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

NCT02926898 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: ZX008-1504
• Study Type: interventional
• Target: 87
• Locations: 7 countries
• Sites: 28

Brief 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.

Conditions

Dravet Syndrome

Keywords

Seizure; Tonic clonic; Epilepsy; Myoclonic; Encephalopathy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period

  15 weeks (combined Titration + Maintenance Period)

• Longest Convulsive Seizure-Free Interval (Days)

  15 weeks (combined Titration + Maintenance Period)

Study Arms (2)

Cohort 2: ZX008 0.5 mg/kg/day

EXPERIMENTAL

ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food.

Drug: ZX008 (Fenfluramine Hydrochloride)

Cohort 2: Matching Placebo

PLACEBO COMPARATOR

Matching placebo administered twice a day (BID) in equally divided doses with food.

Drug: Matching Placebo

Interventions

ZX008 (Fenfluramine Hydrochloride) DRUG

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.

Cohort 2: ZX008 0.5 mg/kg/day

Matching Placebo DRUG

Matching Placebo

Cohort 2: 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:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (28)

University of California San Francisco

San Francisco, California, 94158, United States

Location

Children'S Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Ann & Robert H. Lurie Children'S Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Children'S Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Bc Children'S Hospital Division of Neurology

Vancouver, British Columbia, V6H 3V4, Canada

Location

Chu Sainte-Justine Hospital Neurology Clinic

Montreal, Quebec, H3T 1C5, Canada

Location

Chu Amiens Picardie Service de Neurologie Pédiatrique

Amiens, 80480, France

Location

Chu de Bordeaux Hôpital Des Enfants

Bordeaux, 33076, France

Location

HÔPITAL FEMME-MÈRE-ENFANT Hôpital Service de Neurologie Pédiatrique

Bron, 69677, France

Location

Chru de Lille Hôpital Roger Salengro

Lille, 59037, France

Location

Hôpital de La Timone, Service de Neuro-Métabolisme Pédiatrique

Marseille, 13385, France

Location

Hôpital Necker-Enfants Malades

Paris, 75015, France

Location

Hôpital Robert-Debré

Paris, 75019, France

Location

Chu de Toulouse - Hôpital Des Enfants

Toulouse, 31059, France

Location

Hôpital D'Enfants Chur de Nancy

Vandœuvre-lès-Nancy, 54511, France

Location

Krankenhaus Mara, Epilepsie-Zentrum Bethel

Bielefeld, 33617, Germany

Location

Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie

Kiel, 24105, Germany

Location

Kleinwachau Sächsisches Epilepsiezentrum Radeberg

Radeberg, 01454, Germany

Location

Epilepsiecentrum Kempenhaeghe

Heeze, 5591 VE, Netherlands

Location

Stichting Epilepsie Instellingen Nederland

Zwolle, 8025 BV, Netherlands

Location

Hospital Sant Joan de Déu Barcelona

Barcelona, 08950, Spain

Location

Hospital Ruber Internacional-Servicio de Neurología

Madrid, 28034, Spain

Location

Cliníca Universidad de Navarra Nidad de Neuropediatría

Pamplona, 31008, Spain

Location

Royal Hospital For Children, Queen Elizabeth University, Institute of Neurosciences Hospital

Glasgow, Scotland, G51 4TF, United Kingdom

Location

Alder Hey Children'S Nhs Foundation Trust, Littlewood'S Neurosciences Unit

Liverpool, L12 2AP, United Kingdom

Location

Evelina London Children'S Hospital, Paediatric Neurosciences

London, SE1 7EH, United Kingdom

Location

Great Ormond Street Hospital For Children Nhs Foundation Trust

London, WC1N 3JH, United Kingdom

Location

Related Publications (3)

• 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 Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020 Mar 1;77(3):300-308. doi: 10.1001/jamaneurol.2019.4113.

  PMID: 31790543 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, 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

MeSH Terms

Conditions

Epilepsies, Myoclonic; Seizures; Epilepsy; 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

Results Point of Contact

• Title: UCB
• Organization: Cares

UCBCares@ucb.com

001 844 599 2273

Publication Agreements

• PI is Sponsor Employee: No
• 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: August 10, 2016
• First Posted: October 6, 2016
• Study Start: January 27, 2017
• Primary Completion: June 5, 2018
• Study Completion: June 5, 2018
• Last Updated: November 2, 2022
• Results First Posted: October 19, 2022

Record last verified: 2022-10

Locations

GB (4); US (5); DE (3); ES (3); NL (2); CA (2); FR (9)