ZX008-1601

Principal Investigator: Matthew  Sweney
Keywords: pediatric epilepsy syndrome , Lennox-Gastaut Syndrome , Fenfluramine Hydrochloride Department: Pediatric Administration
IRB Number: 00105040 Co Investigator:  
Specialty: Pediatric Neurology
Sub Specialties: Pediatric Epilepsy
Recruitment Status: Recruiting

Contact Information

Andrew Newton
andrew.newton@hsc.utah.edu
801-587-7514

Brief Summary

STUDY OBJECTIVES AND ENDPOINTS
PART 1
PRIMARY OBJECTIVE

The primary objective of Part 1 is the primary objective of the entire study.

The primary objective of Part 1 is:

  • To evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS) based on the change in frequency of seizures that result in drops between baseline and the combined Titration and Maintenance Periods (T+M).

KEY SECONDARY OBJECTIVESThe key secondary objectives of Part 1 are:
 To evaluate the effect of ZX008 0.2 mg/kg/day versus placebo as adjunctive therapy for the
treatment of uncontrolled seizures in children and adults with LGS based on the change in
frequency of seizures that result in drops between baseline and T+M
 To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on the
following endpoints:
- The proportion of subjects who achieve a ≥50% reduction from baseline in the frequency of
seizures that result in drops
- Change in the frequency of all countable motor seizures between baseline and T+M
(countable seizures include: generalized tonic-clonic seizures [GTC], tonic seizures [TS],
clonic seizures [CS], atonic seizures [AT], tonic/atonic seizures [TA], and clearly
recognizable focal seizures [FS])

See Statistical Methods for hierarchical testing procedure.
 

ADDITIONAL SECONDARY OBJECTIVES
Additional secondary objectives of the study are:
 To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on
the following endpoints:
– Change in the frequency of all countable seizures (ie, motor and non-motor)
between baseline and T+M
– Change in frequency of seizures that result in drops between baseline and the
Maintenance Period (M)
– Change in the frequency of countable motor seizures that do not result in drops
between baseline and M

– The proportion of subjects who achieve a ≥25%, ≥50%, ≥75%, and 100% reduction
between baseline and T+M, and baseline and M, in all countable motor seizures
(GTC, TS, AT, TA, FS); in countable motor seizures that do not result in drops; in
all countable seizures; in all countable seizures that do not result in drops; and in all
seizures that result in drops
– The frequency of rescue medication usage
– Number of seizure-free days, defined as 1) days with no countable seizures and 2)
days with no seizures that result in drops
– The incidence of medical services to treat seizures
– The incidence of status epilepticus.
 To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on
the following endpoints:
– Clinical Global Impression – Improvement rating, as assessed by the principal
investigator.
– Clinical Global Impression – Improvement rating, as assessed by the
parent/caregiver.
– The change from baseline in affective symptoms of the parent/caregiver using the
Hospital Anxiety and Depression Scale (HADS)
 

 SAFETY OBJECTIVE
The safety objectives of the Part 1 are:
 To evaluate the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day versus placebo with
regard to adverse events (AEs), laboratory parameters, physical examination, neurological
examination, suicidality,vital signs (blood pressure, heart rate, temperature, and respiratory
rate), electrocardiograms (ECG), echocardiograms (ECHO), body weight, and BMI
 To evaluate the change from baseline in cognition using age-appropriate versions of the
BRIEF

 PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective of the study is:
 To evaluate the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects < 18 years
and ≥18 years with LGS using a physiologically-based pharmacokinetic (PBPK) model.
 

EXPLORATORY OBJECTIVES
The exploratory objectives of the study are:
 To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, and safety
endpoints.
 To evaluate the effect of ZX008 0.2 and 0.8 mg/kg/day (independently) versus placebo on
the following endpoints:

– The change from baseline in behavior using the Vineland Adaptive Behavior Scale
(VABS)
– The change from baseline in QoL using the QOLCE
– The change from baseline in caregiver burden using the Zarit Caregiver Burden
Inventory

STUDY ENDPOINTS
 Efficacy Endpoints
The efficacy endpoints for Part 1 of the study are:
 Number, frequency, and duration of countable seizures that result in drops
 Number, frequency, and duration of countable seizures that do not result in drops
 Number, frequency, and duration of all countable seizures by type
 Proportion of subjects who achieve a ≥25%, ≥50%, ≥75%, or 100% reduction from baseline
in seizure frequency
 Number of seizure-free days
 Clinical Global Impression – Improvement as assessed by parent/caregiver
 Clinical Global Impression – Improvement as assessed by principal investigator
 Affective symptoms of parent/caregiver using the HADS scale
 Number of episodes of status epilepticus
 Number of instances of rescue medication use and number of doses
 Incidence in use of medical services to treat seizures
Efficacy endpoints for Part 2 are identical, with the exception of the HADS and CGI assessments,
which are exploratory during the open-label extension.

Safety Endpoints
The safety endpoints for Part1 and Part 2 of the study are:
 AEs
 Laboratory safety (hematology, chemistry, urinalysis)
 Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
 Physical examination
 Neurological examination
 BRIEF to measure changes in cognition of the subject
 Columbia Suicidality Severity Rating Scale (C-SSRS)
 12-lead ECGs
 Doppler ECHOs
 Body weight and BMI

Exploratory Endpoints
The exploratory endpoints for Part 1 and Part 2 of the study are:
 VABS
 QOLCE
 Zarit Caregiver Burden Inventory
Part 2 exploratory endoints also include HADs and the CGI assessments.

Inclusion Criteria

1. Subject is male or non-pregnant, non-lactating female, age 2 to 35 years, inclusive as of the
day of the Screening Visit. Female subjects of childbearing potential must not be pregnant or
breast-feeding. Female subjects of childbearing potential must have a negative urine
pregnancy test at screening. Subjects of childbearing or child-fathering potential must be
willing to use medically acceptable forms of birth control, which includes
abstinence, while being treated on this study and for 90 days after the last dose of study drug.

2. Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result in
drops are not completely controlled by current antiepileptic treatments.

3. Subjects must meet all of the following 4 criteria:
a. Onset of seizures at 11 years of age or younger.
b. Multiple seizure types (must include Tonic Seizure (TS) or Tonic/Atonic Seizure (TA)), including countable motor seizures that result in drops. Countable motor seizure types eligible for inclusion are: Generalized tonic-clonic seizure (GTC),Tonic Seizure (TS), Clonic Seizure (CS), Atonic Seizure (AS), and Focal Seizure (FS) with observable motor symptoms.
c. Abnormal cognitive development.
d. Evidence of electroencehpalogram (EEG) in the medical history that shows abnormal background activity accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable evidence includes a copy of the EEG trace, EEG report, or physician note that appropriately describes the EEG findings.)

4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to inclusion (minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks before baseline), by parent/guardian report to investigator or investigator medical notes

5. Receiving at least 1 concomitant Antiepileptic drug (AED) and up to 4 concomitant AEDs, inclusive. KD and
VNS are permitted but do not count towards the total number of AEDs. Rescue medications
for seizures are not counted towards the total number of AEDs.

6. All medications or interventions for epilepsy (including Ketogenic diet (KD) and Vagal Nerve Stimulator/Stimulation (VNS)) must be stable for at
least 4 weeks prior to screening and are expected to remain stable throughout the study.

7. Subject has been informed of the nature of the study and informed consent has been obtained
from the legally responsible parent/guardian.

8. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics
Committee requirements, if capable.

9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit
schedule and study drug accountability.

Exclusion Criteria

1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study
medication.

2. Subject’s etiology of seizures is a degenerative neurological disease.

3. Subject has a history of hemiclonic seizures in the first year of life.

4. Subject only has drop seizures in clusters, where individual seizures cannot be counted
reliably.

5. Subject has pulmonary arterial hypertension.

6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as
cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural
cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular
septal defects, patent ductus arteriosis (note: Patent Foramen Ovale or a bicuspid valve are not
considered exclusionary).

7. Subject has 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.

8. Subject has a current or past history of glaucoma.

9. Subject has had an anoxic episode requiring resuscitation within 6 months of the Screening
Visit.

10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic
impairment (elevated liver enzymes < 3x ULN and/or elevated bilirubin <2x ULN) may be
entered into the study after review and approval by the Medical Monitor in conjunction with
the sponsor, in consideration of comorbidities and concomitant medications.

11. Subject has severe renal impairment (estimated glomerlular filtration rate <30mL/min/1.73m2)

12. Subject is receiving concomitant therapy with any of the following: centrally-acting anorectic
agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically
appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake
inhibition; other centrally-acting noradrenergic agonists, including atomexetine; or
cyproheptadine (see Appendix 1 for a complete list of prohibited medications). (Note: Shortterm
medication requirements for prohibted medications will be handled on a per case basis by
the Medical Monitor.)

13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood
cannabidiol (CBD) at the Screening Visit.

14. Subject is 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.

15. Subject is known to be human immunodeficiency virus (HIV) positive.

16. Subject is known to have active viral hepatitis (B or C)

17. Subject is currently receiving an investigational product.

18. Subject has participated in another clinical trial within the past 30 days (calculated from that
study’s last scheduled visit). Participation in non-treatment trials will be reviewed by the
medical monitor.

19. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or Baseline, which includes suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without specific plan, and the investigator feels that the subject is appropriate for the study considering the potential risks, the investigator must document appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood or behavioral changes, especially around times of dose
adjustment.

20. Subject is unwilling or unable to comply with scheduled visits, drug administration plan,
laboratory tests, other study procedures, and study restrictions.

21. Subject is institutionalized in a general nursing home (ie, in a facility that does not provide
skilled epilepsy care).

22. Subject does not have a reliable caregiver who can provide seizure diary information
throughout the study.

23. 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.