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

• ClinicalTrials.gov Identifier: NCT02682927
• Recruitment Status: Unknown
• First Posted: February 17, 2016
• Last Update Posted: January 7, 2020
• Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• Information provided by (Responsible Party): Zogenix, Inc. ( Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. )

Study Description

Brief Summary:

This is a multicenter, double-blind, parallel-group, placebo-controlled, study to assess the efficacy, safety, and PK of ZX008 when used as adjunctive therapy for uncontrolled seizures in pediatric and young adult subjects with Dravet syndrome. After an initial Screening and Baseline charting of seizure frequency, subjects who qualify for the study will be randomized (1:1:1) to receive either ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization will be stratified by age group (< 6 years, ≥6 to 18 years). All subjects will be titrated to their randomized dose over a 14-day Titration Period. Following titration, subjects will continue treatment at their randomly assigned dose over a 12-week Maintenance Period. Subjects exiting the study will undergo a 2-week taper, unless they enroll in a follow-on study. Subjects will be followed for post-study safety monitoring. Parents/caregivers will use a diary daily to record the number/type of seizures, dosing, and use of rescue medication.

Condition or disease	Intervention/treatment	Phase
Dravet Syndrome; Seizure Disorder	Drug: ZX008 (Fenfluramine Hydrochloride); Drug: Matching Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults With Dravet Syndrome
• Study Start Date: January 2016
• Estimated Primary Completion Date: July 2020
• Estimated Study Completion Date: July 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: 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.
Experimental: 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.	Drug: 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.
Placebo Comparator: Matching Placebo; Placebo will be administered twice a day (BID) in equally divided doses with food.	Drug: Matching Placebo; Placebo solution for ZX008. The product is sugar free and is intended to be compatible with a ketogenic diet.

Outcome Measures

Primary Outcome Measures :

1. Change in mean convulsive seizure frequency comparing the baseline with the combined titration and maintenance period for ZX008 0.8mg/kg/day group compared with placebo group. [ Time Frame: 0-14 weeks ]

Secondary Outcome Measures :

1. Proportion of subjects in each ZX008 treatment arm compared with placebo who were considered treatment responders, defined as those with a ≥40% and ≥50%, reduction in convulsive seizures from baseline. [ Time Frame: 0-14 weeks ]
2. Comparison of subjects' longest seizure-free interval in each ZX008 treatment arm compared with placebo [ Time Frame: 0-14 weeks ]
   Comparison of each subjects' longest convulsive seizure-free interval, and longest interval without any seizures, during the 14-week titration + maintenance period, will be calculated independently for the ZX008 0.8 and 0.2 mg/kg/day treatment groups versus placebo from seizure diary records.
3. Additional secondary outcome measures [ Time Frame: Baseline compared with Titration + Maintenance period, or T+M as appropriate ]
   • The number of convulsive seizure-free days
   • The proportion of subjects who achieve ≥75% reductions from baseline in convulsive seizure frequency
   • The change from baseline in non-convulsive seizure frequency and all seizure frequency
   • The incidence of rescue medication usage, and medical utilization
   • The incidence of status epilepticus
   • Clinical Global Impression - Improvement rating, as assessed by the parent/caregiver
   • The change from baseline in Quality of Life
   • The change from baseline in affective symptoms of the parent/caregiver
4. Safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day compared to placebo [ Time Frame: baseline through study endpoint ]
   Compare safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day and placebo with regard to adverse events (AEs), laboratory parameters, physical examination, neurological examination, vital signs (blood pressure, heart rate, temperature, and respiratory rate), electrocardiograms (ECG), echocardiograms (ECHO), body weight and cognitive function.

Eligibility Criteria

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

Criteria

Key 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.

Key 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.

Contacts and Locations

Locations

United States, Arizona

Phoenix Children's

Phoenix, Arizona, United States, 85016

Center for Neurosciences - Tucson

Tucson, Arizona, United States, 85718

United States, California

Rady Children's Hospital San Diego

San Diego, California, United States, 92123

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, Florida

NW FL Clinical Research Group, LLC

Gulf Breeze, Florida, United States, 32561

Miami Children's Hospital Brain Institute

Miami, Florida, United States, 33155

Neurology and Epilepsy Research Center

Orlando, Florida, United States, 32819

United States, Georgia

Panda Neurology

Atlanta, Georgia, United States, 30328

United States, Illinois

Children's Hospital of Chicago

Chicago, Illinois, United States, 60611

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Boston Children's Hospital

Boston, Massachusetts, United States, 02467

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, New Jersey

Saint Barnabas Medical Center

Livingston, New Jersey, United States, 07039

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Cook Children's Medical Center

Fort Worth, Texas, United States, 76087

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84113

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

MultiCare Institute for Research & Innovation

Tacoma, Washington, United States, 98405

Canada, British Columbia

British Columbia Children's Hospital BCCH

Vancouver, British Columbia, Canada, V6H3V4

Canada

Centre Hospitalier Universitaire Sainte-Justine

Montréal, Canada, H3T 1C5

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Joseph Sullivan, MD; University of California, San Francisco

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

• Responsible Party: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• ClinicalTrials.gov Identifier: NCT02682927
• Other Study ID Numbers: ZX008-1501
• First Posted: February 17, 2016
• Last Update Posted: January 7, 2020
• Last Verified: January 2020

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

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

Additional relevant MeSH terms:

Seizures; Epilepsies, Myoclonic; Epilepsy; Syndrome; Disease; Pathologic Processes; Neurologic Manifestations; Nervous System Diseases; Epilepsy, Generalized; Brain Diseases; Central Nervous System Diseases; Epileptic Syndromes; Fenfluramine; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Physiological Effects of Drugs