Zogenix ZX008-1501

Principal Investigator: Matthew  Sweney
Keywords: Fenfluramine Hydrochloride , Dravet Syndrome , ZX008 Department: Pediatric Administration
IRB Number: 00090337 Co Investigator:  
Specialty: Pediatric Neurology, Neurology
Sub Specialties: Seizures
Recruitment Status: Recruiting

Contact Information

Andrew Newton
u0343476@umail.utah.edu
801-213-9900

Brief Summary

PRIMARY OBJECTIVE
The primary objective of the study is:
• To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between baseline and the combined Titration and Maintenance Periods (T+M).
 
KEY SECONDARY OBJECTIVES
The key secondary objectives of the study are:
• To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome based on change in the frequency of convulsive seizures between baseline and T+M.
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior to placebo on the following endpoints:
o The proportion of subjects who achieve a ≥40% reduction from baseline in convulsive seizure frequency.
o The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive seizure frequency.
o The longest convulsive seizure-free interval.
 
ADDITIONAL SECONDARY OBJECTIVES
Other secondary objectives of the study are:
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior to placebo on the following endpoints:
o The number of convulsive seizure-free days.
o The proportion of subjects who achieve ≥75% reductions from baseline in convulsive seizure frequency.
o The change from baseline in non-convulsive seizure frequency.
o The change from baseline in convulsive + non-convulsive seizure frequency
o The incidence of rescue medication usage
o The incidence of hospitalization to treat seizures
o The incidence of status epilepticus.
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) superior to placebo on the following endpoints:
o Clinical Global Impression – Improvement rating, as assessed by the principal investigator.
o Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver.
o The change from baseline in the QOLCE score.
o The change from baseline in the PedsQL score.
o The change from baseline in the QoL of the parent/caregiver using the EQ-5D-5L scale.
o The change from baseline in the affective symptoms of the parent/caregiver using the HADS.
 
SAFETY OBJECTIVE
The safety objective of the study is:
• To compare the safety and tolerability of ZX008 0.2 and 0.8 mg/kg/day to placebo with regard to AEs, laboratory parameters, physical examination, neurological examination, vital signs (blood pressure, heart rate [HR], temperature, and respiratory rate), ECGs, ECHOs, and body weight. Cognitive Function will be assessed in subjects 5 years and older using the cognition domain score on the QOLCE. Cognitive function will be assessed using age-appropriate versions of the BRIEF.
 
PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objective of the study is:
• To characterize the PK of ZX008 0.2 and 0.8 mg/kg/day at steady state in subjects ages 2-6 years and >6-18 years with Dravet syndrome.
 
EXPLORATORY OBJECTIVE
The exploratory objective of the study is:
• To compare the ZX008 0.2 and 0.8 mg/kg/day doses on primary, secondary, safety and PK endpoints.

Inclusion Criteria

INCLUSION CRITERIA

1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 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. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control (see Section 4.4), which includes abstinence, while being treated on this study and for 90 days after the last dose of study drug.

2. Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.

3. Subjects must meet all of the following 5 criteria:

a. Onset of seizures in the first year of life in an otherwise healthy infant.
b. A history of seizures that are either generalized tonic-clonic or unilateral clonic or bilateral clonic, and are prolonged.
c. Initial development is normal.
d. History of normal brain MRI without cortical brain malformation.
e. Lack of alternative diagnosis.
 
4. Subjects must meet at least one of the following 3 criteria:
a. Emergence of another seizure type, including myoclonic, generalized tonicclonic, tonic, atonic, absence and/or focal has developed after the first seizure type.
b. Prolonged exposure to warm temperatures induces seizures and/or seizures are associated with fevers due to illness or vaccines, hot baths, high levels of activity and sudden temperature changes and/or seizures are induced by strong natural and/or fluorescent lighting, as well as certain visual patterns.
c. Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternative diagnosis.)
 
5. Subject must have had ≥4 convulsive seizures (tonic, tonic-atonic, tonic-clonic,
clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian
report to investigator or investigator medical notes.
 
6. All medications or interventions for epilepsy (including KD and 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) 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

EXCLUSION CRITERIA

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

2. Subject has pulmonary arterial hypertension.

3. Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke.
 
4. 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.
 
5. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and/or responses provided on the C-SSRS. Subjects must be excluded if they report suicidal behavior in the past 6 months as measured by the CSSRS 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.
 
6. Subject has a current or past history of glaucoma.
 
7. Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated bilirubin <2xULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, with consideration of potential cause, concomitant medications, and other risk factors.
 
8. Subject is receiving concomitant therapy with: 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; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or CYP 2D6/3A4/2B6 inhibitors/substrates (see Appendix 1).
(Note: Short-term medication requirements will be handled on a per case basis by the
Medical Monitor.)
 
9. Subject is currently receiving or has received stiripentol in the past 21 days prior to Screening.
 
10. Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
 
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with the Baseline Period and throughout the study.
 
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening Visit.
 
13. Subject has participated in another clinical trial within the past 30 days.
 
14. Subject is currently receiving an investigational product.
 
15. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.