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
- Conditions
- Dravet Syndrome
- Interventions
- Drug: ZX008 (Fenfluramine Hydrochloride)
- Registration Number
- NCT02823145
- Lead Sponsor
- Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
- Brief Summary
This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 375
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description ZX008 ZX008 (Fenfluramine Hydrochloride) 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).
- Primary Outcome Measures
Name Time Method Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment.
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) 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.
Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) 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.
- Secondary Outcome Measures
Name Time Method Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) 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 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.
Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period At Month 1, 2, 3, 4 , 5, and 6 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.
Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) 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.
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 From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) 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.
Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) 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.
Trial Locations
- Locations (67)
Kempenhaeghe
🇳🇱Heeze, Netherlands
Rady Children's Hospital San Diego
🇺🇸San Diego, California, United States
Children's Hospital Of Michigan
🇺🇸Detroit, Michigan, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Ospedale Fatebenefratelli e Oftalmico
🇮🇹Milano, Italy
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Miami Children's Hospital Brain Institute
🇺🇸Miami, Florida, United States
Clinical Integrative Research Center of Atlanta, Panda Neurology
🇺🇸Atlanta, Georgia, United States
Institute of Neurology and Neurosurgery at St. Barnabus
🇺🇸Livingston, New Jersey, United States
Neurology and Epilepsy Research Center
🇺🇸Orlando, Florida, United States
NW FL Clinical Research Group, LLC
🇺🇸Gulf Breeze, Florida, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
CHU Amiens-Picardie Service De Neurologie Pediatrique
🇫🇷Amiens, France
Danish National Epilepsy Centre
🇩🇰Dianalund, Denmark
Universitaetsklinikum Freiburg Zentrum fuer Kinder- und Jugendmedizin
🇩🇪Freiburg, Germany
The Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Melbourne Brain Centre Austin Hospital
🇦🇺Heidelberg, Australia
Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie
🇩🇪Jena, Germany
MultiCare Institute for Research & Innovation
🇺🇸Tacoma, Washington, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital
🇦🇺South Brisbane, Australia
Hôpital Robert Debré Pôle: Pédiatrie Médicale Service: Neurologie Et Maladies Métaboliques
🇫🇷Paris, France
Universitair Ziekenhuis Antwerpen
🇧🇪Edegem, Belgium
The Children's Hospital Westmead Dept. of Neurology and Neurosurgery
🇦🇺Westmead, Australia
Hôpital Universitaire Necker-Enfants Malades Service de neurologie pédiatrique Centre de référence épilepsies rares (CReER)
🇫🇷Paris, France
Universitaetsklinikum Schleswig-Holstein Campus Kiel Klinik fuer Neuropaediatrie
🇩🇪Kiel, Germany
Krankenhaus Mara Epilepsie-Zentrum Bethel
🇩🇪Bielefeld, Germany
A.O. Carlo Poma
🇮🇹Mantova, Italy
Ospedale Civile Maggiore di Borgo Trento - Ospedale della Donna e del Bambino
🇮🇹Verona, Italy
Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische, Tagesklinik fuer Neuropaediatrie
🇩🇪Vogtareuth, Germany
Policlinico A. Gemelli
🇮🇹Roma, Italy
AOU Anna Meyer Clinica di Neurologia Pediatrica
🇮🇹Firenze, Italy
Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia
🇮🇹Genova, Italy
Istituto Neurologica Carlo Besta
🇮🇹Milano, Italy
National Epilepsy Center Shizuoka Institute of Epilepsy and Neurological Disorders
🇯🇵Shizuoka, Japan
Birmingham Children Hospital NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Saitama Children's Medical Center
🇯🇵Saitama, Japan
Tokyo Women's Medical University Hospital
🇯🇵Tokyo, Japan
Hospital Sant Joan de Déu
🇪🇸Barcelona, Spain
Alder Hey Hospital
🇬🇧Liverpool, United Kingdom
Hospital Ruber Internacional Primera Planta Servicio de Neurologia
🇪🇸Madrid, Spain
St. Thomas Hospital
🇬🇧London, United Kingdom
Institute of Neurosciences Queen Elizabeth University Hospital
🇬🇧Glasgow, United Kingdom
Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria
🇪🇸Pamplona, Spain
Sheffield Children's Hospital
🇬🇧Sheffield, United Kingdom
HOPITAL DEL LA TIMONE - HOPITAL HENRI GASTAUT Hôpital De La Timone Neurologie Pédiatrique Pneumologie Pédiatrique Et Médecine Infantile
🇫🇷Marseille, France
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montréal, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, Canada
Minnesota Epilepsy Group, P.A.
🇺🇸Saint Paul, Minnesota, United States
Ann and Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
University of California San Francisco
🇺🇸San Francisco, California, United States
CHRU Lille Antenne Pédiatrique Du CIC - Hôpital Jeanne De Flandre
🇫🇷Lille, France
CHU De Bordeaux Service De Pédiatrie Médicale
🇫🇷Bordeaux, France
Kleinwachau Saechsisches Epilepsiezentrum Radeberg gemeinnuetzige GmbH
🇩🇪Radeberg, Germany
Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III
🇩🇪Tübingen, Germany
Great Ormond Street Hospital for Children NHS Foundation Trust
🇬🇧London, United Kingdom
Le Bonheur Children's Hospital
🇺🇸Memphis, Tennessee, United States
Stichting Epilepsie Instellingen Nederland
🇳🇱Zwolle, Netherlands
Center for Neurosciences - Tucson
🇺🇸Tucson, Arizona, United States
DRK Kliniken Berlin - Westend Epilepsiezentrum / Neuropaediatrie
🇩🇪Berlin, Germany
U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù
🇮🇹Roma, Italy