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

Dravet Syndrome Clinical Trial

— ORCHID  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06118255
• Other study ID #: EP0213
• Secondary ID: 2022-502359-75-0
• Status: Recruiting
• Phase: Phase 3
• Start date: May 21, 2024
• Est. completion date: September 2, 2026

Study information

• Verified date: June 2024
• Source: UCB Pharma
• Contact: UCB Cares
• Phone: 1-844-599-2273 (USA)
• Email: ucbcares[@]ucb.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: September 2, 2026
• Est. primary completion date: May 20, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 23 Months

Eligibility

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

Related Conditions & MeSH terms

• Dravet Syndrome
• Epilepsies, Myoclonic
• Syndrome

Intervention

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).

Locations

Country	Name	City	State
Belgium	Ep0213 502	Bruxelles
Belgium	Ep0213 501	Edegem
Germany	Ep0213 303	Bielefeld
Germany	Ep0213 301	Jena
Italy	Ep0213 202	Florence
Italy	Ep0213 203	Genova
Italy	Ep0213 201	Roma
United Kingdom	Ep0213 403	Glasgow
United Kingdom	Ep0213 401	London
United States	Ep0213 107	Dallas	Texas
United States	Ep0213 105	Memphis	Tennessee
United States	Ep0213 106	Orange	California
United States	Ep0213 103	Seattle	Washington
United States	Ep0213 102	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
UCB BIOSCIENCES, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	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)
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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