ORCHID: 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

Sponsor

UCB BIOSCIENCES, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT06118255

Collaborator

(none)

Enrollment

Location

Arm

28.3

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Dravet Syndrome	Drug: fenfluramine	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Nov 13, 2023

Anticipated Primary Completion Date :

Jan 6, 2026

Anticipated Study Completion Date :

Mar 23, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fenfluramine Open-label 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 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). Other Names: Fintepla

Arm

Intervention/Treatment

Experimental: Fenfluramine Open-label

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

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).

Other Names:

Fintepla

Outcome Measures

Primary Outcome Measures

Change from Baseline in QT interval corrected by Fridericia (QTcF) at Visit 13 (End of Treatment/Early Termination (EOT/ET)) [Week 52 (Visit 13; EOT/ET), compared to Baseline]
QTcF is the QT interval corrected for heart rate according to Fridericia's formula. Higher values correspond to prolongation of QT interval.
Occurrence of a treatment-emergent (ie, post-Baseline through Visit 13 [EOT/ET]) result which meets the FDA case definition of drug associated valvulopathy [From post-Baseline (Day 1) through Visit 13 (EOT/ET) (up to 52 weeks)]
Drug associated valvulopathy refers to aortic regurgitation with severity mild or greater and/or mitral regurgitation with severity moderate or greater.
Occurrence of treatment-emergent (ie, post-Baseline through Visit 13 [EOT/ET]) clinically confirmed valvular heart disease (VHD) [From post-Baseline (Day 1) through Visit 13 (EOT/ET) (up to 52 weeks)]
Clinically confirmed VHD is an aortic regurgitation with mild or greater severity and/or a mitral regurgitation with moderate or greater severity.
Change from Baseline in body weight (Z-score) at each visit [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]
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.
Change from Baseline in recumbent length (Z-score) at each visit [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]
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.
Occurrence of a clinically significant abnormality on the neurological examination at each visit [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]
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.

Secondary Outcome Measures

Percentage change from the Baseline Period (ie, Baseline) in monthly (28 days) countable motor seizure frequency (CMSF), during Weeks 9 through 20 [During Weeks 9 to 20, compared to Baseline]
The percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency," or CMSF, during Weeks 9 through 20
Percentage change from Baseline in CMSF during Weeks 1 through 20 [During Weeks 1 to 20, compared to Baseline]
The percentage change from the Baseline Period (Baseline) in "monthly (28 days) countable motor seizure frequency," or CMSF, during Weeks 1 through 20
Percentage change from Baseline in CMSF during the Treatment Period (Week 1 through the EOT/ET Visit) [During the Treatment Period (Week 1 through EOT/ET) (up to 52 weeks), compared to Baseline]
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)
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 [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.
Achievement of a CGI-I rating of "much improved" or "very much improved" as assessed by the parent/caregiver at Week 20 [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.
Steady-state maximum plasma concentration (Cmax) of fenfluramine and norfenfluramine at Week 12 [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.
Steady-state minimum plasma concentration (Cmin) of fenfluramine and norfenfluramine at Week 12 [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.
Area under the plasma concentration time curve from time zero to 24 hours (AUC0 24) for steady-state fenfluramine and norfenfluramine at Week 12 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 23 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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