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

Dravet Syndrome Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02682927
• Other study ID #: ZX008-1501
• Secondary ID: ZX008-1502
• Status: Completed
• Phase: Phase 3
• Start date: January 15, 2016
• Est. completion date: July 29, 2020

Study information

• Verified date: September 2023
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

Other known NCT identifiers

• NCT02826863

Recruitment information / eligibility

• Status: Completed
• Enrollment: 262
• Est. completion date: July 29, 2020
• Est. primary completion date: July 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Dravet Syndrome
• Epilepsies, Myoclonic
• Epilepsy
• Seizure Disorder
• Seizures
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Australia	Melbourne Brain Centre Austin Hospital	Melbourne
Australia	Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital	South Brisbane
Australia	The Children's Hospital Westmead Dept. of Neurology and Neurosurgery	Westmead
Belgium	Universitair Ziekenhuis Antwerpen	Antwerp
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montréal
Canada	British Columbia Children's Hospital BCCH	Vancouver	British Columbia
Denmark	Danish National Epilepsy Centre	Dianalund
France	French Ref centre Necker Hospital Paris	Paris
Germany	Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche	Berlin
Germany	Krankenhaus Mara Epilepsie-Zentrum Bethel	Bielefeld
Germany	Epilepsiezentrum Freiburg	Freiburg
Germany	Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie	Jena
Germany	Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel	Kiel
Germany	Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH	Radeberg
Germany	Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III	Tübingen
Germany	Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie	Vogtareuth
Italy	AOU Anna Meyer	Firenze
Italy	Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia	Genova
Italy	A.O Carlo Poma	Mantova
Italy	Instituto Neurologica Carlo Besta	Milano
Italy	Ospedale Fatebenefratelli e Oftalmico	Milano
Italy	U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS	Roma
Italy	Ospedal Policlinico Giambattista Rossi diBorga Roma	Verona
Japan	Okayama University Hospital	Okayama-shi	Okayama
Japan	Saitama Children's Medical Center	Saitama-shi	Saitama
Japan	Tokyo Women's Medical University Hospital	Shinjuku-ku	Tokyo
Japan	National Epilepsy Center Shizuoka Institute	Shizuoka-city	Shizuoka
Spain	Hospital Sant Joande Déu	Barcelona
Spain	Hospital Ruber Internacional Primera Planta Servicio de Neurologia	Madrid
Spain	Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria	Pamplona
United Kingdom	Birmingham Children Hospital	Birmingham
United Kingdom	Institute of Neurosciences Queens Elizabeth University Hospital	Glasgow
United Kingdom	Alder Hey Hospital	Liverpool
United Kingdom	Evelina Hospital	London
United Kingdom	Great Ormonnd Street Hospital for Children NHS Foundation Trust	London
United Kingdom	Sheffield Children's Hospital	Sheffield
United States	Panda Neurology	Atlanta	Georgia
United States	The Children's Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Children's Hospital of Chicago	Chicago	Illinois
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	NW FL Clinical Research Group, LLC	Gulf Breeze	Florida
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Miami Children's Hospital Brain Institute	Miami	Florida
United States	Neurology and Epilepsy Research Center	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Rady Children's Hospital San Diego	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	MultiCare Institute for Research & Innovation	Tacoma	Washington
United States	Center for Neurosciences - Tucson	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Japan,  Spain,  United Kingdom, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary	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.	During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary	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.	During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary	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.	During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
Secondary	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.	At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
Secondary	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.	At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
Secondary	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.	At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
Secondary	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.	From Baseline to Day 99
Secondary	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.	From Baseline to Day 99
Secondary	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.	From Baseline to Day 99
Secondary	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.	At Baseline and Day 99
Secondary	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.	From Baseline to Day 99
Secondary	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.	At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary	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.	At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary	Time to Maximum Concentration [Tmax] of ZX008 at Steady State	Tmax is the time to maximum concentration at steady state.	At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Secondary	Elimination Half-life [t1/2 Beta] of ZX008 at Steady State	t1/2 beta is the elimination half-life.	At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose