to Day 99
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.
Measured: From Baseline to Day 99
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.
Measured: At Baseline and Day 99
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.
Measured: From Baseline to Day 99
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.
Measured: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
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.
Measured: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Time to Maximum Concentration [Tmax] of ZX008 at Steady State
Tmax is the time to maximum concentration at steady state.
Measured: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Elimination Half-life [t1/2 Beta] of ZX008 at Steady State
t1/2 beta is the elimination half-life.
Measured: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2016 (estimated)
- Study start15 Jan 2016
- Primary completion29 Jul 2020
- Study completion29 Jul 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Dravet SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 262 participants (actual)
Sponsor and investigators
- Lead sponsor
- Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- UCB Cares, Study director, 001 844 599 2273
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02682927
- Sponsor's protocol ID
- ZX008-1501
- Other IDs
- ZX008-1502
- Status last verified
- Sep 2023
- First submitted
- 5 Feb 2016
- Last updated
- 28 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
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.
PubMed 37543865Cross 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.
PubMed 34768178Sullivan 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.
PubMed 34676542Sullivan 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.
PubMed 33540241Lagae 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.
PubMed 31862249
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02682927
- Acronym / sponsor ID
- ZX008-1501
- Conditions
- Dravet Syndrome, Seizure Disorder
- Keywords
- seizure, tonic-atonic, clonic, epilepsy, myoclonic, encephalopathy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 262 participants (actual)
- Lead sponsor
- Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.Industry (pharma, biotech, devices)
- Study start
- 15 Jan 2016 (actual)
- Primary completion
- 29 Jul 2020 (actual)
- Study completion
- 29 Jul 2020 (actual)
- First posted
- 17 Feb 2016 (estimated)
- Results
- Posted 19 Oct 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| ZX008 - 0.8 mg/kg/day | Experimental | Drug: ZX008 (Fenfluramine Hydrochloride)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. |
| ZX008 - 0.2 mg/kg/day | Experimental | Drug: ZX008 (Fenfluramine Hydrochloride)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. |
| Matching Placebo | Placebo comparator | Drug: Matching PlaceboPlacebo will be administered twice a day (BID) in equally divided doses with food. |
Who may qualify
- Ages
- 2 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Drug | ZX008 - 0.2 mg/kg/day, ZX008 - 0.8 mg/kg/day |
| Matching PlaceboPlacebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet. | Drug | Matching Placebo |
Primary outcome
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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.
24 secondary outcomes
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
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
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Time frame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Time frame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study
Time frame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
Time frame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
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
Time frame: At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
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
Time frame: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo
Time frame: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
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
Time frame: From Baseline to Day 99
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
Time frame: From Baseline to Day 99
Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo
Time frame: From Baseline to Day 99
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
Time frame: At Baseline and Day 99
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
Time frame: From Baseline to Day 99
Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State
Time frame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State
Time frame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Time to Maximum Concentration [Tmax] of ZX008 at Steady State
Time frame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Elimination Half-life [t1/2 Beta] of ZX008 at Steady State
Time frame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 37543865Sullivan 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.
- Derived from this study: PubMed 34768178Cross 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.
- Derived from this study: PubMed 34676542Sullivan 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.
- Derived from this study: PubMed 33540241Sullivan 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.
- Derived from this study: PubMed 31862249Lagae 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
UCB Cares study director
001 844 599 2273
55 sites in 11 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing ZX008 (Fenfluramine Hydrochloride) in people with Dravet Syndrome and Seizure Disorder, run by Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. at 55 sites in 11 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 55 sites in United States, Germany, Italy, United Kingdom, Japan and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Oct 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02682927, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2023.