A Study to Investigate the Efficacy and Safety of ZX008 (Fenfluramine Hydrochloride) as an Adjunctive Therapy in Children and Adults With Lennox-Gastaut Syndrome

Study Overview
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Brief Summary
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This is a two-part, multicenter, double-blind, parallel-group, placebo controlled study to evaluate the effect of ZX008 when used as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS).

Official Title
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A Two-Part Study of ZX008 in Children and Adults With Lennox-Gastaut Syndrome (LGS); Part 1: A Randomized, Double-blind, Placebo-controlled Trial of Two Fixed Doses of ZX008 (Fenfluramine Hydrochloride) Oral Solution as Adjunctive Therapy for Seizures in Children and Adults With LGS, Followed by Part 2: An Open-label Extension to Assess Long-Term Safety of ZX008 in Children and Adults With LGS

Conditions
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Lennox Gastaut Syndrome

Intervention / Treatment
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* Drug: ZX008 0.2 or 0.8 mg/kg/day
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of the day of the Screening Visit. Clinical diagnosis of Lennox-Gastaut syndrome, where seizures that result in drops are not completely controlled by current antiepileptic treatments. Onset of seizures at 11 years of age or younger. Abnormal cognitive development. Must be receiving at least 1 concomitant AED and up to 4 concomitant anti-epileptic treatments. Key Exclusion Criteria: Etiology of seizures is a degenerative neurological disease. History of hemiclonic seizures in the first year of life. Subject only has drop seizures in clusters, where individual seizures cannot be counted reliably. Pulmonary arterial hypertension. Current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke. Receiving concomitant therapy with: centrally-acting anorectic agents; monoamineoxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine. Taking felbamate for less than 1 year prior to screening and/or does not have stable liver function and hematology laboratory tests, and/or the dose has not been stable for at least 60 days prior to the Screening Visit. Currently receiving an investigational product. Institutionalized in a general nursing home (ie, in a facility that does not specialize in epilepsy care). 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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: Double-Blind ZX008 - (0.2 mg/kg/day or 0.8mg/kg/day) or Placebo and Part 2: Open-Label
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ZX008 0.2 or 0.8 mg/kg/day<br>Part 1: ZX008 is supplied as an oral solution. Subjects will be randomized to receive 1 of 2 doses of ZX008 0.2 mg/kg/day or 0.8 mg/kg/day. | Drug: ZX008 0.2 or 0.8 mg/kg/day<br>* ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride. The product is sugar free and is intended to be compatible with a Ketogenic Diet.<br>|
| Placebo Comparator: Matching Placebo<br>Part 1: Matching ZX008 placebo is supplied as an oral solution. | Drug: Matching Placebo<br>* Placebo will be administered twice a day (BID) in equally divided doses.<br>* Other names: Placebo Comparator;|
| Experimental: Open-Label<br>Part 2: ZX008 is supplied as an oral solution. Study medication will be administered twice a day (BID) in equally divided doses. | Drug: ZX008 0.2 or 0.8 mg/kg/day<br>* ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride. The product is sugar free and is intended to be compatible with a Ketogenic Diet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Change from baseline in frequency of seizures that result in drops in subjects receiving ZX008 compared to placebo | Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity | Up to 20 weeks maintenance and taper period (T+M) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Adverse events and related safety parameters in subjects receiving ZX008 compared to placebo | Safety and tolerability evaluated by reported adverse events, laboratory parameters, physical and neurological examination, vital signs, electrocardiograms, echocardiograms, and body weight | Up to 12 months open label | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LGS