A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome

Study Overview
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Brief Summary
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The primary purpose of this study is evaluate the safety and tolerability of fenfluramine hydrochloride (HCl) 0.2 to 0.8 mg/kg/day in infants 1 year to less than 2 years of age with Dravet syndrome.

Official Title
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Open-Label, Single-Arm, Phase 3 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Drug: fenfluramine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is ≥1 to <2 years of age as of the day of the first administration of study drug Participant has a documented diagnosis or likely diagnosis of Dravet syndrome according to the International League Against Epilepsy (ILAE) criteria and as agreed by the Epilepsy Study Consortium (ESC) Participant must be currently receiving ≥1 concomitant antiseizure medication (ASM) at a stable dose for ≥4 weeks prior to the Screening Visit and is expected to remain stable throughout the study. Rescue medications for seizures are not counted towards the total number of ASMs Participants must have ≥4 countable motor seizures (CMS) during the Baseline Period. The CMS include distinct seizures of generalized tonic clonic, bilateral clonic, bilateral tonic, atonic (drop), bilateral tonic/atonic, or focal to bilateral tonic-clonic type. If the participant fails to have ≥4 qualifying seizures in 28 days, the Baseline Period may be extended by an additional 14 days with Sponsor approval. Participants with an extended Baseline Period must still have ≥4 CMS in the 28 days immediately prior to the day of the first administration of study drug. Body weight is ≥8 kg Males and females. Exclusion Criteria: Participant has a known hypersensitivity to fenfluramine hydrochloride (HCl) or any of the excipients in the study drug Participant has an exclusionary cardiovascular or cardiopulmonary abnormality based on echocardiogram (ECHO), electrocardiogram (ECG), or physical examination and is not approved for entry by the central cardiac reader Participant has a diagnosis of pulmonary arterial hypertension Participant 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 in the opinion of the Investigator would negatively impact study participation, collection of study data, or pose a risk to the participant Participant 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.) Participant has a current or past history of glaucoma Participant has moderate to severe hepatic impairment, assessed based on the Child-Pugh classification system Participant has moderate to severe renal impairment (estimated glomerular filtration rate <50 mL/min/1.73 m^2 calculated with the updated Bedside Schwartz equation for children QT interval corrected (QTc) >450 msec Participant is taking >4 concomitant ASMs Participant is receiving concomitant treatment with cannabidiol other than Epidiolex/Epidyolex or is being actively treated with tetrahydrocannabinol (THC) or any marijuana product for any condition Participant 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. Disallowed medications are subject to washout of ≥5 half-lives before the first day of study drug administration Participant is currently receiving another investigational product(s) or has received another investigational product within 30 days or within <5 times the half-life of that investigational product, whichever is longer, prior to the Screening Visit Participant has previously been treated with Fintepla (fenfluramine HCl) prior to the Screening Visit

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 23 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fenfluramine Open-label<br>All study participants will initiate fenfluramine hydrochloride (HCl) treatment at 0.2 mg/kg/day in the Dose-Finding Period and may be up-titrated to a maximum of 0.8 mg/kg/day based on the Investigators discretion. The dose of fenfluramine HCl can be flexibly titrated during the Maintenance Period. Study participants, who discontinue early will participate in the Taper Period. All participants will complete an End of Treatment (EOT) Visit. | Drug: fenfluramine<br>* The study drug, fenfluramine HCl, is an oral solution to be administered in equal doses twice daily (BID). It will be based on the current dose and participant's weight (kg).<br>* Other names: Fintepla;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in QT interval corrected by Fridericia (QTcF) at Visit 13 (End of Treatment/Early Termination (EOT/ET)) | QTcF is the QT interval corrected for heart rate according to Fridericia's formula. Higher values correspond to prolongation of QT interval. | Week 52 (Visit 13; EOT/ET), compared to Baseline | 
| Occurrence of a treatment-emergent (ie, post-Baseline through Visit 13 [EOT/ET]) result which meets the FDA case definition of drug associated valvulopathy | Drug associated valvulopathy refers to aortic regurgitation with severity mild or greater and/or mitral regurgitation with severity moderate or greater. | From post-Baseline (Day 1) through Visit 13 (EOT/ET) (up to 52 weeks) | 
| Occurrence of treatment-emergent (ie, post-Baseline through Visit 13 [EOT/ET]) clinically confirmed valvular heart disease (VHD) | Clinically confirmed VHD is an aortic regurgitation with mild or greater severity and/or a mitral regurgitation with moderate or greater severity. | From post-Baseline (Day 1) through Visit 13 (EOT/ET) (up to 52 weeks) | 
| Change from Baseline in body weight (Z-score) at each visit | Body weight (Z-score) refers to the number of standard deviations a participant's body weight lies from the mean, when compared to others of similar gender and age. | Week 1 (Visit 3), Week 4 (Visit 5), Week 8 (Visit 7), Week 12 (Visit 8), Week 16 (Visit 9), Week 20 (Visit 10), Week 26 (Visit 11), Week 39 (Visit 12), Week 52 (Visit 13), Postdose Safety Follow-Up (Visit 14), compared to Baseline | 
| Change from Baseline in recumbent length (Z-score) at each visit | Recumbent length (Z-score) refers to the number of standard deviations a participant's body weight lies from the mean, when compared to others of similar gender and age. | Week 1 (Visit 3), Week 4 (Visit 5), Week 8 (Visit 7), Week 12 (Visit 8), Week 16 (Visit 9), Week 20 (Visit 10), Week 26 (Visit 11), Week 39 (Visit 12), Week 52 (Visit 13), Postdose Safety Follow-Up (Visit 14), compared to Baseline | 
| Occurrence of a clinically significant abnormality on the neurological examination at each visit | A complete neurological examination will be conducted by the investigator for each participant covering cranial nerves, muscle strength and tone, reflexes, coordination, sensory function, and gait. | Week 1 (Visit 3), Week 4 (Visit 5), Week 8 (Visit 7), Week 12 (Visit 8), Week 16 (Visit 9), Week 20 (Visit 10), Week 26 (Visit 11), Week 39 (Visit 12), Week 52 (Visit 13), Postdose Safety Follow-Up (Visit 14), compared to Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change from the Baseline Period (ie, Baseline) in monthly (28 days) countable motor seizure frequency (CMSF), during Weeks 9 through 20 | The percentage change from the Baseline Period (Baseline) in monthly (28 days) countable motor seizure frequency, or CMSF, during Weeks 9 through 20 | During Weeks 9 to 20, compared to Baseline | 
| Percentage change from Baseline in CMSF during Weeks 1 through 20 | The percentage change from the Baseline Period (Baseline) in monthly (28 days) countable motor seizure frequency, or CMSF, during Weeks 1 through 20 | During Weeks 1 to 20, compared to Baseline | 
| Percentage change from Baseline in CMSF during the Treatment Period (Week 1 through the EOT/ET Visit) | The percentage change from the Baseline Period (Baseline) in monthly (28 days) countable motor seizure frequency, or CMSF, during the Treatment Period (Week 1 through the EOT/ET Visit; up to 52 weeks) | During the Treatment Period (Week 1 through EOT/ET) (up to 52 weeks), compared to Baseline | 
| Achievement of a Clinical Global Impression - Improvement (CGI-I) rating of much improved or very much improved as assessed by the Principal Investigator at Week 20 | The CGI-I rating scale permits a global evaluation of the participant's improvement over time by the investigator on a 7-point scale. | At Week 20 | 
| Achievement of a CGI-I rating of much improved or very much improved as assessed by the parent/caregiver at Week 20 | The CGI-I rating scale permits a global evaluation of the participant's improvement over time by the parent/caregiver on a 7-point scale. | At Week 20 | 
| Steady-state maximum plasma concentration (Cmax) of fenfluramine and norfenfluramine at Week 12 | Mean peak (maximum) plasma concentration of fenfluramine and norfenfluramine will be reported at Study Week 12 when participants are in the Maintenance Period. | At Week 12 | 
| Steady-state minimum plasma concentration (Cmin) of fenfluramine and norfenfluramine at Week 12 | Mean minimum plasma concentration of fenfluramine and norfenfluramine will be reported at Study Week 12 when participants are in the Maintenance Period. | At Week 12 | 
| Area under the plasma concentration time curve from time zero to 24 hours (AUC0 24) for steady-state fenfluramine and norfenfluramine at Week 12 | Mean AUC0-24 values of fenfluramine and norfenfluramine will be reported at Study Week 12 when participants are in the Maintenance Period. | At Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dravet syndrome, pediatrics, Fintepla, fenfluramine