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: Completed
• 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: Percent Change From Baseline in the Frequency of Seizures That Result in Drops (ESC-confirmed) in the Combined Titration and Maintenance Period (T+M) in the ZX008 0.8 mg/kg/Day Group Compared to the Placebo Group	Percent change in frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and Maintenance (T+M) and Baseline. The percent change from Baseline DSF was calculated as the change in DSF between T+M and Baseline / DSF during Baseline* 100. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 2: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	An Adverse event (AE) was defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of investigational product, or whether considered related to the investigational product. A TEAE in Part 2 was defined as any AE with an onset on or after the first dose in Part 2. AEs with onset in Part 1 that are ongoing in Part 2 were not included in the count of AEs in Part 2.	From Part 2 Baseline until end of the OLE Period (up to 72 months)
Part 2: Percentage of Participants With Serious TEAEs	A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is medically significant.	From Part 2 Baseline until end of the OLE Period (up to 72 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Percent Change From Baseline in the Frequency of Seizures That Result in Drops (ESC-confirmed) in T+M in the ZX008 0.2 mg/kg/Day Group Compared to the Placebo Group	Percent change in frequency of seizures that result in drops (DSF: drop seizure frequency) per 28 days between the combined Titration and Maintenance (T+M) and Baseline. The percent change from Baseline DSF was calculated as the change in DSF between T+M and Baseline / DSF during Baseline* 100. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percentage of Participants Who Achieve a >=50% Reduction From Baseline in the Frequency of Seizures That Result in Drops Comparing the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. Participants who achieved a >=50% reduction from Baseline in the DSF, ie, a decrease in DSF of at least 50 percentage points per 28 days during Titration and Maintenance Period.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percentage of Participants Who Achieve Improvement (Minimally, Much or Very Much Improved) in the CGI-I Scale as Assessed by Principal Investigator Comparing ZX008 0.8 and 0.2 mg/kg/Day Groups Independently Versus Placebo	Clinical Global Impression - Improvement (CGI-I) scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse.	At Day 99 (Visit 12)
Part 1: Percent Change From Baseline in Frequency of All Seizures That Typically Result in Drops in T+M, Whether ESC-confirmed as Drop or Not in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Seizures that typically result in drops included all: generalized tonic-clonic seizures [GTC], secondarily generalized tonic-clonic [SGTC], tonic seizures [TS], atonic seizures [AS], and tonic/atonic seizures [TA], whether confirmed by the ESC or not. Seizures that result in a drop were defined as seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the patient's position at the time of the seizure.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percent Change From Baseline in the Frequency of All Countable Motor Seizures in T+M in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Change From Baseline in the Frequency of All Countable Non-motor Seizures in T+M in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable non-motor seizures included: focal seizures [FS] without clear observable signs, myoclonic seizures [MS], absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percent Change From Baseline in the Frequency of All Countable Seizures (Motor and Non-motor) in T+M in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percent Change From Baseline in the Frequency of Seizures That Result in Drops (ESC Confirmed) Between Baseline and the Maintenance Period	The frequency of drop seizures during a given interval was derived from the number and type of events recorded in participant electronic diaries. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops.	During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percent Change From Baseline in the Frequency of Seizures That Typically Result in Drops in the Maintenance Period in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not.	During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percent Change From Baseline in the Frequency of All Countable Motor Seizures in the Maintenance Period in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable motor seizures included: GTC, SGTC,TS, AS, TA, CS, HS, and FS with clearly observable signs.	During Maintenance Period (12 weeks), compared to Baseline
Part 1: Change From Baseline in the Frequency of All Countable Non-motor Seizures in the Maintenance Period in the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable non-motor seizures included: focal seizures [FS] without clear observable signs, myoclonic seizures [MS], absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28.	During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percent Change From Baseline in the Frequency of All Countable Seizures (Motor and Non-motor) in the Maintenance Period in ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures.	During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percent Change From Baseline in Frequency of Countable Seizures That do Not Result in Drops (ESC Confirmed)	Non-drop seizures were defined as any countable seizure types that did not meet the criteria of drop seizures, ie, are classified as CS, HC, FS with or without observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, or other; or are seizures of the following classifications that were approved for each participant as non-drop seizure types by the ESC: GTC, SGTC, TS, AS, or TA.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline (ie <=0% Reduction), or >0, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in Seizures That Result in Drops	The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline, or >0%, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in Seizures That Typically Results in Drops	Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline, or >0%, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in All Countable Motor Seizures	Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline, or >0%, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in Countable Motor Seizures That do Not Result in Drops	Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline (ie <= 0% Reduction), or >0%, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in All Countable Seizures	Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Percentage of Participants Who Achieved a Worsening From Baseline, or >0%, >=25%, >=50%, >=75%, 100% Reduction, and "Near Seizure Freedom" Between Baseline and T+M, and Baseline and M, in All Countable Non-motor Seizures	Countable non-motor seizures include: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during T+M); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during combined T+M Period and Maintenance Period were reported.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Change From Baseline in Number of Seizure-free Days During T+M and M Period	A day with no seizures leading to a drop was defined as a day for which electronic (e) diary data were available and no drop seizures were reported. The total number of drop seizure-free days was calculated per 28 days for Baseline and for T+M.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]; During Maintenance Period (12 weeks), compared to Baseline
Part 1: Duration of Longest Interval (Days) Between Seizures That Result in Drops Comparing the ZX008 0.8 mg/kg/Day and 0.2 mg/kg/Day Groups Independently Versus Placebo	The longest interval between seizures leading to drops were obtained from the eDiary entries in Titration and Maintenance Period. The interval was derived as the maximum value of the number of days between consecutive drop seizures.	From Baseline up to 14 weeks [Titration Period (2 weeks) + Maintenance Period (12 weeks)]
Part 1: Clinical Global Impression - Improvement as Assessed by the Parent/Caregiver	CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved, 2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse.	At Days 15, 43, 71 and 99
Part 1: Percentage of Participants With TEAEs	Adverse events were defined as any unfavorable and unintended sign (including an abnormal, clinically significant laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A TEAE in Part 1 was defined as any AE that, based on start date information, occurred after the first dose of study drug in Part 1, but not on or after the first dose of study drug in Part 2.	Baseline up to 14 weeks + Taper/Transition (2 weeks)
Part 1: Percentage of Participants With Serious TEAEs	A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is medically significant.	Baseline up to 14 weeks + Taper/Transition (2 weeks)
Part 1: Maximum Observed Plasma Concentration of Fenfluramine and Norfenfluramine Determined Directly From the Concentration Time Profile [Cmax] at Steady State	Cmax is the maximum plasma concentration determined directly from the concentration time profile.	At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose
Part 1: Minimum Observed Plasma Concentration of Fenfluramine and Norfenfluramine at Steady State Determined Directly From the Concentration-time Profile [Cmin] at Steady State	Cmin is the minimum plasma concentration determined directly from the concentration-time profile.	At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose
Part 1: Area Under the Concentration-time Curve of Fenfluramine and Norfenfluramine From Time Zero to Time 24 Hours [AUC0-24hours] at Steady State	AUC0-24 is the area under the concentration-time curve from time 0 to 24 hours.	At Visit 8 (Day 43) of the Maintenance Period: pre-dose, 1, 2, and 4-6 hours post-dose
Part 2: Percent Change From Baseline in the Frequency of Seizures That Result in Drops (ESC Confirmed) in OLE Period	The frequency of drop seizures during a given interval was derived from the number and type of events recorded in participant electronic diaries. The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percent Change From Baseline in the Frequency of All Seizures That Typically Result in Drops Between Baseline and the OLE Period Whether ESC Confirmed as Drop or Not	Seizures that typically result in drops included all: generalized tonic-clonic seizures [GTC], secondarily generalized tonic-clonic [SGTC], tonic seizures [TS], atonic seizures [AS], and tonic/atonic seizures [TA], whether confirmed by the ESC or not. Seizures that result in a drop were defined as seizures involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the participant's head hitting a surface or that could have led to a fall or injury, depending on the patient's position at the time of the seizure.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percent Change From Baseline in the Frequency of All Countable Motor Seizures in OLE Period	Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Change From Baseline in the Frequency of All Countable Non-motor Seizures in OLE Period	Countable non-motor seizures included: focal seizures [FS] without clear observable signs, myoclonic seizures [MS], absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percent Change From Baseline in the Frequency of All Countable Seizures (ESC Confirmed or Not) in OLE Period	Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Change From Baseline in the Frequency of All Countable Seizures That Did Not Result in Drops (ESC Confirmed) in OLE Period	Nondrop seizures were defined as any countable seizure types that did not meet the criteria of drop seizures, ie, are classified as CS, HC, FS with or without observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, or other; or are seizures of the following classifications that were approved for each subject as non-drop seizure types by the ESC: GTC, SGTC, TS, AS, or TA. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percentage of Participants Who Achieved a Worsening From Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% Reduction, and "Near Seizure Freedom" From Baseline in Frequency of Seizures That Result in Drops (ESC Confirmed)	The seizure types included in the count were: atonic, tonic, tonic/atonic, generalized tonic-clonic, and secondarily generalized tonic-clonic seizures resulting in drops. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percentage of Participants Who Achieved a Worsening From Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% Reduction, and "Near Seizure Freedom" From Baseline in Frequency of Seizures That Typically Result in Drops	Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percentage of Participants Who Achieved a Worsening From Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% Reduction, and "Near Seizure Freedom" From Baseline in Frequency of All Countable Motor Seizures	Countable motor seizures included: GTC, SGTC, TS, AS, TA, CS, HS, and FS with clearly observable signs. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percentage of Participants Who Achieved a Worsening From Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% Reduction, and "Near Seizure Freedom" From Baseline in Frequency of All Countable Non-motor Seizures	Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Percentage of Participants Who Achieved a Worsening From Baseline, or > 0%, >=25%, >= 50%, >= 75%, 100% Reduction, and "Near Seizure Freedom" From Baseline in Frequency of All Countable Seizures	Countable motor seizures included: GTC, SGTC; TS, AS, TA, CS, HS, and FS with clearly observable signs. Countable non-motor seizures included: FS without clear observable signs, MS, absence/atypical absence, infantile spasms, epileptic spasms, and other seizures. The participants who experienced a worsening or no change from Baseline (ie <= 0% reduction); >0%, >=25%, >=50%, >=75%, and 100% reduction (a 100% reduction was equivalent to achieving seizure freedom during OLE Period); and "near seizure freedom," (defined as 0 or 1 seizure leading to a drop) during OLE Period were reported.	From OLE Month 1 to Month12, compared to Baseline (Part 1)
Part 2: Change From Baseline in Number of Seizure-free Days Per 28 Days (ESC Confirmed) in OLE Period	A day with no seizures leading to a drop was defined as a day for which ediary data were available and no drop seizures were reported.	From Part 2 Baseline until end of OLE Period (up to 72 months)
Part 2: Change From Baseline in Duration of Longest Interval Between Seizures That Result in Drops (ESC Confirmed) in OLE Period	The longest interval between seizures leading to drops were obtained from the eDiary entries in OLE Period. The interval was derived as the maximum value of the number of days between consecutive drop seizures.	From Part 2 Baseline until end of the OLE Period (up to 72 months)
Part 2: Clinical Global Impression - Improvement as Assessed by the Principal Investigator	CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse.	At OLE Day 1, OLE Months (M) 1, 2, 3, 6, 9, 12, and Last Assessment (up to 72 months)
Part 2: Clinical Global Impression - Improvement as Assessed by the Parent/Caregiver	CGI-I scale measures improvement in the participant's condition from Baseline. The severity of a participant's condition was rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), as follows: 1-very much improved,2-much improved, 3-minimally improved, 4- no change, 5-minimally worse, 6-much worse and 7-very much worse.	At OLE Day 1, OLE Months (M) 1, 2, 3, 6, 9, 12, and Last Assessment (up to 72 months)

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 (Actual): May 23, 2024
• Study Completion (Actual): May 23, 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): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 16, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: LGS
• Additional Relevant MeSH Terms: Epileptic Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Disease; 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