A study to learn how safe fenfluramine is, how well it works, and how it moves through the bloodstream in infants with Dravet syndrome

Overview

Sponsor-declared trial summary

Key facts

Sponsor

UCB Biosciences Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

3 Jul 2024 → ongoing

Decision date (initial)

2023-09-21

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

UCB Biosciences Inc., 4000 Paramount Parkway, Suite 200, Morrisville, NC USA, 27560

External identifiers

EU CT number

2022-502359-75-00

WHO UTN

U1111-1289-2867

ClinicalTrials.gov

NCT06118255

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Others, Pharmacokinetic

To evaluate the safety and tolerability of fenfluramine hydrochloride (HCl) 0.2 to 0.8 mg/kg/day in infants 1 to less than 2 years of age with Dravet syndrome

Secondary objectives 1

1. -To assess the effectiveness of fenfluramine HCl in infants 1 to less than 2 years of age with Dravet syndrome -To determine the pharmacokinetic (PK) profile of fenfluramine HCl and norfenfluramine at steady state in infants 1 year to less than 2 years of age with Dravet syndrome

Conditions and MedDRA coding

Dravet syndrome

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001990-PIP01-16

Plan to share IPD

Yes

IPD plan description

Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. - 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 -Participant must have drug resistant epilepsy as defined as a history of failure of adequate trials of 2 tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom -Participants must have ≥1 countable motor seizures (CMS) during the Baseline Period. The CMS include distinct seizures of generalized tonic-clonic, bilateral clonic, focal motor, bilateral tonic, atonic (drop), bilateral tonic/atonic, or focal to bilateral tonic-clonic type. If the participant fails to have ≥1 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 ≥1 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 1

1. - 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 m2 calculated with the updated Bedside Schwartz equation for children - QT interval corrected (QTc) >450msec - 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Change from Baseline in QT interval corrected by Fridericia (QTcF) at Visit 13 (End of Treatment/Early Termination (EOT/ET))
2. Occurrence of a treatment-emergent (ie, post- Baseline through Visit 13 [EOT/ET]) result which meets the FDA case definition of drug associated valvulopathy
3. Occurrence of treatment-emergent (ie, post- Baseline through Visit 13 [EOT/ET]) clinically confirmed valvular heart disease (VHD)
4. Change from Baseline in body weight (Z-score) at each visit
5. Change from Baseline in recumbent length (Z-score) at each visit
6. Occurrence of a clinically significant abnormality on the neurological examination at each visit

Secondary endpoints 8

1. Percentage change from the Baseline Period (ie, Baseline) in monthly (28 days) countable motor seizure frequency (CMSF), during Weeks 9 through 20
2. Percentage change from Baseline in CMSF during Weeks 1 through 20
3. Percentage change from Baseline in CMSF during the Treatment Period (Week 1 through the EOT/ET Visit)
4. 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
5. Achievement of a CGI-I rating of “much improved” or “very much improved” as assessed by the parent/caregiver at Week 20
6. Steady-state maximum plasma concentration (Cmax) of fenfluramine and norfenfluramine at Week 12
7. Steady-state minimum plasma concentration (Cmin) of fenfluramine and norfenfluramine at Week 12
8. Area under the plasma concentration time curve from time zero to 24 hours (AUC0-24) for steady-state fenfluramine and norfenfluramine at Week 12

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

UCB Biosciences Inc.

Sponsor organisation

UCB Biosciences Inc.

Address

4000 Paramount Parkway Suite 200

City

Morrisville

Postcode

27560-8484

Country

United States

Scientific contact point

Organisation

UCB Biosciences Inc.

Contact name

UCB Cares

Public contact point

Organisation

UCB Biosciences Inc.

Contact name

UCB Cares

Third parties 21

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 91 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications