A Trial of Two Fixed Doses of ZX008 (Fenfluramine HCl) in Children and Young Adults With Dravet Syndrome

NCT ID: NCT02682927

Last Updated: 2023-09-28

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

262 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-01-15

Study Completion Date

2020-07-29

Brief Summary

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Study 1 and Study 3 are the prospective, merged analyses of 2 identical double-blind, placebo-controlled studies, ZX008-1501 and ZX008-1502, to assess the efficacy, safety, and pharmacokinetics of ZX008 when used as adjunctive therapy in pediatric and young adult subjects with Dravet syndrome. Study 1501 and Study 1502 were conducted in parallel; Study 1501 was conducted at approximately 30 study sites in North America; Study 1502 was conducted at approximately 30 study sites in Europe, Asia and Australia. Upon completion of the Baseline Period after initial Screening and Baseline charting of seizure frequency, subjects who qualified for the studies were randomized (1:1:1) in a double-blind manner to receive either 1 of 2 doses of ZX008 (0.2 mg/kg/day or 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization was stratified by age group (\< 6 years, ≥6 to 18 years) to achieve balance across treatment arms, with the target of 25% of subjects in each age group. All subjects were titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects continued treatment at their randomly assigned dose over a 12-week Maintenance Period. Subjects exiting the study underwent a 2-week taper, unless they enrolled in a follow-on study. Subjects were followed for post-study safety monitoring.

Detailed Description

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Conditions

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Dravet Syndrome Seizure Disorder

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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ZX008 - 0.8 mg/kg/day

ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.

Group Type EXPERIMENTAL

ZX008 (Fenfluramine Hydrochloride)

Intervention Type DRUG

ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet.

ZX008 - 0.2 mg/kg/day

ZX008 (fenfluramine HCl) is supplied as an oral solution in concentrations of 1.25, 2.5, and 5 mg/mL. ZX008 will be administered twice a day (BID) in equally divided doses with food.

Group Type EXPERIMENTAL

ZX008 (Fenfluramine Hydrochloride)

Intervention Type DRUG

ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet.

Matching Placebo

Placebo will be administered twice a day (BID) in equally divided doses with food.

Group Type PLACEBO_COMPARATOR

Matching Placebo

Intervention Type DRUG

Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.

Interventions

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ZX008 (Fenfluramine Hydrochloride)

ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5. The product is sugar free and is intended to be compatible with a ketogenic diet.

Intervention Type DRUG

Matching Placebo

Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the Screening Visit.
* Clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
* Must have a minimum # of convulsive seizures per 4-week period for past 12 weeks prior to screening.
* All medications or interventions for epilepsy must be stable for at least 4 weeks prior to screening and expected to remain stable throughout the study.
* No cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or physical examination.
* Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.

Exclusion Criteria

* Pulmonary arterial hypertension.
* Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke.
* Current or past history of glaucoma.
* Moderate or severe hepatic impairment.
* Receiving concomitant therapy with: anorectic agents; monoamine-oxidase inhibitors; medications that act via serotonin including serotonin reuptake inhibitors; atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine.
* Currently receiving or has received stiripentol in the past 21 days prior to Screening.
* Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days.
* Positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test at the Screening Visit.
* A clinically significant medical condition,that would interfere with study participation, collection of study data, or pose a risk to the subject.
Minimum Eligible Age

2 Years

Maximum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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UCB Cares

Role: STUDY_DIRECTOR

001 844 599 2273

Locations

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Phoenix Children's

Phoenix, Arizona, United States

Site Status

Center for Neurosciences - Tucson

Tucson, Arizona, United States

Site Status

Rady Children's Hospital San Diego

San Diego, California, United States

Site Status

University of California San Francisco

San Francisco, California, United States

Site Status

The Children's Hospital Colorado

Aurora, Colorado, United States

Site Status

NW FL Clinical Research Group, LLC

Gulf Breeze, Florida, United States

Site Status

Miami Children's Hospital Brain Institute

Miami, Florida, United States

Site Status

Neurology and Epilepsy Research Center

Orlando, Florida, United States

Site Status

Panda Neurology

Atlanta, Georgia, United States

Site Status

Children's Hospital of Chicago

Chicago, Illinois, United States

Site Status

Massachusetts General Hospital

Boston, Massachusetts, United States

Site Status

Boston Children's Hospital

Boston, Massachusetts, United States

Site Status

Mayo Clinic

Rochester, Minnesota, United States

Site Status

Saint Barnabas Medical Center

Livingston, New Jersey, United States

Site Status

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Site Status

Cook Children's Medical Center

Fort Worth, Texas, United States

Site Status

University of Utah

Salt Lake City, Utah, United States

Site Status

Seattle Children's Hospital

Seattle, Washington, United States

Site Status

MultiCare Institute for Research & Innovation

Tacoma, Washington, United States

Site Status

Melbourne Brain Centre Austin Hospital

Melbourne, , Australia

Site Status

Children's Health Queensland Hospital and Health Service at Lady Cilento Children's Hospital

South Brisbane, , Australia

Site Status

The Children's Hospital Westmead Dept. of Neurology and Neurosurgery

Westmead, , Australia

Site Status

Universitair Ziekenhuis Antwerpen

Antwerp, , Belgium

Site Status

British Columbia Children's Hospital BCCH

Vancouver, British Columbia, Canada

Site Status

Centre Hospitalier Universitaire Sainte-Justine

Montreal, , Canada

Site Status

Danish National Epilepsy Centre

Dianalund, , Denmark

Site Status

French Ref centre Necker Hospital Paris

Paris, , France

Site Status

Epilepsiezentrum / Neuropädiatrie Hedwig-von-Rittberg-Zentrum Für Kinder und Jugendliche

Berlin, , Germany

Site Status

Krankenhaus Mara Epilepsie-Zentrum Bethel

Bielefeld, , Germany

Site Status

Epilepsiezentrum Freiburg

Freiburg im Breisgau, , Germany

Site Status

Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie

Jena, , Germany

Site Status

Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel

Kiel, , Germany

Site Status

Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH

Radeberg, , Germany

Site Status

Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III

Tübingen, , Germany

Site Status

Schoen Klinik Vogtareuth Neuropaediatrie und Neurologische Rehabilitation, Epilepsiezentrum fuer Kinder und Jugendlische,Tagesklinik fuer Neuropaediatrie

Vogtareuth, , Germany

Site Status

AOU Anna Meyer

Florence, , Italy

Site Status

Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia

Genova, , Italy

Site Status

A.O Carlo Poma

Mantova, , Italy

Site Status

Instituto Neurologica Carlo Besta

Milan, , Italy

Site Status

Ospedale Fatebenefratelli e Oftalmico

Milan, , Italy

Site Status

U.O. Neurologia Dipartimento di Neuroscienze Ospedale Pediatrico Bambino Gesù, IRCS

Roma, , Italy

Site Status

Ospedal Policlinico Giambattista Rossi diBorga Roma

Verona, , Italy

Site Status

Okayama University Hospital

Okayama, Okayama-ken, Japan

Site Status

Saitama Children's Medical Center

Saitama-shi, Saitama, Japan

Site Status

National Epilepsy Center Shizuoka Institute

Shizuoka, Shizuoka, Japan

Site Status

Tokyo Women's Medical University Hospital

Shinjuku-ku, Tokyo, Japan

Site Status

Hospital Sant Joande Déu

Barcelona, , Spain

Site Status

Hospital Ruber Internacional Primera Planta Servicio de Neurologia

Madrid, , Spain

Site Status

Clinica Universitaria de Navarra Fase 4. Segunda planta, Consulta de Pediatria

Pamplona, , Spain

Site Status

Birmingham Children Hospital

Birmingham, , United Kingdom

Site Status

Institute of Neurosciences Queens Elizabeth University Hospital

Glasgow, , United Kingdom

Site Status

Alder Hey Hospital

Liverpool, , United Kingdom

Site Status

Evelina Hospital

London, , United Kingdom

Site Status

Great Ormonnd Street Hospital for Children NHS Foundation Trust

London, , United Kingdom

Site Status

Sheffield Children's Hospital

Sheffield, , United Kingdom

Site Status

Countries

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

References

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Sullivan J, Lagae L, Cross JH, Devinsky O, Guerrini R, Knupp KG, Laux L, Nikanorova M, Polster T, Talwar D, Ceulemans B, Nabbout R, Farfel GM, Galer BS, Gammaitoni AR, Lock M, Agarwal A, Scheffer IE; FAiRE DS Study Group. Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial. Epilepsia. 2023 Oct;64(10):2653-2666. doi: 10.1111/epi.17737. Epub 2023 Aug 17.

Reference Type RESULT
PMID: 37543865 (View on PubMed)

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.

Reference Type DERIVED
PMID: 34768178 (View on PubMed)

Sullivan J, Specchio N, Devinsky O, Auvin S, Perry MS, Strzelczyk A, Gil-Nagel A, Dai D, Galer BS, Gammaitoni AR. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis. Epilepsia. 2022 Jan;63(1):130-138. doi: 10.1111/epi.17106. Epub 2021 Oct 22.

Reference Type DERIVED
PMID: 34676542 (View on PubMed)

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.

Reference Type DERIVED
PMID: 33540241 (View on PubMed)

Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019 Dec 21;394(10216):2243-2254. doi: 10.1016/S0140-6736(19)32500-0. Epub 2019 Dec 17.

Reference Type DERIVED
PMID: 31862249 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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ZX008-1502

Identifier Type: OTHER

Identifier Source: secondary_id

ZX008-1501

Identifier Type: -

Identifier Source: org_study_id

NCT02826863

Identifier Type: -

Identifier Source: nct_alias

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