An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution in Children and Young Adults With Dravet Syndrome

An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride HCl) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome

This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.

Study Overview

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

Detailed Description

This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who participated in one of the core studies (ZX008-1501 and ZX008-1502) and are candidates for continuous treatment for an extended period of time. This trial will consist of a 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing Period.

• Study Type: Interventional
• Enrollment (Actual): 375
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Heidelberg, Australia
    • Melbourne Brain Centre Austin Hospital
  • South Brisbane, Australia
    • Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital
  • Westmead, Australia
    • The Children's Hospital Westmead Dept. of Neurology and Neurosurgery
• Belgium
  • Edegem, Belgium
    • Universitair Ziekenhuis Antwerpen
• Canada
  • Montréal, Canada
    • Centre Hospitalier Universitaire Sainte-Justine
  • Vancouver, Canada
    • British Columbia Children's Hospital
• Denmark
  • Dianalund, Denmark
    • Danish National Epilepsy Centre
• France
  • Amiens, France
    • CHU Amiens-Picardie Service De Neurologie Pediatrique
  • Bordeaux, France
    • CHU De Bordeaux Service De Pédiatrie Médicale
  • Lille, France
    • CHRU Lille Antenne Pédiatrique Du CIC - Hôpital Jeanne De Flandre
  • Marseille, France
    • HOPITAL DEL LA TIMONE - HOPITAL HENRI GASTAUT Hôpital De La Timone Neurologie Pédiatrique Pneumologie Pédiatrique Et Médecine Infantile
  • Paris, France
    • Hôpital Robert Debré Pôle: Pédiatrie Médicale Service: Neurologie Et Maladies Métaboliques
  • Paris, France
    • Hôpital Universitaire Necker-Enfants Malades Service de neurologie pédiatrique Centre de référence épilepsies rares (CReER)
• Germany
  • Berlin, Germany
    • DRK Kliniken Berlin - Westend Epilepsiezentrum / Neuropaediatrie
  • Bielefeld, Germany
    • Krankenhaus Mara Epilepsie-Zentrum Bethel
  • Freiburg, Germany
    • Universitaetsklinikum Freiburg Zentrum fuer Kinder- und Jugendmedizin
  • Jena, Germany
    • Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie
  • Kiel, Germany
    • Universitaetsklinikum Schleswig-Holstein Campus Kiel Klinik fuer Neuropaediatrie
  • Radeberg, Germany
    • Kleinwachau Saechsisches Epilepsiezentrum Radeberg gemeinnuetzige GmbH
  • Tübingen, Germany
    • Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III
  • Vogtareuth, Germany
    • Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische, Tagesklinik fuer Neuropaediatrie
• Italy
  • Firenze, Italy
    • AOU Anna Meyer Clinica di Neurologia Pediatrica
  • Genova, Italy
    • Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia
  • Mantova, Italy
    • A.O. Carlo Poma
  • Milano, Italy
    • Ospedale Fatebenefratelli e Oftalmico
  • Milano, Italy
    • Istituto Neurologica Carlo Besta
  • Roma, Italy
    • Policlinico A. Gemelli
  • Roma, Italy
    • U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù
  • Verona, Italy
    • Ospedale Civile Maggiore di Borgo Trento - Ospedale della Donna e del Bambino
• Japan
  • Saitama, Japan
    • Saitama Children's Medical Center
  • Shizuoka, Japan
    • National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorders
  • Tokyo, Japan
    • Tokyo Women's Medical University Hospital
• Netherlands
  • Heeze, Netherlands
    • Kempenhaeghe
  • Zwolle, Netherlands
    • Stichting Epilepsie Instellingen Nederland
• Spain
  • Barcelona, Spain
    • Hospital Sant Joan de Déu
  • Madrid, Spain
    • Hospital Ruber Internacional Primera Planta Servicio de Neurologia
  • Pamplona, Spain
    • Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Children Hospital NHS Foundation Trust
  • Glasgow, United Kingdom
    • Institute of Neurosciences Queen Elizabeth University Hospital
  • Liverpool, United Kingdom
    • Alder Hey Hospital
  • London, United Kingdom
    • St. Thomas Hospital
  • London, United Kingdom
    • Great Ormond Street Hospital For Children NHS Foundation Trust
  • Sheffield, United Kingdom
    • Sheffield Children's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
    • Tucson, Arizona, United States, 85718
      • Center for Neurosciences - Tucson
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92123
      • Rady Children's Hospital San Diego
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital Colorado
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • NW FL Clinical Research Group, LLC
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital Brain Institute
    • Orlando, Florida, United States, 32819
      • Neurology and Epilepsy Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Clinical Integrative Research Center of Atlanta, Panda Neurology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Paul, Minnesota, United States, 55102
      • Minnesota Epilepsy Group, P.A.
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Institute of Neurology and Neurosurgery at St. Barnabus
  • Ohio
    • Cleveland, Ohio, United States, 44103
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Le Bonheur Children's Hospital
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research & Innovation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the core study Screening Visit.
• Satisfactory completion of the core study in the opinion of the investigator and the sponsor.
• Subjects who are >18 to ≤35 years of age at the time of screening and did not participate in one of the core studies may be eligible for participation.
• A documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
• Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
• Subject's parent/caregiver has been compliant with diary completion during the core study, in the opinion of the investigator (eg, at least 90% compliant).

Key Exclusion Criteria:

• Current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
• Current cardiac valvulopathy or pulmonary hypertension that is clinically significant and warrants discontinuation of study medication.
• Current or past history of glaucoma.
• Moderate or severe hepatic impairment.
• Receiving concomitant therapy with: centrally-acting anorectic agents; monoamineoxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
• Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
• A clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness at Visit 1, 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: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZX008; ZX008 is supplied as an oral solution in a concentration of 2.5 mg/mL. Subjects will be titrated to an effective dose beginning with 0.2 mg/kg/day (maximum: 30 mg/day).	Drug: ZX008 (Fenfluramine Hydrochloride)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period	Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment.	From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period	A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported.	From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period	Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion.	From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period	Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo participants (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.	From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period	Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.	From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36)	Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where, i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE.	At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36
Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period	Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to <0.4 mg/kg), medium (0.4 to <0.6 mg/kg), and high dose (>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected.	From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period	Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported.	At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period

Collaborators and Investigators

• Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• Investigators: Study Director: UCB Cares, 001 844 599 2273

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.

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2016
• Primary Completion (Actual): January 27, 2023
• Study Completion (Actual): January 27, 2023

Study Registration Dates

• First Submitted: June 13, 2016
• First Submitted That Met QC Criteria: July 5, 2016
• First Posted (Estimated): July 6, 2016

Study Record Updates

• Last Update Posted (Actual): September 25, 2023
• Last Update Submitted That Met QC Criteria: September 22, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: epilepsy; seizure; myoclonic; encephalopathy; tonic clonic
• 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; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Selective Serotonin Reuptake Inhibitors; Fenfluramine
• Other Study ID Numbers: ZX008-1503; 2016-002804-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

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