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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Lennox Gastaut Syndrome
• Intervention / Treatment: Drug: ZX008 0.2 or 0.8 mg/kg/day; Drug: Matching Placebo

• Study Type: Interventional
• Enrollment (Actual): 296
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Heidelberg, Australia
    • Ep0214 301
  • South Brisbane, Australia
    • Ep0214 302
• Belgium
  • Brussels, Belgium
    • Ep0214 802
  • Bruxelles, Belgium
    • Ep0214 803
  • Edegem, Belgium
    • Ep0214 801
• Canada
  • Toronto, Canada
    • Ep0214 204
  • Vancouver, Canada
    • Ep0214 201
• Denmark
  • Dianalund, Denmark
    • Ep0214 701
• France
  • Bordeaux Cedex, France
    • Ep0214 1004
  • Bron, France
    • Ep0214 1006
  • Lille Cedex, France
    • Ep0214 1005
  • Marseilles, France
    • Ep0214 1007
  • Paris, France
    • Ep0214 1001
  • Paris, France
    • Ep0214 1002
• Germany
  • Bielefeld, Germany
    • Ep0214 902
  • Freiburg, Germany
    • Ep0214 906
  • Jena, Germany
    • Ep0214 905
  • Kiel, Germany
    • Ep0214 908
  • Radeberg, Germany
    • Ep0214 903
  • Vogtareuth, Germany
    • Ep0214 901
• Italy
  • Bologna, Italy
    • Ep0214 1211
  • Firenze, Italy
    • Ep0214 1201
  • Genova, Italy
    • Ep0214 1204
  • Roma, Italy
    • Ep0214 1206
  • Roma, Italy
    • Ep0214 1208
• Japan
  • Fukuoka, Japan
    • Ep0214 1510
  • Niigata-city, Japan
    • Ep0214 1505
  • Okayama, Japan
    • Ep0214 1501
  • Omura, Japan
    • Ep0214 1504
  • Osaka, Japan
    • Ep0214 1507
  • Sapporo-city, Japan
    • Ep0214 1508
  • Shinjuku-ku, Japan
    • Ep0214 1506
  • Shizuoka, Japan
    • Ep0214 1502
• Mexico
  • Guadalajara, Mexico
    • Ep0214 1604
• Netherlands
  • Zwolle, Netherlands
    • Ep0214 1401
• Poland
  • Bydgoszcz, Poland
    • Ep0214 1702
  • Krakow, Poland
    • Ep0214 1701
• Spain
  • Barcelona, Spain
    • Ep0214 1105
  • Barcelona, Spain
    • Ep0214 1107
  • Mirasierra, Spain
    • Ep0214 1101
  • Pamplona, Spain
    • Ep0214 1102
• Sweden
  • Göteborg, Sweden
    • Ep0214 502
• United States
  • Arizona
    • Tucson, Arizona, United States, 85718
      • Ep0214 107
  • California
    • Los Angeles, California, United States, 90095-1752
      • Ep0214 144
    • San Francisco, California, United States, 94158
      • Ep0214 101
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Ep0214 103
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Ep0214 149
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • Ep0214 115
    • Miami, Florida, United States, 33155
      • Ep0214 104
    • Orlando, Florida, United States, 32803
      • Ep0214 141
    • Orlando, Florida, United States, 32819
      • Ep0214 121
  • Georgia
    • Atlanta, Georgia, United States, 30328
      • Ep0214 117
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ep0214 110
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Ep0214 140
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Ep0214 112
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Ep0214 136
    • Royal Oak, Michigan, United States, 48073
      • Ep0214 147
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Ep0214 109
    • Saint Paul, Minnesota, United States, 55102
      • Ep0214 132
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Ep0214 105
    • Livingston, New Jersey, United States, 07039
      • Ep0214 118
  • New York
    • Hartsdale, New York, United States, 10530
      • Ep0214 150
    • New York, New York, United States, 10016
      • Ep0214 142
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Ep0214 131
  • Oregon
    • Portland, Oregon, United States, 97239
      • Ep0214 143
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Ep0214 120
    • York, Pennsylvania, United States, 17403
      • Ep0214 139
  • Texas
    • Dallas, Texas, United States, 75235
      • Ep0214 146
    • Fort Worth, Texas, United States, 76104
      • Ep0214 126
    • San Antonio, Texas, United States, 78207-3108
      • Ep0214 145
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Ep0214 106
  • Washington
    • Tacoma, Washington, United States, 98405
      • Ep0214 125

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ZX008 0.2 or 0.8 mg/kg/day; 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; 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.
Placebo Comparator: Matching Placebo; Part 1: Matching ZX008 placebo is supplied as an oral solution.	Drug: Matching Placebo; Placebo will be administered twice a day (BID) in equally divided doses.; Other Names: Placebo Comparator
Experimental: Open-Label; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
• Investigators: Study Director: UCB Cares, 001 844 599 2273

Publications and helpful links

General Publications

• Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A. Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial. JAMA Neurol. 2022 Jun 1;79(6):554-564. doi: 10.1001/jamaneurol.2022.0829.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: June 19, 2017
• First Submitted That Met QC Criteria: November 21, 2017
• First Posted (Actual): November 28, 2017

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: LGS
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Disease; Genetic Diseases, Inborn; Epilepsy; Syndrome; Lennox Gastaut Syndrome
• Other Study ID Numbers: ZX008-1601; 2017-002628-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No