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

• ClinicalTrials.gov Identifier: NCT02926898
• Recruitment Status: Completed
• First Posted: October 6, 2016
• Last Update Posted: June 13, 2019
• 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:

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

• 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

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

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

• 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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Sponsors and Collaborators

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

More Information

• 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: June 13, 2019
• Last Verified: June 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:

Epilepsies, Myoclonic; Spasms, Infantile; Syndrome; Disease; Pathologic Processes; Epilepsy, Generalized; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; 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