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

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.

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.

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.

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.

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.

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.

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.

Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs.

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.

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 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.

Seizures that typically result in drops included all: GTC, SGTC, TS, AS, and TA, whether confirmed by the ESC or not.

Countable motor seizures included: GTC, SGTC,TS, AS, TA, CS, HS, and FS with clearly observable signs.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Cmax is the maximum plasma concentration determined directly from the concentration time profile.

Cmin is the minimum plasma concentration determined directly from the concentration-time profile.

AUC0-24 is the area under the concentration-time curve from time 0 to 24 hours.

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.

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.

Countable motor seizures included: GTC, SGTC, TS, AS, TA, clonic seizures [CS], hemiclonic seizures [HS], and focal seizures [FS] with clearly observable signs.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.