Zogenix ZX008-1503 Open Label Extension

Principal Investigator: Matthew  Sweney
Keywords: Dravet Syndrome , (Fenfluramine Hydrochloride) Oral Solution , Pediatrics , epilepsy Department: Pediatric Administration
IRB Number: 00096973 Co Investigator:  
Specialty: Pediatrics, General
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

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

Brief Summary

Based on several published reports of fenfluramine’s successful treatment of refractory childhood epilepsy in the 1980s (Aicardi and Gaustaut 1985; Aicardi 1988) and its successful treatment of 11 refractory pediatric epilepsy patients in Belgium (Boel 1996), in 2002 Drs. Ceulemans and Lagae were granted authorization to prescribe fenfluramine to their patients with refractory pediatric epilepsy conditions, including DS, under an approved protocol under a Belgium government program (Royal Decree). To date, these pediatric neurologists have DS patients (infants, children, young adults, and now also adults), being successfully treated with fenfluramine for over 27 years. The efficacy and safety of this therapeutic approach has been reported to be overwhelmingly favorable. In the most recent assessment of efficacy of these patients reported by the investigators in 2014, the average length of treatment was over 12 years, with one patient being successfully treated for 26 years. Of the 15 DS treated patients, 10 (67%) were reported as seizure-free, with the average time of seizure-freedom being 6 years (range 1-19 years). Twelve patients (87%) had a greater than 90% reduction in seizure frequency and 14 patients (93%) with greater than 70% reduction in seizure frequency.
 
In addition, numerous publications discuss the use of fenfluramine in over 500 children with neurobehavioral conditions for the treatment of mostly autism and ADHD, without any reports
of any cardiovascular adverse events (ZX008 IB 2016).
 
Prior to being withdrawn from the market, fenfluramine was marketed at doses of 20 mg and 40 mg three times daily for the management of obesity in adults. The doses tested thus far in DS range from 0.12 to 0.9 mg/kg/day in subjects over 1 year of age to adults. Doses tested in pediatric studies evaluating autism and ADHD ranged from 0.65 mg/kg/day to 3.6 mg/kg/day, but a  commonly used dose was 1.5 mg/kg/day. Occasionally, fixed doses of 30 to 80 mg were used. The PK exposure associated with the proposed doses in DS studies of 0.2 mg/kg/day to 0.8 mg/kg/day administered orally (in equally divided doses BID) is expected to be lower than that obtained at the doses used in the past for the treatment of obesity in adults and of neurobehavioral conditions in children and adolescents (ZX008 IB 2016). The doses used in this study are based on the data from the DS patients being successfully treated in Belgium discussed above.
 
Currently, there is only one treatment approved for adjunctive treatment of seizures in children with Dravet syndrome in Europe and Canada (ie, STP), and it is administered in conjunction with two other antiepileptic drugs, VPA and CLB. Further, the recent survey conducted in Europe by Aras and colleagues (2015) revealed that in spite of the availability of an array of antiepileptic medications, the most common drug combination was CLB, VPA, and STP, with 42% of the patients currently taking STP.
 
The rationale for conducting this open-label extension study is primarily to evaluate the longterm safety of ZX008 in DS. This protocol also provides the opportunity for continued treatment for subjects responding to treatment from the core study, and an opportunity for initial treatment with ZX008 for subjects randomized to placebo in the core study.
 
STUDY OBJECTIVES AND ENDPOINTS
PRIMARY OBJECTIVE
The primary objective of the study is:
  • To assess the long-term safety and tolerability of ZX008.
SECONDARY OBJECTIVES
The secondary objectives of the study are:
  • To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness measures:
  • The change in the frequency of convulsive seizures.
  • The proportion of subjects who achieve a ≥40%, ≥50%, and ≥75% reduction inconvulsive seizure frequency.
  • The longest convulsive seizure-free interval.
  • The percentage of convulsive seizure-free days.
  • The non-convulsive seizure frequency.
  • The convulsive + non-convulsive seizure frequency.
  • To estimate the incidence of the following on subjects receiving ZX008:
  • Use of rescue medication
  • Hospitalization to treat seizures
  • Status epilepticus

To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following QoL measures:

  • QOLCE score
  • PedsQL score
  • QoL of the parent/caregiver using the EQ-5D-5L scale
  • Affective symptoms of the parent/caregiver using the HADS.
 
  • To assess the effect of ZX008 on the following QoL measures:
  • Clinical Global Impression – Improvement rating, as assessed by the principal investigator.
  • Clinical Global Impression – Improvement rating, as assessed by the parent/caregiver
 
EXPLORATORY OBJECTIVES
The exploratory objectives for subjects from core study ZX008-1504 are:
  • To assess the effect of ZX008 on the following QoL measures
  • Sleep quality and mealtime behavior, as assessed by the parent/caregiver
  • Karolinska Sleep Scale
  • Health and social care resource use (These measures include planned and unplanned hospital visits, use of ambulances, GP visits, speech and language therapy utilization, occupational and physical therapy utilization).
STUDY ENDPOINTS
Effectiveness Endpoints
The effectiveness endpoints of the study are:
  • Number of seizures by type
  • Convulsive seizure-free interval
  • Clinical Global Impression – Improvement as assessed by parent/caregiver
  • Clinical Global Impression – Improvement as assessed by principal investigator
  • QOLCE to measure changes in quality of life of the subject
  • PedsQL to measure changes in quality of life of the subject
  • QoL of parent/caregiver using the EQ-5D-5L scale
  • Affective symptoms of parent/caregiver using the HADS (in parents/caregivers fromcore studies ZX008-1501 and ZX008-1502 only)
  • Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had duration >2 minutes)
  • Number of episodes of status epilepticus
  • Number of instances of rescue medication use and number of doses
  • Number of inpatient hospital admissions due to seizures
Safety Endpoints
The safety endpoints of the study are:
  • AEs
  • Laboratory safety (hematology, chemistry, urinalysis)
  • Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
  • Physical examination
  • Neurological examination
  • 12-lead ECGs
  • Doppler ECHOs
  • Body weight
  • BRIEF to measure cognition.
Exploratory Endpoints
For subjects from core study ZX008-1504 only, the exploratory endpoints of this study are:
  • Health and social care resource use, including GP visits, speech and language, occupational and physical therapy, in addition to acute hospital and institutional length of stay, loss of work, etc
  • Sleep quality
  • Mealtime behavior
  • Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness

Inclusion Criteria

INCLUSION CRITERIA
 
Subjects meeting all of the following inclusion criteria may be enrolled into the study:
 
1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.
Subject is male or non-pregnant, non-lactating female. 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 childfathering
potential must be willing to use medically acceptable forms of birth control,
which includes abstinence, while being treated on this study and for 30 days after the
last dose of study drug.
 
2. Subject has satisfactorily completed the core study in the opinion of the investigator and
the sponsor.
 
3. Subject has documented medical history to support a clinical diagnosis of Dravet
syndrome, where convulsive seizures are not completely controlled by current
antiepileptic drugs.
 
4. Subject has been informed of the nature of the study and informed consent has been
obtained from the legally responsible parent/guardian.
 
5. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
 
6. Subject’s caregiver is willing and able to be compliant with diary completion, visit
schedule and study drug accountability.
 
7. Subject’s parent/caregiver has been compliant with diary completion during the core
study, in the opinion of the investigator (eg, at least 90% compliant).
 
8. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant
and stable dose of clobazam, valproic acid, and stiripentol (Cohort 1 Dose Regimen 3
and Cohort 2 only) for at least 4 weeks prior to screening and are expected to remain
stable throughout the study.

Exclusion Criteria

EXCLUSION CRITERIA
Subjects meeting any of the following exclusion criteria must not be enrolled into the study:
 
1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the
study medication.
 
2. Subject has current or past history of cardiovascular or cerebrovascular disease,
myocardial infarction or stroke.
 
3. Subject with current cardiac valvulopathy or pulmonary hypertension that the
investigator, parent, IPCAB, IDSMC, or sponsor deems clinically significant and
warrants discontinuation of study medication.
 
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 responses provided on the Columbia-Suicide Severity
Rating Scale (C-SSRS). Subjects must be excluded if they report suicidal behavior as
measured by the C-SSRS Since Last Visit, 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. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild
hepatic impairment (elevated liver enzymes <3x upper limited of normal [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.
 
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 cytochrome P450 (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 taking carbamazepine, oxcarbamazepine, eslicarbazepine,
phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as
maintenance therapy.
 
10. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504
(Cohort 1/Dose Regimens 1 & 2): Subject is currently receiving or has received
stiripentol in the past 21 days prior to core study Visit 1.
 
11. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville
oranges, and their juices beginning with Visit 1 and throughout the study.
 
12. Subject has positive result on urine THC Panel or whole blood CBD at Visit 1.
 
13. Subject is unwilling or unable to comply with scheduled visits, drug administration
plan, laboratory tests, other study procedures, and study restrictions.
 
14. Subject has a clinically significant condition, or has had clinically relevant symptoms
or a clinically significant illness in the 4 weeks prior to Visit 1, other than epilepsy, that
would negatively impact study participation, collection of study data, or pose a risk to
the subject.