Clinical trial NCT02682927: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Dravet Syndrome
Seizure Disorder
Keywords: seizure
tonic-atonic
clonic
epilepsy
myoclonic
encephalopathy
Lead sponsor: UCB Pharma
Sponsor class: INDUSTRY
First posted: 2016-02-17
Enrollment: 262
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
Secondary outcomes:
measure: 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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: 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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: 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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: 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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: 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
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: Longest Convulsive Seizure-free Interval in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
timeFrame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
measure: Number of Convulsive Seizure-free Days in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
timeFrame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
measure: Change From Baseline in Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: Change From Baseline in Convulsive + Non-convulsive Seizure Frequency to the Combined Titration and Maintenance Period in Each ZX008 Treatment Arm Compared to Placebo
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: Percentage of Participants With Rescue Medication Usage in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
timeFrame: From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]
measure: Percentage of Participants With Hospitalization and Healthcare Resource Utilization to Treat Seizures in Each ZX008 Treatment Arm Compared to Placebo During Study
timeFrame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
measure: Percentage of Participants With Status Epilepticus (SE) in Each ZX008 Treatment Arm Compared to Placebo During the Titration and Maintenance Period
timeFrame: During 14 weeks Titration (2 weeks) and Maintenance Period (12 weeks) (average of 99 days)
measure: 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
timeFrame: At Baseline and 14 weeks of Titration (2 weeks) and Maintenance Period (12 weeks)
measure: 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
timeFrame: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
measure: Percentage of Participants With Clinical Global Impression - Improvement Rating Score, as Assessed by the Parent/Caregiver in Each ZX008 Treatment Arm Compared to Placebo
timeFrame: At Visit 6 (Day 15), 8 (Day 43), 10 (Day 71) and 12 (Day 99)
measure: 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
timeFrame: From Baseline to Day 99
measure: 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
timeFrame: From Baseline to Day 99
measure: Change From Baseline to Day 99 in the Total Score From PedsQL Family Impact Module Score in Each ZX008 Treatment Arm Compared to Placebo
timeFrame: From Baseline to Day 99
measure: 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
timeFrame: At Baseline and Day 99
measure: 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
timeFrame: From Baseline to Day 99
measure: Maximum Observed Concentration of ZX008 Determined Directly From the Concentration Time Profile [Cmax] at Steady State
timeFrame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
measure: Area Under the Concentration Time Curve of ZX008 From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State
timeFrame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
measure: Time to Maximum Concentration [Tmax] of ZX008 at Steady State
timeFrame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
measure: Elimination Half-life [t1/2 Beta] of ZX008 at Steady State
timeFrame: At Visit 8 (Day 43): pre-dose, 1, 2, and 4-6 hours postdose
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's
state: Arizona
city: Tucson
country: United States
facility: Center for Neurosciences - Tucson
state: Arizona
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: The Children's Hospital Colorado
state: Colorado
city: Gulf Breeze
country: United States
facility: NW FL Clinical Research Group, LLC
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital Brain Institute
state: Florida
city: Orlando
country: United States
facility: Neurology and Epilepsy Research Center
state: Florida
city: Atlanta
country: United States
facility: Panda Neurology
state: Georgia
city: Chicago
country: United States
facility: Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Tacoma
country: United States
facility: MultiCare Institute for Research & Innovation
state: Washington
city: Melbourne
country: Australia
facility: Melbourne Brain Centre Austin Hospital
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital
city: Westmead
country: Australia
facility: The Children's Hospital Westmead Dept. of Neurology and Neurosurgery
city: Antwerp
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital BCCH
state: British Columbia
city: Montréal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
city: Dianalund
country: Denmark
facility: Danish National Epilepsy Centre
city: Paris
country: France
facility: French Ref centre Necker Hospital Paris
city: Berlin
country: Germany
facility: Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche
city: Bielefeld
country: Germany
facility: Krankenhaus Mara Epilepsie-Zentrum Bethel
city: Freiburg
country: Germany
facility: Epilepsiezentrum Freiburg
city: Jena
country: Germany
facility: Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie
city: Kiel
country: Germany
facility: Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel
city: Radeberg
country: Germany
facility: Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH
city: Tübingen
country: Germany
facility: Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III
city: Vogtareuth
country: Germany
facility: Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie
city: Firenze
country: Italy
facility: AOU Anna Meyer
city: Genova
country: Italy
facility: Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia
city: Mantova
country: Italy
facility: A.O Carlo Poma
city: Milano
country: Italy
facility: Instituto Neurologica Carlo Besta
city: Milano
country: Italy
facility: Ospedale Fatebenefratelli e Oftalmico
city: Roma
country: Italy
facility: U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS
city: Verona
country: Italy
facility: Ospedal Policlinico Giambattista Rossi diBorga Roma
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Saitama-shi
country: Japan
facility: Saitama Children's Medical Center
state: Saitama
city: Shizuoka-city
country: Japan
facility: National Epilepsy Center Shizuoka Institute
state: Shizuoka
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo
city: Barcelona
country: Spain
facility: Hospital Sant Joande Déu
city: Madrid
country: Spain
facility: Hospital Ruber Internacional Primera Planta Servicio de Neurologia
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria
city: Birmingham
country: United Kingdom
facility: Birmingham Children Hospital
city: Glasgow
country: United Kingdom
facility: Institute of Neurosciences Queens Elizabeth University Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Hospital
city: London
country: United Kingdom
facility: Evelina Hospital
city: London
country: United Kingdom
facility: Great Ormonnd Street Hospital for Children NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
Study officials:
affiliation: 001 844 599 2273
name: UCB Cares
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.