Clinical trial NCT02926898: A 2-Part Study to Investigate the Dose-Ranging Safety and Pharmacokinetics, Followed by the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children ≥ 2 Years Old and Young Adults With Dravet Syndrome
Official title: A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults With Dravet Syndrome (Cohort 2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Dravet Syndrome
Keywords: Seizure
Tonic clonic
Epilepsy
Myoclonic
Encephalopathy
Lead sponsor: UCB Pharma
Sponsor class: INDUSTRY
First posted: 2016-10-06
Enrollment: 87
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: The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of ZX008 (fenfluramine hydrochloride) when added to adjunctive antiepileptic stiripentol treatment in children and young adults with Dravet syndrome.

Detailed description: This is a multicenter, 2-cohort trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to a standard Dravet syndrome treatment regimen containing valproate (VPA) and clobazam (CLB), with or without stiripentol (STP) (Cohort 1), followed by a randomized, double-blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2).

Eligibility criteria: Key Inclusion Criteria:

* Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive).
* Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
* Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only).
* Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only).

Key Exclusion Criteria:

* Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
* Subject has pulmonary arterial hypertension.
* Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke.
* Subject has a current or recent history of anorexia nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month.
* Subject has a current or past history of glaucoma.
* Subject is receiving concomitant therapy with: centrally acting anorectic agents; monoamine-oxidase inhibitors; any centrally acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
* Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
* Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit.
* Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.

Primary outcomes:
measure: Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
timeFrame: 15 weeks (combined Titration + Maintenance Period)
Secondary outcomes:
measure: Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
timeFrame: 15 weeks (combined Titration + Maintenance Period)
measure: Longest Convulsive Seizure-Free Interval (Days)
timeFrame: 15 weeks (combined Titration + Maintenance Period)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: Children'S Hospital Colorado
state: Colorado
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children'S Hospital of Chicago
state: Illinois
city: Detroit
country: United States
facility: Children'S Hospital of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Vancouver
country: Canada
facility: Bc Children'S Hospital Division of Neurology
state: British Columbia
city: Montréal
country: Canada
facility: Chu Sainte-Justine Hospital Neurology Clinic
state: Quebec
city: Amiens
country: France
facility: Chu Amiens Picardie Service de Neurologie Pédiatrique
city: Bordeaux
country: France
facility: Chu de Bordeaux Hôpital Des Enfants
city: Bron
country: France
facility: HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique
city: Lille
country: France
facility: Chru de Lille Hôpital Roger Salengro
city: Marseille
country: France
facility: Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
city: Paris
country: France
facility: Hôpital Robert-Debré
city: Toulouse
country: France
facility: Chu de Toulouse - Hôpital Des Enfants
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpital D'Enfants Chur de Nancy
city: Bielefeld
country: Germany
facility: Krankenhaus Mara, Epilepsie-Zentrum Bethel
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
city: Radeberg
country: Germany
facility: Kleinwachau Sächsisches Epilepsiezentrum Radeberg
city: Heeze
country: Netherlands
facility: Epilepsiecentrum Kempenhaeghe
city: Zwolle
country: Netherlands
facility: Stichting Epilepsie Instellingen Nederland
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Déu Barcelona
city: Madrid
country: Spain
facility: Hospital Ruber Internacional-Servicio de Neurología
city: Pamplona
country: Spain
facility: Cliníca Universidad de Navarra Nidad de Neuropediatría
city: Glasgow
country: United Kingdom
facility: Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital
state: Scotland
city: Liverpool
country: United Kingdom
facility: Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit
city: London
country: United Kingdom
facility: Evelina London Children'S Hospital, Paediatric Neurosciences
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children Nhs Foundation Trust
Study officials:
References:
citation: Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, Stephani U, Laux L, Wirrell E, Knupp K, Chiron C, Farfel G, Galer BS, Morrison G, Lock M, Agarwal A, Auvin S; FAiRE, DS Study Group. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020 Mar 1;77(3):300-308. doi: 10.1001/jamaneurol.2019.4113.
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, 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.