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

Dravet Syndrome Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02926898
• Other study ID #: ZX008-1504
• Status: Completed
• Phase: Phase 3
• Start date: January 27, 2017
• Est. completion date: June 5, 2018

Study information

• Verified date: October 2022
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: June 5, 2018
• Est. primary completion date: June 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Dravet Syndrome
• Epilepsies, Myoclonic
• Syndrome

Intervention

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.
• Matching Placebo
Matching Placebo

Locations

Country	Name	City	State
Canada	Chu Sainte-Justine Hospital Neurology Clinic	Montréal	Quebec
Canada	Bc Children'S Hospital Division of Neurology	Vancouver	British Columbia
France	Chu Amiens Picardie Service de Neurologie Pédiatrique	Amiens
France	Chu de Bordeaux Hôpital Des Enfants	Bordeaux
France	HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique	Bron
France	Chru de Lille Hôpital Roger Salengro	Lille
France	Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique	Marseille
France	Hôpital Necker-Enfants Malades	Paris
France	Hôpital Robert-Debré	Paris
France	Chu de Toulouse - Hôpital Des Enfants	Toulouse
France	Hôpital D'Enfants Chur de Nancy	Vandœuvre-lès-Nancy
Germany	Krankenhaus Mara, Epilepsie-Zentrum Bethel	Bielefeld
Germany	Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie	Kiel
Germany	Kleinwachau Sächsisches Epilepsiezentrum Radeberg	Radeberg
Netherlands	Epilepsiecentrum Kempenhaeghe	Heeze
Netherlands	Stichting Epilepsie Instellingen Nederland	Zwolle
Spain	Hospital Sant Joan de Déu Barcelona	Barcelona
Spain	Hospital Ruber Internacional-Servicio de Neurología	Madrid
Spain	Cliníca Universidad de Navarra Nidad de Neuropediatría	Pamplona
United Kingdom	Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital	Glasgow	Scotland
United Kingdom	Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit	Liverpool
United Kingdom	Evelina London Children'S Hospital, Paediatric Neurosciences	London
United Kingdom	Great Ormond Street Hospital For Children Nhs Foundation Trust	London
United States	Children'S Hospital Colorado	Aurora	Colorado
United States	Ann & Robert H. Lurie Children'S Hospital of Chicago	Chicago	Illinois
United States	Children'S Hospital of Michigan	Detroit	Michigan
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Netherlands,  Spain,  United Kingdom, 

References & Publications (1)

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 Seizu — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)