Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy for Seizures in Patients with Rare Seizure Disorders Such as Epileptic Encephalopathies Including Dravet Syndrome and Lennox-Gastaut Syndrome
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is:
• To assess the long-term safety and tolerability of ZX008
Secondary outcome
The secondary objectives of the study are: • To assess the effect of ZX008 on
the following effectiveness measures: - Investigator assessment of convulsive
seizure response (<25%, >=25%, >=50%, >=75%, or 100% [ie, seizure-free]
improvement) - Clinical Global Impression - Improvement (CGI-I) rating, as
assessed by the investigator - CGI-I rating, as assessed by the
parent/caregiver - Symptomatic CGI-I for cognition, behavior, motor abilities,
as assessed by the investigator - Symptomatic CGI-I for cognition, behavior,
motor abilities, as assessed by the parent/caregiver
Background summary
This is an international, multicenter, open-label, long-term safety study of
ZX008 in patients with rare seizure disorders, epileptic encephalopathy,
including Dravet syndrome or Lennox-Gastaut syndrome. Subjects eligible for
participation are those with Dravet syndrome who are currently enrolled in
Study ZX008 1503, or those with LGS who have successfully completed Study
ZX008-1601-Part 2, and are candidates for continued treatment with ZX008 for an
extended period of time, or those with Dravet syndrome, Lennox-Gastaut
syndrome, or another epileptic encephalopathy who have completed participation
in a Zogenix-sponsored study and have been invited to participate in this
study.
Study objective
Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution
as an Adjunctive Therapy for Seizures in Patients with Rare Seizure Disorders
Such as Epileptic Encephalopathies Including Dravet Syndrome and Lennox-Gastaut
Syndrome
Study design
Subject will be eligible to participate in this trial for up to 36-months, or
until ZX008 is approved in a subject*s country of residence and listed on a
patient*s health plan formulary. Thus, the maximum duration for participation
is 36 months.
Subjects entering this OLE study who have participated in 1503 or 1601 will
receive ZX008 initially at the dose prescribed at the last visit in Study 1503
or Study 1601 Part 2. Dose increases, to a maximum of 0.8 mg/kg/day (maximum 30
mg/day) for subjects not receiving concomitant stiripentol (STP) or 0.5
mg/kg/day (maximum 20 mg/day) for subjects receiving concomitant stiripentol
(STP), during this OLE study should not occur more frequently than every 7 days
in dose increments of not more than 0.2 mg/kg/day. Dose increases may only
occur after a review of reported adverse events (AEs), and if, in the
investigator*s opinion, seizure frequency, severity, or duration indicates a
change in medication regimen is warranted. Dose decreases for tolerability or
safety concerns can occur at the investigator*s discretion, in dose amounts and
frequency appropriate for the clinical situation. ZX008 dose adjustments
outside of these parameters should be discussed with the Medical Monitor prior
to initiation. Changes in dosage of concomitant AEDs may be implemented as
clinically necessary, and concomitant AEDs may be withdrawn completely, but all
subjects must remain on a minimum of 1 concomitant AED plus ZX008 unless it is
deemed clinically appropriate by the investigator (after discussion with the
Medical Monitor) to dose as monotherapy. New concomitant AEDs or anti-epileptic
treatments may be introduced at the investigator*s discretion, as would be
typically indicated in clinical practice. Clinical worsening leading to a
change in medication must be documented in the source notes and case report
form (CRF) and all medication dose changes must be documented with a clinical
explanation and justification. Any medication dosage change or addition of a
new AED must be discussed with the Medical Monitor prior to implementation.
Echocardiograms (ECHO) and other safety assessments detailed in the schedule of
assessments (SoA) will be conducted every 6 months, unless more frequent
follow-up is clinically indicated or required by the Sponsor or IDSMC.
Follow-up cardiac safety assessments will be performed after study drug
discontinuation for subjects who do not transition to commercially available
ZX008.
Caregivers will be asked to use a diary to record the number/type of seizures
to support investigator determination of treatment benefit; however, diary data
collection is not mandatory, nor will it be collected in the database.
Intervention
Participation for subjects will be up to 36 months or until ZX008 is approved
in a subject*s country of residence and listed on a patient*s health plan
formulary, whichever occurs first.
Study burden and risks
Safety:
AEs, vital signs (blood pressure, heart rate, temperature, and respiratory
rate), physical examination, neurological examination, Doppler ECHOs, and body
height/weight will be assessed at each visit. Laboratory safety parameters
(hematology, chemistry), 12 lead ECGs, EEGs (in Italy only), and chest-x-ray
(in France and Netherlands only), will be assessed as clinically indicated.
Effectiveness (assessed at each visit):
• CGI-I as assessed by parent/caregiver
• CGI-I as assessed by investigator (or designee)
• Symptomatic CGI-I for cognition, behavior, motor abilities, as assessed by
the investigator (or designee)
• Symptomatic CGI-I for cognition, behavior, motor abilities, as assessed by
parent/caregiver
• Percent improvement in seizure burden as assessed by the investigator (or
designee)
Assessments by the investigator (or designee) should be performed by the same
rater for each subject whenever possible. If the rater changes permanently, a
new baseline should be established (see Section 7.1).
The same parent/caregiver should perform each assessment. If the same
parent/caregiver is not available, the assessment should be skipped.
External Committees: The ZX008 clinical program will employ an Independent
Data and Safety Monitoring Committee (IDSMC) that will be responsible for
safety oversight. A separate International Cardiology Advisory Board (ICAB)
will monitor the cardiac safety of the ZX008 clinical trials. ECHOs will be
centrally read (ERT, Inc.) and interpreted using pre-specified criteria, and if
necessary, with review by the ICAB.
The Pearce Building, West Street NAP
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The Pearce Building, West Street NAP
Maidenhead SL6 1RL
GB
Listed location countries
Age
Inclusion criteria
1. Subject is currently enrolled in core Study ZX008-1503
ORSubject has successfully completed core Study ZX008-1601-Part 2
OR
Subject with a rare seizure disorder, such as epileptic encephalopathy, that
has successfully completed another Zogenix-sponsored clinical trial with ZX008,
and has been invited to participate in this study by the Sponsor.
2. Subjects must, in the medical opinion of the Investigator, be candidates for
continued treatment for an extended period of time with ZX008 (ie, subject has
demonstrated a clinically meaningful benefit with ZX008 in the prior trial, and
benefits of continued treatment outweigh potential risks).
3. Subject is male or a nonpregnant, nonlactating female. Female subjects of
childbearing potential must not be pregnant or breast-feeding. Female subjects
of childbearing potential must have a negative pregnancy test prior to study
entry. 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.
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 Institutional Review Board
(IRB)/Independent Ethics Committee (IEC) requirements, if capable.
6. Subject*s caregiver is willing and able to be compliant with study
procedures, 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 has current cardiac valvulopathy
or pulmonary hypertension that the investigator, ICAB, IDSMC, or Sponsor deems
reason for exclusion. 3. 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. 4. Subject has
moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic
impairment (elevated liver enzymes < 3x upper limit 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. 5. Administration
of monoamine oxidase inhibitors, serotonin agonists, serotonin antagonists, and
serotonin reuptake inhibitors within 14 days of receiving ZX008. 6. Subject is
unwilling or unable to comply with scheduled visits, drug administration plan,
laboratory tests, other study procedures, and study restrictions. 7. Subject
has a clinically significant condition, or has had clinically relevant symptoms
or a clinically significant illness at Visit 1, other than epilepsy, that would
negatively impact study participation, collection of study data, or pose a risk
to the subject, including chronic obstructive pulmonary disease, interstitial
lung disease, or portal hypertension. 8. Subject has participated in another
clinical treatment trial within the past 30 days (ie, the last visit of the
previous study was in the past 30 days), with the exception of a ZX008 clinical
study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-001331-31-NL |
| ClinicalTrials.gov | NCT03936777 |
| CCMO | NL72209.075.19 |