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

Dravet Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02823145
• Other study ID #: ZX008-1503
• Secondary ID: 2016-002804-14
• Status: Completed
• Phase: Phase 3
• Start date: June 8, 2016
• Est. completion date: January 27, 2023

Study information

• Verified date: September 2023
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 375
• Est. completion date: January 27, 2023
• Est. primary completion date: January 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 35 Years

Eligibility

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.

Related Conditions & MeSH terms

• Dravet Syndrome
• Epilepsies, Myoclonic
• Syndrome

Intervention

Drug:
• ZX008 (Fenfluramine Hydrochloride)

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  France,  Germany,  Italy,  Japan,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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