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

Sponsor

Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc. (Industry)

Overall Status

Unknown status

CT.gov ID

NCT02682927

Collaborator

(none)

130

Enrollment

Locations

Arms

Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

Anticipated 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 :

Jan 1, 2016

Anticipated Primary Completion Date :

Jul 1, 2020

Anticipated Study Completion Date :

Jul 1, 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.

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

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. [0-14 weeks]

Secondary Outcome Measures

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. [0-14 weeks]
Comparison of subjects' longest seizure-free interval in each ZX008 treatment arm compared with placebo [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.
Additional secondary outcome measures [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
Safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day compared to placebo [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

Criteria

Ages Eligible for Study:

2 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Phoenix Children's	Phoenix	Arizona	United States	85016
2	Center for Neurosciences - Tucson	Tucson	Arizona	United States	85718
3	Rady Children's Hospital San Diego	San Diego	California	United States	92123
4	University of California San Francisco	San Francisco	California	United States	94143
5	The Children's Hospital Colorado	Aurora	Colorado	United States	80045
6	NW FL Clinical Research Group, LLC	Gulf Breeze	Florida	United States	32561
7	Miami Children's Hospital Brain Institute	Miami	Florida	United States	33155
8	Neurology and Epilepsy Research Center	Orlando	Florida	United States	32819
9	Panda Neurology	Atlanta	Georgia	United States	30328
10	Children's Hospital of Chicago	Chicago	Illinois	United States	60611
11	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
12	Boston Children's Hospital	Boston	Massachusetts	United States	02467
13	Mayo Clinic	Rochester	Minnesota	United States	55905
14	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
15	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
16	Cook Children's Medical Center	Fort Worth	Texas	United States	76087
17	University of Utah	Salt Lake City	Utah	United States	84113
18	Seattle Children's Hospital	Seattle	Washington	United States	98105
19	MultiCare Institute for Research & Innovation	Tacoma	Washington	United States	98405
20	British Columbia Children's Hospital BCCH	Vancouver	British Columbia	Canada	V6H3V4
21	Centre Hospitalier Universitaire Sainte-Justine	Montréal		Canada	H3T 1C5