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

NCT02682927 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: ZX008-1501ZX008-1502
• Study Type: interventional
• Target: 262
• Locations: 11 countries
• Sites: 55

Brief Summary

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.

Conditions

Dravet Syndrome; Seizure Disorder

Keywords

seizure; tonic-atonic; clonic; epilepsy; myoclonic; encephalopathy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in the Mean Convulsive Seizures Frequency (MCSF) to the Combined Titration and Maintenance Periods (T+M) in Participants Receiving ZX008 0.8 mg/kg/Day Compared to Placebo

  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.

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Secondary Outcomes (24)

• Change From Baseline in the Mean Convulsive Seizures Frequency to the Combined Titration and Maintenance Period (T+M) in Participants Receiving ZX008 0.2 mg/kg/Day Compared to Placebo

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

• Percentage of Participants Who Achieved Greater Than or Equal to 25% (≥25%) Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

• Percentage of Participants Who Achieved a ≥50% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

• Percentage of Participants Who Achieved a ≥75% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

• Percentage of Participants Who Achieved a 100% Reduction in Convulsive Seizure Frequency in Each ZX008 Treatment Arm Compared to Placebo From Baseline During the Titration and Maintenance Period

  From Baseline up to 14 weeks [Titration Period (2 weeks) plus Maintenance Period (12 weeks)]

Study Arms (3)

ZX008 - 0.8 mg/kg/day

EXPERIMENTAL

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.

Drug: ZX008 (Fenfluramine Hydrochloride)

ZX008 - 0.2 mg/kg/day

EXPERIMENTAL

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.

Drug: ZX008 (Fenfluramine Hydrochloride)

Matching Placebo

PLACEBO COMPARATOR

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

Drug: Matching Placebo

Interventions

ZX008 (Fenfluramine Hydrochloride) 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 - 0.8 mg/kg/day

Matching Placebo DRUG

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

Matching Placebo

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.: lead

Study Sites (55)

Phoenix Children's

Phoenix, Arizona, 85016, United States

Location

Center for Neurosciences - Tucson

Tucson, Arizona, 85718, United States

Location

Rady Children's Hospital San Diego

San Diego, California, 92123, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

The Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

NW FL Clinical Research Group, LLC

Gulf Breeze, Florida, 32561, United States

Location

Miami Children's Hospital Brain Institute

Miami, Florida, 33155, United States

Location

Neurology and Epilepsy Research Center

Orlando, Florida, 32819, United States

Location

Panda Neurology

Atlanta, Georgia, 30328, United States

Location

Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02467, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Saint Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Cook Children's Medical Center

Fort Worth, Texas, 76087, United States

Location

University of Utah

Salt Lake City, Utah, 84113, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

MultiCare Institute for Research & Innovation

Tacoma, Washington, 98405, United States

Location

Melbourne Brain Centre Austin Hospital

Melbourne, Australia

Location

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

South Brisbane, Australia

Location

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

Westmead, Australia

Location

Universitair Ziekenhuis Antwerpen

Antwerp, Belgium

Location

British Columbia Children's Hospital BCCH

Vancouver, British Columbia, V6H3V4, Canada

Location

Centre Hospitalier Universitaire Sainte-Justine

Montreal, H3T 1C5, Canada

Location

Danish National Epilepsy Centre

Dianalund, Denmark

Location

French Ref centre Necker Hospital Paris

Paris, France

Location

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

Berlin, Germany

Location

Krankenhaus Mara Epilepsie-Zentrum Bethel

Bielefeld, Germany

Location

Epilepsiezentrum Freiburg

Freiburg im Breisgau, Germany

Location

Universitaetsklinikum Jena Klinik fuer Kinder- und Jugendmedizin Neuropaediatrie

Jena, Germany

Location

Klinik für Neuropädiatrie Universitätsklinikum Schleswig Holstein Campus Kiel

Kiel, Germany

Location

Kleinwachau Saechsisches Epilepsiezentrum Radeberggemeinnuetzige GmbH

Radeberg, Germany

Location

Universitaetsklinik fuer Kinder- und Jugendmedizin Abteilung III

Tübingen, Germany

Location

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

Vogtareuth, Germany

Location

AOU Anna Meyer

Florence, 50139, Italy

Location

Istituto Pediatrico Giannina Gaslini Dipartimento di Neurologia

Genova, Italy

Location

A.O Carlo Poma

Mantova, 46100, Italy

Location

Instituto Neurologica Carlo Besta

Milan, 20133, Italy

Location

Ospedale Fatebenefratelli e Oftalmico

Milan, Italy

Location

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

Roma, 00165, Italy

Location

Ospedal Policlinico Giambattista Rossi diBorga Roma

Verona, 37134, Italy

Location

Okayama University Hospital

Okayama, Okayama-ken, Japan

Location

Saitama Children's Medical Center

Saitama-shi, Saitama, Japan

Location

National Epilepsy Center Shizuoka Institute

Shizuoka, Shizuoka, Japan

Location

Tokyo Women's Medical University Hospital

Shinjuku-ku, Tokyo, Japan

Location

Hospital Sant Joande Déu

Barcelona, Spain

Location

Hospital Ruber Internacional Primera Planta Servicio de Neurologia

Madrid, Spain

Location

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

Pamplona, Spain

Location

Birmingham Children Hospital

Birmingham, United Kingdom

Location

Institute of Neurosciences Queens Elizabeth University Hospital

Glasgow, United Kingdom

Location

Alder Hey Hospital

Liverpool, United Kingdom

Location

Evelina Hospital

London, United Kingdom

Location

Great Ormonnd Street Hospital for Children NHS Foundation Trust

London, United Kingdom

Location

Sheffield Children's Hospital

Sheffield, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 37543865 RESULT

• 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.

  PMID: 34768178 DERIVED

• 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.

  PMID: 34676542 DERIVED

• 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.

  PMID: 33540241 DERIVED

• 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.

  PMID: 31862249 DERIVED

MeSH Terms

Conditions

Epilepsies, Myoclonic; Epilepsy; Seizures; Brain Diseases

Interventions

Fenfluramine

Condition Hierarchy (Ancestors)

Epilepsy, Generalized; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Limitations and Caveats

The full results posting consists of the pooled analysis 1 and 2 of the studies with study ID ZX008-1501 and ZX008-1502. Pooled analysis 1 is referenced as Study 1 in the respective statistical analysis plan (SAP) and corresponding clinical study report (CSR). Pooled analysis 2 is referenced as Study 2 in the respective SAP and, due to the timing of regulatory submissions, Study 3 in the corresponding CSR and in this results posting.

Results Point of Contact

• Title: UCB
• Organization: Cares

UCBCares@ucb.com

001 844 599 2273

Study Officials

• UCB Cares

  001 844 599 2273

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2016
• First Posted: February 17, 2016
• Study Start: January 15, 2016
• Primary Completion: July 29, 2020
• Study Completion: July 29, 2020
• Last Updated: September 28, 2023
• Results First Posted: October 19, 2022

Record last verified: 2023-09

Locations

DK (1); AU (3); JP (4); IT (7); CA (2); GB (6); BE (1); ES (3); DE (8); US (19); FR (1)