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

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)

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.

Study Overview

• Status: Completed
• Conditions: Dravet Syndrome
• Intervention / Treatment: Drug: Matching Placebo; Drug: ZX008 (Fenfluramine Hydrochloride)

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).

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Bc Children'S Hospital Division of Neurology
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • Chu Sainte-Justine Hospital Neurology Clinic
• France
  • Amiens, France, 80480
    • Chu Amiens Picardie Service de Neurologie Pédiatrique
  • Bordeaux, France, 33076
    • Chu de Bordeaux Hôpital Des Enfants
  • Bron, France, 69677
    • HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique
  • Lille, France, 59037
    • CHRU de Lille Hôpital Roger Salengro
  • Marseille, France, 13385
    • Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique
  • Paris, France, 75015
    • Hôpital Necker-Enfants Malades
  • Paris, France, 75019
    • Hôpital Robert-Debré
  • Toulouse, France, 31059
    • CHU de Toulouse - Hôpital des Enfants
  • Vandœuvre-lès-Nancy, France, 54511
    • Hôpital D'Enfants Chur de Nancy
• Germany
  • Bielefeld, Germany, 33617
    • Krankenhaus Mara, Epilepsie-Zentrum Bethel
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
  • Radeberg, Germany, 01454
    • Kleinwachau Sächsisches Epilepsiezentrum Radeberg
• Netherlands
  • Heeze, Netherlands, 5591 VE
    • Epilepsiecentrum Kempenhaeghe
  • Zwolle, Netherlands, 8025 BV
    • Stichting Epilepsie Instellingen Nederland
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu Barcelona
  • Madrid, Spain, 28034
    • Hospital Ruber Internacional-Servicio de Neurología
  • Pamplona, Spain, 31008
    • Cliníca Universidad de Navarra Nidad de Neuropediatría
• United Kingdom
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital For Children NHS Foundation Trust
  • London, United Kingdom, SE1 7EH
    • Evelina London Children'S Hospital, Paediatric Neurosciences
  • Scotland
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital
• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 2: ZX008 0.5 mg/kg/day; 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.	Drug: ZX008 (Fenfluramine Hydrochloride); ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. *Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base.
Placebo Comparator: Cohort 2: Matching Placebo; Matching placebo administered twice a day (BID) in equally divided doses with food.	Drug: Matching Placebo; Matching Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) 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.	15 weeks (combined Titration + Maintenance Period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the 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.	15 weeks (combined Titration + Maintenance Period)
Longest Convulsive Seizure-Free Interval (Days)	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.	15 weeks (combined Titration + Maintenance Period)

Collaborators and Investigators

• Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2017
• Primary Completion (Actual): June 5, 2018
• Study Completion (Actual): June 5, 2018

Study Registration Dates

• First Submitted: August 10, 2016
• First Submitted That Met QC Criteria: October 4, 2016
• First Posted (Estimate): October 6, 2016

Study Record Updates

• Last Update Posted (Actual): November 2, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Epilepsy; Encephalopathy; Seizure; Tonic clonic; Myoclonic
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Disease; Epilepsy; Epilepsies, Myoclonic; Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Fenfluramine
• Other Study ID Numbers: ZX008-1504

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No