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
- Conditions
- Dravet Syndrome
- Interventions
- Drug: ZX008 (Fenfluramine Hydrochloride)Drug: Matching Placebo
- Registration Number
- NCT02926898
- Lead Sponsor
- Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 87
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 2: ZX008 0.5 mg/kg/day ZX008 (Fenfluramine Hydrochloride) ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food. Cohort 2: Matching Placebo Matching Placebo Matching placebo administered twice a day (BID) in equally divided doses with food.
- Primary Outcome Measures
Name Time Method Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period 15 weeks (combined Titration + Maintenance Period) Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period 15 weeks (combined Titration + Maintenance Period) Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.
Longest Convulsive Seizure-Free Interval (Days) 15 weeks (combined Titration + Maintenance Period) Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups.
Trial Locations
- Locations (28)
Evelina London Children'S Hospital, Paediatric Neurosciences
🇬🇧London, United Kingdom
Ann & Robert H. Lurie Children'S Hospital of Chicago
🇺🇸Chicago, Illinois, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital
🇬🇧Glasgow, Scotland, United Kingdom
Chu Sainte-Justine Hospital Neurology Clinic
🇨🇦Montréal, Quebec, Canada
Bc Children'S Hospital Division of Neurology
🇨🇦Vancouver, British Columbia, Canada
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Children'S Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Children'S Hospital Colorado
🇺🇸Aurora, Colorado, United States
Chu de Bordeaux Hôpital Des Enfants
🇫🇷Bordeaux, France
HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique
🇫🇷Bron, France
Chu Amiens Picardie Service de Neurologie Pédiatrique
🇫🇷Amiens, France
Hôpital Robert-Debré
🇫🇷Paris, France
Hôpital D'Enfants Chur de Nancy
🇫🇷Vandœuvre-lès-Nancy, France
Krankenhaus Mara, Epilepsie-Zentrum Bethel
🇩🇪Bielefeld, Germany
Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
🇩🇪Kiel, Germany
Hôpital Necker-Enfants Malades
🇫🇷Paris, France
Chu de Toulouse - Hôpital Des Enfants
🇫🇷Toulouse, France
Chru de Lille Hôpital Roger Salengro
🇫🇷Lille, France
Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique
🇫🇷Marseille, France
Epilepsiecentrum Kempenhaeghe
🇳🇱Heeze, Netherlands
Kleinwachau Sächsisches Epilepsiezentrum Radeberg
🇩🇪Radeberg, Germany
Cliníca Universidad de Navarra Nidad de Neuropediatría
🇪🇸Pamplona, Spain
Stichting Epilepsie Instellingen Nederland
🇳🇱Zwolle, Netherlands
Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit
🇬🇧Liverpool, United Kingdom
Hospital Sant Joan de Déu Barcelona
🇪🇸Barcelona, Spain
Great Ormond Street Hospital For Children Nhs Foundation Trust
🇬🇧London, United Kingdom
Hospital Ruber Internacional-Servicio de Neurología
🇪🇸Madrid, Spain