This study has been transitioned to CTIS with ID 2023-506269-78-00 check the CTIS register for the current data. Objectives for Part 1: Primary (Efficacy): To demonstrate that the efficacy of fenfluramine (ZX008) 0.8 mg/kg/day is superior to placebo…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1:
Efficacy
Percentage Change from Baseline in CMSF during T+M
Part 2:
Safety
Treatment emergent adverse events (TEAEs)
Abnormal physical examination findings
Abnormal neurological examination findings
Positive response to self-harm question
Increase in valvular regurgitation from baseline (except absent to trace)
Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment
on repeat testing
Change from Baseline at end of OLE Period in Laboratory parameters (hematology,
hormones, chemistry, urinalysis)
Change from Baseline at end of OLE Period in Vital signs (blood pressure, heart
rate, temperature, and respiratory rate)
Change from Baseline at end of OLE Period in Body weight
Change from Baseline at end of OLE Period in Tanner Staging
Secondary outcome
Part 1
Efficacy:
Key secondary
Achievement of a >= 50% reduction from Baseline in CMSF during T+M
Achievement of a CGI-I rating of much or very much improved as assessed by the
Investigator at the end of T+M
Percentage change from Baseline in monthly GTC seizure frequency during T+M
Additional secondary
Achievement of Categorized Percentage change in seizures from Baseline in CMSF
during T+M Periods (no reduction or worsening, >= 25%, >= 75%, or 100%
reduction)
Achievement of *near seizure freedom* (0 or 1 seizures) during T+M
Achievement of a CGI-I rating of much or very much improved as assessed by the
parent/caregiver at the end of T+M
Achievement of improvement (minimal, much, or very much improved) in the CGI-I
rating as assessed, independently, by the Investigator at the end of T+M
Achievement of improvement (minimal, much, or very much improved) in the CGI-I
rating as assessed, independently, by the parent/caregiver at the end of T+M
Percentage change from Baseline in the monthly frequency of all seizures during
T+M
Change from Baseline in the monthly frequency of CMS-free days during T+M
Exploratory
Percentage change from Baseline in the monthly frequency of all seizure types
not included as CMS (ie, *non-CMS* seizures) during T+M
The longest CMS-free interval (in days) during T+M
Change from Baseline in subject quality of life as measured using the
Quality-of-Life Inventory-Disability (QI Disability)
Change from Baseline in parent/caregiver quality of life as measured by EQ-5D-5L
Change from Baseline in subject*s sleep behavior as measured by CGI-I by
parent/caregiver
Safety
Treatment emergent adverse events (TEAEs)
Abnormal physical examination findings
Abnormal neurological examination findings
Positive response to self-harm question
Increase in valvular regurgitation from baseline (except absent to trace)
Pulmonary arterial hypertension (PASP > 35 mmHg) at any time during treatment
on repeat testing
Change from Baseline in Laboratory parameters (hematology, hormones, chemistry,
urinalysis)
Change from Baseline in Vital signs (blood pressure, heart rate, temperature,
and respiratory rate)
Change from Baseline in Body weight
Change from Baseline in Tanner Staging
Part 2
Effectiveness
Percentage change from Baseline in CMSF during the OLE Treatment Period
Achievement of Categorized Percentage change in seizures from Baseline in CMSF
during OLE Treatment Period (no reduction or worsening, >= 25%, >= 50%, >= 75%, or
100% reduction)
Achievement of *near seizure freedom* (0 or 1 seizures) during T+M
Achievement of a CGI-I rating of much or very much improved as assessed by the
Investigator and by the parent/caregiver at the end of the OLE Treatment Period
Achievement of improvement (minimal, much, or very much improved) in the CGI-I
rating as assessed by the Investigator at the end of the OLE Treatment Period
Achievement of improvement (minimal, much, or very much improved) in the CGI-I
rating as assessed by the Parent/Caregiver at the end of the OLE Treatment
Period
Percentage change from Baseline in monthly GTC seizure frequency during the OLE
Treatment Period
Change from Baseline in the monthly frequency of CMS-free days during the OLE
Treatment Period
Exploratory
Percentage change from Baseline in the monthly frequency of non-CMS seizures
The longest CMS-free interval (in days) during the OLE Treatment Period
Change from Baseline at end of OLE Treatment Period in subject quality of life
as measured using the Quality-of-Life Inventory-Disability (QI Disability)
Change from Baseline at end of OLE Treatment Period in parent/caregiver quality
of life as measured by EQ-5D-5L
Change from Baseline at the end of OLE Treatment Period in subject*s sleep
behavior as measured by CGI-I by parent/caregiver
Background summary
5.1 Overview of Disease and Disease Burden
CDKL5 deficiency disorder (CDD) is a rare genetic disorder that is caused by a
mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X
chromosome. The CDKL5 protein is a serine-threonine kinase, that is implicated
in normal brain development and function (Olson 2019). CDD is a debilitating
developmental disease with severe sequelae including frequent seizures that
cause multisystemic abnormalities. Increased seizure frequency and intensity
are often associated with catastrophic consequences of interfering with
intellectual and psychomotor development (Jakimiec 2020).
It is estimated that CDD affects 1 in 40,000 to 60,000 live births (Demarest
2019, Jakimiec 2020). The majority of patients with CDD are female (ie, the
female/male ratio is estimated to be 4:1) (Fehr 2015; Jakimiec 2020; Mirzaa
2013). In general, a CDD diagnosis is made on the basis of a patient*s history,
symptoms, physical examination, and genetic testing. Additionally, there are
proposed minimal criteria for diagnosis, including a pathogenic or likely
pathogenic variant in the CDKL5 gene, epilepsy with onset in the first year of
life, and motor and cognitive developmental delays (Olson 2019). The disorder
encompasses a wide array of clinical symptoms that range from mild to severe
across multiple systems. Male patients tend to have more severe symptoms than
female patients (Jakimiec 2020). The majority of patients with CDD have
treatment-resistant and long-term epilepsy (Olson 2019). Additional symptoms of
CDD include cortical visual impairment, hypotonia, gastrointestinal
dysfunction, gross motor impairment, sleep disturbances, respiratory ailments,
and feeding difficulties. The comorbidities associated with the disorder not
only severely impact the patients themselves, but also the caregivers.
Of the numerous symptoms that are associated with the manifestation of CDD,
early onset epilepsy is the initial symptom to occur within the first 3 months
of life (Olson 2019). Seizures in patients with CDD are more severe and begin
at a much younger age when compared with other epileptic encephalopathies
(Cutri French 2020). Epileptic spasms are one of the most common seizure types
during disease onset; however, this type of seizure can manifest at any time
throughout the course of a patient*s life (Demarest 2019; Olson 2019). Other
presenting seizure types include tonic seizures, generalized tonic-clonic
(GTC), hypermotor tonic spams, myoclonic seizures, and atonic seizures (Cutri
French 2020; Demarest 2019). A unique feature of CDD is that the epileptic
episodes may have diverse morphology (Jakimiec 2020). Some patients with CDD
can experience several seizure types during their lifetime (Demarest 2019), and
seizure types vary/change with age. Children and adults with CDD are
functionally impaired due to the debilitating symptoms including severe
cognitive and motor development delays, which significantly impact their daily
lives.
5.1.1 Current Management of CDKL5 Deficiency Disorder
One proposed mechanistic approach to treating CDD is reduction of seizure
burden. Accordingly, early intervention with an effective antiepileptic
treatment (AET) could be crucial for improved disease outcomes. Antiepileptic
treatment regimens include antiseizure medications (ASMs), vagus nerve
stimulation (VNS), responsive neurostimulation (RNS), ketogenic diet (KD),
surgery, and other non-pharmacological interventions.
Antiseizure medications have the potential to reduce the frequency, severity,
and duration of seizures associated with CDD. The effectiveness of many ASMs
tend to follow a pattern, which includes a period of high efficacy in the first
3 months but gradually declines over the course of a year (Müller 2016).
Antiseizure medications typically used in CDD include sodium valproate,
levetiracetam, lamotrigine, vigabatrin, clobazam, zonisamide, felbamate, and
steroids (Müller 2016; Amin 2017; Olson 2019). In addition, ganaxolone was
recently approved in the US for the treatment of CDD. Patients continue to
experience inadequate seizure control despite the usage of numerous ASMs; early
susceptibility to drug-resistance remains a hurdle for drug development.
Clinicians continue to need to consider each patient individually, considering
the potential benefit of each therapy weighed against the risk of adverse
effects.
Study objective
This study has been transitioned to CTIS with ID 2023-506269-78-00 check the CTIS register for the current data.
Objectives for Part 1:
Primary (Efficacy): To demonstrate that the efficacy of fenfluramine (ZX008)
0.8 mg/kg/day is superior to placebo as an adjunctive therapy for pediatric and
adult subjects with CDD
Secondary (Safety): To characterize the safety and tolerability of fenfluramine
(ZX008) in pediatric and adult subjects with CDD
Objectives for Part 2:
Primary (Safety)
To characterize the long-term safety and tolerability of fenfluramine (ZX008)
in pediatric and adult subjects with CDD
Secondary (Effectiveness)
To assess long-term effectiveness of fenfluramine (ZX008) as an adjunctive
therapy for pediatric and adult subjects with CDD
Study design
Methodology:
This is a 2-part multicenter trial. Part 1 is a 20-week randomized,
double-blind, placebo-controlled, fixed-dose, parallel-group study to examine
the efficacy and safety of fenfluramine (ZX008) as an adjunctive therapy (to
existing concomitant treatment with antiepileptic treatments [AETs]) in
subjects 1 to 35 years of age with a CDD diagnosis and uncontrolled seizures.
The primary study analysis to evaluate the efficacy and safety of fenfluramine
(ZX008) in subjects with CDD will be based on Part 1 data in all randomized
subjects.
Part 1 of the study is 20 weeks in duration and will consist of the following
stages: Baseline Period (ie, Baseline; 4 weeks including the Screening Visit
and Baseline observation), Titration Period (ie, Titration; 2 weeks),
Maintenance Period (ie, Maintenance; 12 weeks), and a 2-week Transition Period
(ie, Transition; 2 weeks) to the open-label starting dose.
Part 2 is a 54-week, open-label, flexible-dose, long term extension for
subjects who complete Part 1. Part 2 includes an Open-Label Extension (OLE)
Treatment Period (52 weeks) with a Taper Period (ie, Taper; 2 weeks). A cardiac
follow-up visit will be conducted 6 months after the last dose of study drug.
Intervention
Investigational product, dosage, and mode of administration:
Fenfluramine (ZX008) is supplied as an oral solution in concentrations of 1.25,
2.5, and 5 mg/mL. In Part 1, subjects will be randomized to receive either
fenfluramine (ZX008) 0.8 mg/kg/day or placebo. Subjects receiving concomitant
STP and randomized to fenfluramine (ZX008) 0.8 mg/kg/day will receive
fenfluramine (ZX008) 0.5 mg/kg/day. In Part 2, open-label fenfluramine (ZX008)
will be administered using a flexible dosing regimen, up to fenfluramine
(ZX008) 0.8 mg/kg/day. The maximum dose of fenfluramine (ZX008) allowed during
the study is 30 mg/day (or 20 mg/day for those receiving concomitant STP).
Study drug will be administered twice a day (BID) in equally divided doses with
or without food.
Study burden and risks
5.4 Risk-Benefit Assessment
The clinical benefit of fenfluramine (ZX008) in subjects who participated in 3
positive, adequate, and well controlled, randomized, double-blind,
placebo-controlled trials for Dravet syndrome, Study 1, Study 2 Cohort 2, and
Study 3 demonstrated a statistically significant and clinically meaningful
reduction in monthly convulsive seizure frequency and was generally well
tolerated. Moreover, the Phase 3, randomized placebo-controlled trial for LGS
Study 1601 also demonstrated clinically meaningful reduction in monthly drop
seizures. No subject had valvular heart disease or pulmonary arterial
hypertension in any study.
Fenfluramine (ZX008) was additionally evaluated in an Investigator-initiated
trial in subjects 2 to 35 years of age with CDD (Devinsky 2020). The trial
demonstrated that fenfluramine provided a clinically meaningful reduction in
both GTCs (90%) and tonic seizures (55%) in patients with CDD.
Fenfluramine has been used successfully for up to 30 years in Belgium in
refractory pediatric epilepsy patients, including those with Dravet syndrome
(Boel 1996; Ceulemans 2012; Schoonjans 2015; Schoonjans 2017). The doses used
in this study (ZX008-2103/EP0216) are based on data from the patients being
successfully treated in Belgium discussed above, and from four fenfluramine
(ZX008) studies (Study 1, Study 2 Cohort 2, Study 3 in Dravet syndrome and
Study 1601 in LGS). Fenfluramine (ZX008) 0.8 mg/kg/day dose is believed to be a
likely therapeutic dose, which could provide sufficient antiepileptic effect
for a sustained period of time during this study.
In summary, considering the clinical activity and well-tolerated safety profile
with fenfluramine (ZX008) as a treatment for seizures associated with Dravet
syndrome and with LGS, as well as the clinical benefit seen in an
Investigator-initiated study in patients with CDD, there is a positive benefit
risk assessment and strong scientific and clinical rationale for the broad
development of fenfluramine (ZX008) in a population of subjects with CDD.
5.4.1 Risk/Benefit Assessment for Minors or Cognitively Disabled
For minors or persons of legal age not capable of understanding the nature,
significance, and implications of the clinical trial and expressing their
wishes accordingly, the degree of burden and risk threshold should be monitored
carefully. Section 5.2.3 and the IB (please see the current effective ZX008 IB)
list the AEs that have been commonly reported in several ongoing and completed
clinical trials of fenfluramine (ZX008) for the treatment of seizures in
epileptic encephalopathies. The burden of these AEs should be monitored and
weighed against the benefits of seizure reduction or other improvements of the
CDD condition that the participant may be experiencing. Section 8.4 addresses
criteria for withdrawal from the study in cases in which the risk threshold for
these participants may be reached.
West Street The Pearce Building
Maidenhead, Berkshire SL6 1RL
GB
West Street The Pearce Building
Maidenhead, Berkshire SL6 1RL
GB
Listed location countries
Age
Inclusion criteria
To be eligible to enroll in this study, subjects must meet the following
inclusion criteria:
1. Subject has a confirmed pathogenic or likely pathogenic mutation in the
CDKL5 gene and a clinical diagnosis of CDD with epilepsy onset in the first
year of life, plus motor and developmental delays.
2. Subject is male or female, aged 1 to 35 years, inclusive, as of the day of
the Screening Visit. Subjects aged 1 to < 2 years will ONLY be permitted to
enroll in the trial AFTER the DSMB has determined that it is appropriate to do
so based on a planned unblinded interim safety review to be conducted after
approximately 40 subjects aged >= 2 to 35 years have completed Visit 6.
3. Subject must have failed to achieve seizure control despite previous or
current use of 2 or more AETs.
4. Subject is currently receiving at least 1 concomitant antiseizure treatment:
antiseizure medication (ASM), vagus nerve stimulation (VNS), responsive
neurostimulation (RNS), or ketogenic diet (KD). During the trial, rescue
medications (may include ASMs) or interventions for rescue treatment of
seizures will not be counted towards the total number of antiseizure treatments
established at Baseline.
5. All medications or interventions for epilepsy (including VNS, RNS, and KD)
must be stable prior to screening and are expected to remain stable throughout
the study. In order to establish stability at Baseline, duration of treatment
with medications or interventions for epilepsy prior to the Screening visit
must be as follows: VNS and RNS: >= 6 months duration; ASMs or KD: >= 4 weeks
duration.
6. At the Screening Visit, parent/caregiver reports that subject has >= 4
countable motor seizures (CMS) per week. CMS include distinct seizures of the
generalized tonic-clonic [GTC], bilateral clonic, bilateral tonic, atonic
(drop), bilateral tonic/atonic (drop), or focal to bilateral tonic-clonic type
lasting approximately 3 seconds or longer, to distinguish from short-clustered
seizures, spasms, or jerks.
7. Subject (and/or subject*s parent[s]/legal guardian[s]) has provided written
informed consent (and assent if applicable).
8. Subject (and/or subject*s parent/caregiver) is willing and able to comply
with study requirements (including diary completion, visit schedule, and study
drug accountability).
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from
enrollment in this study:
1. Subject has a known hypersensitivity to fenfluramine or any of the
excipients in the study drug.
2. Subject has a diagnosis of pulmonary arterial hypertension.
3. Subject has a clinically significant medical condition, including chronic
obstructive pulmonary disease, interstitial lung disease, or portal
hypertension, or has had clinically relevant symptoms or a clinically
significant illness currently or 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.
4. Subject has current or past history of cardiovascular or cerebrovascular
disease, such as cardiac valvulopathy, myocardial infarction or stroke, severe
ventricular arrhythmias, or clinically significant structural cardiac
abnormality, including but not limited to mitral valve prolapse, atrial or
ventricular septal defects, patent ductus arteriosus, and patent foramen ovale
with reversal of shunt. (Note: Patent foramen ovale or a bicuspid aortic valve
are not considered exclusionary.)
5. Subject has current eating disorder that suggests anorexia nervosa or
bulimia.
6. Subject has a current or past history of glaucoma.
7. Subject is taking > 4 concomitant ASMs. Rescue medications are not included
in the count.
8. Subject is receiving concomitant treatment with cannabidiol (CBD) other than
Epidiolex/Epidyolex or is being actively treated with tetrahydrocannabinol
(THC) or any marijuana product for any condition. Disallowed medications are
subject to wash-out requirements.
9. Subject has moderate to severe hepatic impairment, assessed based on the
Child-Pugh system (Appendix 1).
10. Subject has moderate to severe renal impairment (estimated glomerular
filtration rate < 50 mL/min/1.73 m2 calculated with the Isotope Dilution Mass
Spectrometry [IDMS] Traceable Schwartz equation for children and the Chronic
Kidney Disease Epidemiology Collaboration [CKD-EPI] equation for adults, using
actual body weight).
11. 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 atomoxetine; or
cyproheptadine (see Appendix 2 for a list of prohibited medications). (Note:
Short-term requirements for prohibited medications will be handled on a per
case basis by the study physician or delegate.)
12. Subject is currently receiving another investigational product(s) or has
received another investigational product within 30 days or within < 5 times the
half-lives of the investigational product, whichever is longer, prior to the
Screening Visit.
13. Female subjects of childbearing potential must not be pregnant or
breastfeeding. Female subjects of childbearing potential must have a negative
urine or serum pregnancy test at Screening. Subjects of childbearing or
child-fathering potential must be willing to use an approved method of highly
effective contraception, which includes abstinence, while participating in this
study and for 90 days after the last dose of study drug.
14. Subject is known to be human immunodeficiency virus positive.
15. Subject is known to have active viral hepatitis B or C.
16. Subject is institutionalized in a facility that does not provide skilled
epilepsy care.
17. Subject has previously been treated with Fintepla® (fenfluramine) prior to
the Screening Visit.
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 |
|---|---|
| EU-CTR | CTIS2023-506269-78-00 |
| EudraCT | EUCTR2021-003222-76-NL |
| CCMO | NL80928.028.22 |