A Two-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

Study Description

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Brief Summary:

The primary purpose of this study is to evaluate the safety, tolerability and efficacy of a single dose of ZX008 (Fenfluramine Hydrochloride) when added to standard of care and when added to Adjunctive Antiepleptic therapy to Stiripentol treatment in children and young adults with Dravet Syndrome

Condition or disease	Intervention/treatment	Phase
Dravet Syndrome	Drug: ZX008 - 0.2 mg/kg/day; Drug: ZX008 - 0.4 mg/kg/day; Drug: ZX008 - 20 mg/day maximum dose; Drug: Matching Placebo	Phase 3

Detailed Description:

This is a multicenter, two-cohort trial to assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to Dravet syndrome treatment regimen containing VPA and CLB, with or without 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). Cohort 2 will not be dosed until the PK and safety data from Cohort 1 have been collected and evaluated. The PK and safety data from Cohort 1 will determine the dose of ZX008 to be used in Cohort 2.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	105 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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 , 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
Study Start Date :	September 2016
Actual Primary Completion Date :	June 2018
Actual Study Completion Date :	January 8, 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: ZX008 - 0.2 mg/kg/day - Cohort 1; ZX008 0.2 mg/kg/day is supplied as an oral solution and will be administered twice a day (BID) in equally divided doses with food. Product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH5	Drug: ZX008 - 0.2 mg/kg/day; ZX008 - 0.2 mg/kg/day ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 1.25 mg/mL, 2.5 mg/ mL, and 5 mg/mL. The product is sugar free and is intended to be compatible with KD.; Other Name: Cohort 1
Experimental: ZX008 - 0.4 mg/kg/day - Cohort 1; ZX008 - 0.4 mg/kg/day is supplied as an oral solution and will be administered twice a day (BID) in equally divided doses with food. Product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH5	Drug: ZX008 - 0.4 mg/kg/day; ZX008 - 0.4 mg/kg/day ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 1.25 mg/mL, 2.5 mg/ mL, and 5 mg/mL. The product is sugar free and is intended to be compatible with KD.; Other Name: Cohort 1
Experimental: ZX008 - 20 mg/day maximum - Cohort 2; ZX008 - 20 mg/day maximum dose is supplied as an oral solution administered twice a day day (BID) in equally divided doses with food. Dose to be determined based on based on Cohort 1 . Product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH5	Drug: ZX008 - 20 mg/day maximum dose; ZX008 - 20 mg/day maximum dose ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and; Other Name: Cohort 2
Placebo Comparator: Matching Placebo - Cohort 2; Matching placebo will be administered twice a day (BID) in equally divided doses with food.	Drug: Matching Placebo; ZX008 Matching Placebo; Other Name: Cohort 2

Outcome Measures

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Primary Outcome Measures :

1. Change from baseline in frequency of convulsive seizures in subjects receiving ZX008 0.2 mg/kg/day as adjunctive therapy compared to placebo [ Time Frame: Time between 6-week baseline assessment period and 12 week treatment and maintenance period ]
   Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity

Secondary Outcome Measures :

1. Change from baseline in frequency of convulsive seizures in subjects receiving ZX008 0.4 mg/kg/day as adjunctive therapy compared to placebo [ Time Frame: Time between 6-week baseline assessment period and 12 week treatment and maintenance period ]
   Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity
2. Proportion of subjects achieving a ≥40% or ≥50% reduction from baseline in convulsive seizure frequency and longest seizure-free interval in subjects receiving ZX008 0.2 and 0.4 mg/kg/day as adjunctive therapy compared to placebo [ Time Frame: Time between 6-week baseline assessment period and combined 12 week treatment and maintenance period ]
   Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity

Other Outcome Measures:

1. Safety and tolerability of ZX008 0.2 and 0.4 mg/kg/day as adjunctive therapy compared to placebo [ Time Frame: Week 1 through Week 12 ]
   Safety and tolerability evaluated by reported adverse events, laboratory parameters, physical and neurological examination, vital signs, electrocardiograms, echocardiograms, and body weight. (Cognitive function will be assessed using age-appropriate versions of the Brief Rating Inventory of Executive Function [BRIEF].)

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 18 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Key Inclusion Criteria:

• Subject must be male or non-pregnant, non-lactating female, age 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 CLB, VP, and STP for at least 4 weeks prior to screening and are expected to remain stable throughout the study (Cohort 2 only).
• Subject must be receiving a stable dose of CLB and VPA, administered twice daily, to be eligible for Dose Regimen 1 and 2 or subject must be receiving a stable dose of CLB, VPA, and STP, administered twice daily, 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 re-uptake inhibition; triptans, atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or CYP 2D6/3A4/2B6 inhibitors/substrates.
• Subject is currently taking carbamazepine, oxcarbamazepine, 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 THC Panel or whole blood 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.

Contacts and Locations

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Locations

United States, California
University of California San Francisco
San Francisco, California, United States, 94143
United States, Colorado
The Children'S Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Illinois
Ann & Robert Lurie Children'S Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Canada, British Columbia
British Columbia Children'S Hospital
Vancouver, British Columbia, Canada, V6H3V4
Canada, Quebec
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
France
Chu Amiens Picardie Service de Neurologie Pediatrique
Amiens, France, 80054
CHU DE BORDEAUX Service De Pédiatrie Médicale
Bordeaux, France, 33000
CHRU LILLE Centre Hospitalier Régional Universitaire De Lille 2
Lille, France, 59037
HÔPITAL FEMME-MÈRE-ENFANT Hôpital Femme-mère-enfant Service De Neurologie Pédiatrique
Lyon, France, 69500
Hôpital La Timone, Service de Neurologie Pédiatrique
Marseille, France, 13385
Hôpital Necker
Paris, France, 75743
Hôpital Robert Debré
Paris, France, 75743
CENTRE REFERENT DES EPILEPSIES Hopital De Hautpierre
Strasbourg Cedex, France, F-67098
HÔPITAL DES ENFANTS Pédiatrie
Toulouse Cedex 9, France, 31059
Hopital Denfants Chru de Nancy
Vandoeuvre Les Nancy Cedex, France, 54511
Germany
Krankenhaus Mara Ggmbh, Epilepsiezentrum Bethel
Bielefeld, Germany, 33617
Universitätsklinikum Schleswig-Holstein, Klinik Für Neuropädiatrie
Kiel, Germany, 24105
Kleinwachau Sächsisches Epilepsiezentrum Radeberg Gemeinnützige Gmbh
Radeberg, Germany, 1454
Netherlands
Kempenhaeghe
Heeze, Netherlands, 5590 Ab
Stichting Epilepsie Instellingen Nederland
Zwolle, Netherlands, 8025 BV
Spain
Hospital Sant Joan de Déu
Barcelona, Spain, 08950
Hospital Ruber Internacional Primera Planta Servicio de Neurologia
Madrid, Spain, 28034
Clinica Universitaria de Navarra
Pamplona, Spain, 31008
United Kingdom
Institute of Neurosciences Queens Elizabeth University
Glasgow, United Kingdom, G51 4TF
Alder Hey Children'S Nhs Foundation Trust
Liverpool, United Kingdom, L12 2AP
Evelina Hospital
London, United Kingdom, SE1 7EH
Great Ormonnd Street Hospital For Children Nhs Foundation Trust
London, United Kingdom, WC1N 3JH

Sponsors and Collaborators

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

More Information

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Responsible Party:	Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
ClinicalTrials.gov Identifier:	NCT02926898 History of Changes
Other Study ID Numbers:	ZX008-1504
First Posted:	October 6, 2016
Last Update Posted:	January 10, 2019
Last Verified:	January 2019

Keywords provided by Zogenix, Inc. ( Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. ):

seizure; tonic clonic; epilepsy; myoclonic; encephalopathy

Additional relevant MeSH terms:

Syndrome; Epilepsies, Myoclonic; Spasms, Infantile; Rett Syndrome; Disease; Pathologic Processes; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations	Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Pharmaceutical Solutions; Fenfluramine; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs