Prolonged fenfluramine use in open‐label studies of Dravet or Lennox–Gastaut syndromes: Long‐term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness

Antonio Gil‐Nagel; Kelly G Knupp; Boudewijn Gunning; Domenica Immacolata Battaglia; Elizabeth A Thiele; Ingrid E Scheffer; An‐Sofie Schoonjans; Rima Nabbout; Nathalie Villeneuve; Kerstin Alexandra Klotz; Nicola Specchio; Rocio Sanchez‐Carpintero; Marta Zolnowska; Anne‐Liv Schulz; Lily Perrin; Najla Dickson; Mélanie Langlois; Amélie Lothe; Joseph Sullivan

doi:10.1002/epi.70371

. 2026 Jul 4;67(10):5227–5242. doi: 10.1002/epi.70371

Prolonged fenfluramine use in open‐label studies of Dravet or Lennox–Gastaut syndromes: Long‐term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness

Antonio Gil‐Nagel ^1,^✉, Kelly G Knupp ², Boudewijn Gunning ³, Domenica Immacolata Battaglia ^4,⁵, Elizabeth A Thiele ⁶, Ingrid E Scheffer ^7,^8,^9,¹⁰, An‐Sofie Schoonjans ¹¹, Rima Nabbout ^12,^13,¹⁴, Nathalie Villeneuve ¹⁵, Kerstin Alexandra Klotz ^16,¹⁷, Nicola Specchio ^18,¹⁹, Rocio Sanchez‐Carpintero ²⁰, Marta Zolnowska ²¹, Anne‐Liv Schulz ²², Lily Perrin ^23,²⁴, Najla Dickson ²⁵, Mélanie Langlois ²⁶, Amélie Lothe ²⁶, Joseph Sullivan ²⁷

^¹Hospital Ruber Internacional, Madrid, Spain

^²University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA

^³Stichting Epilepsie Instellingen Nederland, Zwolle, the Netherlands

^⁴Fondazione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy

^⁵Università Cattolica del Sacro Cuore, Rome, Italy

^⁶Massachusetts General Hospital, Boston, Massachusetts, USA

^⁷University of Melbourne, Austin Health, Heidelberg, Victoria, Australia

^⁸Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

^⁹University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia

^¹⁰Murdoch Children's Research Institute, Parkville, Victoria, Australia

^¹¹University Hospital Antwerp, Antwerp, Belgium

^¹²Reference Center for Rare Epilepsies, Necker Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris (APHP), member of European Reference Network EpiCARE, Paris, France

^¹³Institut Imagine, Paris, France

^¹⁴Université Paris Cité, Paris, France

^¹⁵La Timone Children Hospital, Assistance Publique – Hôpitaux de Marseille (APHM), Marseille, France

^¹⁶University Hospital of Bonn, member of European Reference Network EpiCARE, Bonn, Germany

^¹⁷Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^¹⁸Bambino Gesù Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), member of European Reference Network EpiCARE, Rome, Italy

^¹⁹University Hospitals Katholieke Universiteit (KU), Leuven, Belgium

^²⁰Clínica Universidad de Navarra, Pamplona, Spain

^²¹Plejady Medical Center, Kraków, Poland

^²²UCB, Monheim am Rhein, Germany

^²³UCB, Slough, UK

^²⁴Veramed, London, UK

^²⁵UCB, Morrisville, North Carolina, USA

^²⁶UCB, Courbevoie, France

^²⁷Weill Institute for Neurosciences and Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA

Correspondence , Antonio Gil‐Nagel, Department of Neurology Epilepsy Program, Hospital Ruber Internacional, La Masó 38, 28034 Madrid, Spain. Email: agnagel@ruberinternacional.es

^✉

Corresponding author.

PMCID: PMC13675763 PMID: 42400405

Abstract

Objective

Long‐term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS) treated with fenfluramine in an open‐label extension (OLE) study after participating in a previous open‐label feeder study.

Methods

Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open‐label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day [26 mg/day] without stiripentol or .4 mg/kg/day [17 mg/day] with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long‐term safety/tolerability. Global functioning using caregiver‐ and investigator‐reported Clinical Global Impression of Improvement (CGI–I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc.

Results

A total of 412 patients enrolled (DS: 265 [64.3%], LGS: 147 [35.7%]); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8–1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171–2800). In this OLE, ≥1 treatment‐emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine‐related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as “improved or no change” on CGI–I versus this study baseline; subdomain ratings of “improved or no change” were largely consistent with global assessment.

Significance

In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long‐term fenfluramine use in pediatric and adult patients with DS or LGS.

Keywords: CGI–I, developmental and epileptic encephalopathy, DS, LGS, seizure

This graphical abstract provides an overview of the content from this open‐label extension study of fenfluramine use in patients with Dravet syndrome or Lennox‐Gastaut syndrome.

graphic file with name EPI-67-5227-g002.webp

Key points.

In this long‐term DS and LGS OLE, 412 patients (31% adult) received fenfluramine for a median 2 years (4 years median exposure with feeder studies).
No new or unexpected safety signals were observed; commonly reported TEAEs were consistent with those reported in previous DS/LGS studies.
More than 90% of patients had a CGI–I global rating of “improved or no change” compared with this OLE baseline (receiving fenfluramine at OLE entry).
Proportions of patients with clinically meaningful improvement on last visit CGI–I global and subdomain assessments ranged from 12% to 48%.
Within each age cohort, safety outcomes and global functioning were consistent across pediatric and adult groups of DS or LGS.

1. INTRODUCTION

Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare, lifelong developmental and epileptic encephalopathies (DEEs) characterized by high seizure burden and cognitive and behavioral impairments. ¹ , ² , ³ DS and LGS are drug‐resistant conditions, and achieving seizure freedom is unlikely, with seizures and nonseizure symptoms persisting into adulthood. ² , ³ , ⁴ , ⁵ An unmet need remains for safe, tolerable, and effective long‐term treatment that may contribute to improved overall function and quality of life of patients and their caregivers and families. ⁵

Fenfluramine differs from other treatments for DEEs and neurodevelopmental disorders due to its mechanism of action, involving modulation of serotonin release and signaling at multiple serotonin receptors (including 5‐HT_1D, 5‐HT_2A, 5‐HT_2C, and 5‐HT₄), as well as sigma‐1 signaling; ⁶ moreover, it carries minimal risk for CYP450‐related drug–drug interactions. ⁴ , ⁷ , ⁸ Currently, fenfluramine is approved for treatment of seizures associated with DS and LGS in patients ≥2 years old in the United States ⁹ and as add‐on treatment for patients ≥2 years old with seizures associated with DS and LGS in many countries. ¹⁰ , ¹¹ , ¹² , ¹³

Efficacy of fenfluramine was established in three randomized controlled trials (RCTs) ¹⁴ , ¹⁵ , ¹⁶ with a subsequent open‐label extension (OLE) study ¹⁷ in DS and one RCT with an associated OLE study in LGS. ¹⁸ , ¹⁹ In the DS OLE study in 324 patients, the median percent change in monthly convulsive seizure frequency from Month 2 to end of study compared with baseline was −67.8% (p < .001; median exposure of 824 days [range = 7–1280]). ¹⁷ In the fenfluramine LGS OLE study (in 240 patients who previously received a median of 7 antiseizure medications [ASMs]), the median percent change in the frequency of seizures associated with a fall from Month 2 to end of study compared with baseline was −31.1% (median exposure of 364 days [range = 19–537]); in this study, generalized tonic–clonic seizures were the most responsive seizure type (median percent change of −47.0% from Month 2 to end of study compared with baseline [p < .001]). ¹⁹

As management of DEEs should extend beyond seizure reduction, in these clinical trials, Clinical Global Impression of Improvement (CGI–I) ratings were obtained from caregiver and investigator at each study visit to evaluate global functioning as secondary study endpoints. In both OLE studies, at last visit, >50% of patients demonstrated improvement from study baseline in global functioning as indicated by CGI–I ratings by investigator and caregiver. Overall, fenfluramine was well tolerated; adverse events (AEs) were the primary reason for study discontinuation in 2.9% and 5.3% of patients in the DS OLE and LGS OLE, respectively. The fenfluramine long‐term safety profile (in the OLE studies) was consistent with that from the RCTs; the treatment‐emergent AEs (TEAEs) reported in ≥10% of patients in both studies were decreased appetite, nasopharyngitis, seizure, and pyrexia. ¹⁷ , ¹⁹

Following participation in the prior open‐label studies, patients could continue receiving fenfluramine in the present OLE until fenfluramine was approved locally for treatment of the patient's DEE, until a managed access program was established in the country of residence, or until investigational development for a patient's indicated DEE was stopped, whichever came first.

To better inform patients, caregivers, and providers on long‐term treatment effects of fenfluramine, here we report the long‐term safety and global functioning analyses from this OLE study in pediatric and adult patients with DS or LGS treated with fenfluramine who had participated in a previous fenfluramine open‐label study.

2. MATERIALS AND METHODS

This study (Clinical Trial Registration NCT03936777, ZX008‐1900/EP0215) complied with current International Council for Harmonization Good Clinical Practice guidelines and was approved by the applicable regulatory authorities and independent ethics committee/institutional review board at each institution. All legal representatives provided signed informed consent before enrollment.

2.1. Study design and participants

In this international, multicenter OLE study, pediatric and adult patients with DS or LGS were eligible to enroll if they had previously participated in a fenfluramine open‐label study (ZX008‐1503/EP0212, NCT02823145 [DS] ¹⁷ ; ZX008‐1601/EP0214 Part 2, NCT03355209 [LGS] ¹⁹ ; or ZX008‐1602/EP0207, NCT03467113 [DS/LGS, fenfluramine + concomitant cannabidiol] ²⁰ ). Additional eligibility criteria were generally consistent with those for entry into feeder studies; patients with current valvulopathy, pulmonary arterial hypertension (PAH), or moderate/severe hepatic impairment were excluded. In the DS and LGS RCTs and corresponding OLE studies, patients could not receive any form of cannabidiol, ¹⁷ , ¹⁹ but concomitant cannabidiol was permitted in the present OLE study.

2.2. Study interventions

Patients received an oral solution of fenfluramine hydrochloride containing 2.2 mg/mL fenfluramine, administered twice daily in equal doses. At entry of this OLE, patients continued fenfluramine at the last dose prescribed in the previous OLE study (ZX008‐1503/EP0212 or ZX008‐1601/EP0214 Part 2). For patients entering from ZX008‐1602/EP0207, the starting dose was determined through consultation between the investigator and study sponsor (Figure S1). Doses were then flexibly titrated; dose increases could not be performed more frequently than every 7 days and by no more than .2 mg/kg/day. Fenfluramine dose caps applied: maximum .7 mg/kg/day (26 mg/day) without stiripentol or .4 mg/kg/day (17 mg/day) if receiving stiripentol concomitantly. At least one ASM was required to be given concomitantly with fenfluramine unless fenfluramine monotherapy was deemed clinically appropriate by the investigator; dose changes in concomitant ASMs were permitted as clinically necessary, and new concomitant antiseizure treatments could be introduced at the investigator's discretion. After discontinuing fenfluramine, patients who did not transition to commercially available fenfluramine product underwent a 2‐week taper. A cardiac follow‐up (including Doppler echocardiogram [ECHO] and physical examination) was performed 6 months after the last dose, with additional cardiac follow‐ups 12 months after the last dose for patients enrolled in the United Kingdom and 24 months for patients enrolled in Germany, France, and the Netherlands.

2.3. Study outcomes

The primary objective was to assess the long‐term safety and tolerability of fenfluramine. Secondary objectives included evaluation of the effect of fenfluramine on global functioning as assessed by caregiver and investigator on the CGI–I scale, globally and for specific subdomains (cognition, behavior, motor abilities). Safety and effectiveness assessments were performed at baseline of this OLE study and every 6 months until end of study. Global and subdomain CGI–I ratings at last treatment visit were compared to Clinical Global Impression of Severity (CGI–S) scores obtained at study baseline (i.e., at time of entrance into this OLE). Outcomes were analyzed by DEE cohort (DS and/or LGS). Post hoc analyses were conducted to describe outcomes by age group (pediatric: <18 years old, adult: ≥18 years old), as well as mean daily dose and overall treatment exposure.

2.4. Definitions and statistical analysis

Baseline characteristics and safety were analyzed in the safety population, defined as all patients who received ≥1 dose of fenfluramine during this study. Modified intent‐to‐treat (mITT) population included all patients who received ≥1 dose of fenfluramine and had ≥1 valid assessment of effectiveness after the first postbaseline visit of this OLE (i.e., approximately 6 months of treatment in the current study). An overview of the CGI–I assessment is provided in Table S1. MedDRA version 21.1 was used to classify AEs. Per the agreement with the US Food and Drug Administration, valvular heart disease (VHD) was defined as mild, moderate, or severe aortic regurgitation (AR) or moderate or severe mitral regurgitation, with additional characteristics and/or physical signs or symptoms attributable to VHD (such as valve thickening, restricted valve motion). PAH was defined as pulmonary arterial systolic pressure of >35 mmHg. Descriptive statistics were used, with no formal statistical testing performed.

3. RESULTS

3.1. Patients

A total of 412 patients were enrolled in the study (DS: 265 [64.3%], LGS: 147 [35.7%]) and comprised the safety population (Figure S1). The mITT population consisted of 410 patients: 264 (64.4%) with DS and 146 (35.6%) with LGS. Of the 412 enrolled patients, 360 (87.4%) completed the study (Table 1, Figure S1).

TABLE 1.

Patient enrollment, study disposition, and baseline and clinical characteristics by developmental and epileptic encephalopathy cohort and age group.

Characteristic	DS, n = 265		LGS, n = 147		All, N = 412
	Age group		Age group		Age group
	2 to <18 years, n = 193	≥18 years, n = 72	2 to <18 years, n = 92	≥18 years, n = 55	2 to <18 years, n = 285	≥18 years, n = 127
Completed the study, n (%) ^a	186 (96.4)	71 (98.6)	65 (70.7)	38 (69.1)	251 (88.1)	109 (85.8)
Discontinued, n (%)	7 (3.6)	1 (1.4)	27 (29.3)	17 (30.9)	34 (11.9)	18 (14.2)
Reason for discontinuation, n (%)
Adverse event	0	0	2 (2.2)	1 (1.8)	2 (.7)	1 (.8)
Death ^b	1 (.5)	0	1 (1.1)	1 (1.8)	2 (.7)	1 (.8)
Lack of Efficacy	4 (2.1)	0	13 (14.1)	7 (12.7)	17 (6.0)	7 (5.5)
Lost to follow‐up	0	0	1 (1.1)	2 (3.6)	1 (.4)	2 (1.6)
Physician decision	0	0	1 (1.1)	0	1 (.4)	0
Subject withdrawal	1 (.5)	1 (1.4)	5 (5.4)	4 (7.3)	6 (2.1)	5 (3.9)
Other	0	0	0	1 (1.8)	0	1 (.8)
Missing ^c	1 (.5)	0	4 (4.3)	1 (1.8)	5 (1.8)	1 (.8)
Age at enrollment in this OLE study (ZX008‐1900), years, median (range)	10 (3–17)	20 (18–33)	10 (3–17)	22 (18–37)	10 (3–17)	21.0 (18–37)
Sex, male, n (%)	109 (56.5)	35 (48.6)	48 (52.2)	29 (52.7)	157 (55.1)	64 (50.4)
Weight at enrollment in this OLE study (ZX008‐1900), kg, median (range) ^d	29.9 (13.6–88.2)	56.5 (35.0–101.6)	31.8 (12.8–78.8)	57.3 (27.1–90.8)	30.5 (12.8–88.2)	57.1 (27.1–101.6)
Prior ASMs, median (range) ^e	0 (0–2)	0 (0–2)	0 (0–1)	0 (0–1)	0 (0–2)	0 (0–2)
Prior and concomitant ASMs, median (range) ^f	3 (0–6)	3 (1–7)	3 (0–6)	3 (1–6)	3 (0–6)	3 (1–7)
Concomitant ASMs, median (range) ^g	1 (0–7)	0 (0–6)	2 (0–7)	2 (0–9)	1 (0–7)	1 (0–9)
Fenfluramine exposure in this study, days, median (range)	449.0 (8–1544)	370.0 (182–1431)	993.0 (189–1443)	894.0 (123–1445)	730.0 (8–1544)	722.0 (123–1445)
Mean daily dose, mg/kg/day (SD)	.5 (.2)	.4 (.1)	.6 (.1)	.4 (.1)	.5 (.2)	.4 (.1)

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Abbreviations: ASM, antiseizure medication; DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; OLE, open‐label extension.

^{^a}

The status “completed the study” indicated completion of 36 months of treatment (or 24 months in Denmark) or transition to commercial drug.

^{^b}

Three deaths were attributed to cardiac arrest (n = 1), noncompaction cardiomyopathy (n = 1), and status epilepticus (n = 1); none was deemed by the investigator to be related to fenfluramine.

^{^c}

Patients who were incorrectly reported as having completed the study but had not completed 36 months of treatment (or 24 months in Denmark) and thus having no reported reason for discontinuation were classified as missing disposition data.

^{^d}

Weight was available in 283 of 285 pediatric and 124 of 127 adult patients.

^{^e}

“Prior ASM” indicates an ASM that had been started before Visit 1 but was not ongoing at Visit 1.

^{^f}

“Prior and concomitant ASM” indicates an ASM that had been started prior to Visit 1 and was ongoing at Visit 1.

^{^g}

“Concomitant ASM” indicates an ASM that was started after Visit 1.

Most baseline characteristics were balanced between the DEE cohorts (Table 1). Mean (SD) age for the overall population was 14.1 (6.8) years; most patients were pediatric (285/412 [69.2%], 2 to <18 years; 127/412 [30.8%] were ≥18 years). A higher proportion of patients with LGS (55/147, 37.4%) versus those with DS (72/265, 27.2%) enrolled in this study as adults. In both DEE cohorts, a median of 3 ASMs were previously tried before initiating fenfluramine and were continued concomitantly with fenfluramine while in this study (Table 1). Of the patients with DS, 143 (54.0%) and 23 (8.7%) had previously tried 3–4 ASMs and ≥5 ASMs, respectively; 97 (66.0%) patients with LGS had previously tried 3–4 ASMs, and 20 (13.6%) had previously tried ≥5 ASMs.

The most commonly used ASMs, started before entry into this OLE and continued concomitantly with fenfluramine while in the study, were valproate (all forms/salts, n = 280, 68.0%), clobazam (n = 233, 56.6%), and diazepam (n = 138, 33.5%; rescue and/or maintenance). Overall, 57 (13.8%) patients were receiving stiripentol as a prior and concomitant ASM; all had DS. At any point in this OLE study, 77 (18.7%) patients received concomitant cannabidiol (any form/salt); 45 (58.4%) had LGS.

The most common baseline global CGI–S ratings were “markedly ill” (113/412 [27.4%]) as assessed by caregiver and “moderately ill” (141/412 [34.2%]) assessed by investigator (Table S2). On CGI–S, more adults were rated “markedly ill,” “severely ill,” or “among the most extremely ill” by both caregiver and investigator (57.5%, 48.8%, respectively) versus pediatric patients (47.4%, 35.4%, respectively). Similar to the baseline global CGI–S results, “moderately ill” was the most common rating by investigator in the behavior and motor abilities subdomains; the most common rating by investigator in the cognition subdomain was “markedly ill.” The most common ratings by caregiver in the cognition, behavior, and motor abilities subdomains were “severely ill,” “markedly ill,” and “moderately ill,” respectively.

Median fenfluramine exposure in this study was 2 years (729.5 days [range = 8–1544]); exposure in either DEE was higher in pediatric patients than in adults (Table 1). Median exposure was 440.0 days (range = 8–1544) in patients with DS and 940.0 days (range = 123–1445) in patients with LGS. Overall median exposure, including duration of fenfluramine treatment in the previous feeder studies, was 4 years (1464.5 days [range = 171–2800]). In patients with DS, the median overall exposure was 1520.0 days (range = 171–2800) and in patients with LGS, 1371.0 days (range = 599–1960). Mean fenfluramine (SD) daily dose throughout this OLE study was .5 (.2) mg/kg/day (Table 1). In both DEE cohorts, as was somewhat expected, mean weight‐adjusted daily dose was lower in adult (.4 [SD = .1] mg/kg/day) versus pediatric patients (.5 [SD = .2] mg/kg/day).

3.2. Safety

In this OLE study, three patients (all with LGS) discontinued the study due to an AE (Table 1), and one patient experienced a TEAE that contributed to study discontinuation, although it was not listed as the primary reason for study withdrawal (Table 2). Incidence of any TEAE was consistent across the age groups but was numerically higher in patients with LGS versus patients with DS. The two most commonly reported serious TEAEs included seizure (17/412, 4.1%) and status epilepticus (9/412, 2.2%).

TABLE 2.

Safety summary by developmental and epileptic encephalopathy cohort and age group.

	DS, n = 265		LGS, n = 147		All, N = 412
	Age group		Age group		Age group
	2 to <18 years, n = 193	≥18 years, n = 72	2 to <18 years, n = 92	≥18 years, n = 55	2 to <18 years, n = 285	≥18 years, n = 127
Patients with any TEAEs, n (%)	134 (69.4)	49 (68.1)	80 (87.0)	48 (87.3)	214 (75.1)	97 (76.4)
Patients with serious TEAEs, n (%)	19 (9.8)	10 (13.9)	22 (23.9)	16 (29.1)	41 (14.4)	26 (20.5)
Patients with TEAEs leading to study discontinuation, n (%) ^a	0	0	2 (2.2)	2 (3.6)	2 (.7)	2 (1.6)
Patients with treatment‐related TEAEs, n (%) ^b	20 (10.4)	9 (12.5)	14 (15.2)	8 (14.5)	34 (11.9)	17 (13.4)
Patients with treatment‐related serious TEAEs, n (%) ^b	0	1 (1.4)	1 (1.1)	3 (5.5)	1 (.4)	4 (3.1)
Patients with TEAEs leading to death, n (%) ^c	1 (.5)	0	1 (1.1)	1 (1.8)	2 (.7)	1 (.8)
TEAEs reported in ≥10% of all patients, n (%)
Coronavirus infection	30 (15.5)	13 (8.1)	20 (21.7)	22 (40.0)	50 (17.5)	35 (27.6)
Seizure	20 (10.4)	6 (8.3)	25 (27.2)	12 (21.8)	45 (15.8)	18 (14.2)
Pyrexia	30 (15.5)	9 (12.5)	9 (9.8)	6 (10.9)	39 (13.7)	15 (11.8)
Nasopharyngitis	27 (14.0)	7 (9.7)	10 (10.9)	5 (9.1)	37 (13.0)	12 (9.4)
Weight loss, n/N (%)
≥7% reduction in body weight at last visit	3/184 (1.6)	3/66 (4.5)	6/90 (6.7)	10/50 (20.0)	9/274 (3.3)	13/116 (11.2)
≥10% reduction in body weight at last visit	1/184 (.5)	2/66 (3.0)	3/90 (3.3)	6/50 (12.0)	4/274 (1.5)	8/116 (6.9)
≥7% reduction in body weight at any visit	7/185 (3.8)	9/66 (13.6)	10/90 (11.1)	16/51 (31.4)	17/275 (6.2)	25/117 (21.4)
≥10% reduction in body weight at any visit	4/185 (2.2)	4/66 (6.1)	5/90 (5.6)	12/51 (23.5)	9/275 (3.3)	16/117 (13.7)

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Abbreviations: AE, adverse event; DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; TEAE, treatment‐emergent AE.

^{^a}

One patient did not have an AE listed as the primary reason for discontinuation as noted in Table 1.

^{^b}

AE causality is based on the investigator's assessment.

^{^c}

Three deaths were attributed to cardiac arrest (n = 1), noncompaction cardiomyopathy (n = 1), and status epilepticus (n = 1); none was deemed by the investigator to be related to fenfluramine.

TEAEs reported in ≥10% of all patients were coronavirus infection (85/412, 20.6%), seizure (63/412, 15.3%), pyrexia (54/412, 13.1%), and nasopharyngitis (49/412, 11.9%). Separate from the three patients who reported a TEAE leading to study discontinuation, two pediatric patients (one with DS and one with LGS) and one adult patient with LGS died (Table 2); these deaths (cardiac arrest [n = 1], noncompaction cardiomyopathy [n = 1], status epilepticus [n = 1]) were deemed unrelated to fenfluramine by the investigator.

At last visit, ≥7% reduction in body weight was reported in 22 of 390 (5.6%) patients, six of whom were patients with DS and 16 were patients with LGS. A reduction in body weight of ≥10% was reported in three patients with DS and nine patients with LGS for a total of 12 of 390 (3.1%) patients.

There was no evidence of a clinically significant effect of fenfluramine on the electrocardiographic parameter (QT corrected for heart rate by Fridericia's cube root formula). No cases of PAH or VHD were reported in this study. Three adult patients with LGS with mild AR met the definition for aortic valvulopathy. Of these, two patients had mild AR at baseline and at every subsequent ECHO, and one patient (who had trace AR at baseline) had a single instance of transient mild AR at Month 18 of treatment.

3.3. Effectiveness

At the last visit global CGI–I assessment, caregivers and investigators rated most patients as “improved or no change” relative to baseline of this OLE study (i.e., patients were receiving fenfluramine at this OLE study entrance) for the DS and LGS cohorts and the overall population in either age group (Figure 1A–C). Most patients were also rated by caregiver and investigator as “improved or no change” in CGI–I subdomains of cognition (Figure 2A–C), behavior (Figure 3A–C), and motor abilities (Figure 4A–C). More than one third of all patients were rated as having clinically meaningful improvement (“very much improved” or “much improved”) on global CGI–I by both caregiver and investigator when continuing fenfluramine treatment in this OLE study (Figure 1C); including the subdomain CGI–I assessments in all patients (either DS or LGS), proportions of patients with clinically meaningful improvement ranged from 11.5% to 48.4% (Figure 1C, Figure 2C, Figure 3C, Figure 4C). In the overall global and subdomain assessments, a numerically higher proportion of patients were rated as demonstrating clinically meaningful improvement by caregiver versus investigator (Figure 1C, Figure 2C, Figure 3C, Figure 4C). Overall, 24 patients (5.8%) discontinued fenfluramine due to lack of efficacy.

Last visit Clinical Global Impression of Improvement relative to Clinical Global Impression of Severity at baseline of this open‐label extension study by caregiver and investigator and developmental and epileptic encephalopathy. DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; y, years.

Last visit Clinical Global Impression of Improvement ratings for the cognition subdomain relative to Clinical Global Impression of Severity at baseline of this open‐label extension study by caregiver and investigator and developmental and epileptic encephalopathy. DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; y, years.

Last visit Clinical Global Impression of Improvement ratings for the behavior subdomain relative to Clinical Global Impression of Severity at baseline of this open‐label extension study by caregiver and investigator and developmental and epileptic encephalopathy. DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; y, years.

Last visit Clinical Global Impression of Improvement ratings for the motor abilities subdomain relative to Clinical Global Impression of Severity at baseline of this open‐label extension study by caregiver and investigator and developmental and epileptic encephalopathy. DS, Dravet syndrome; LGS, Lennox–Gastaut syndrome; y, years.

4. DISCUSSION

In this long‐term OLE study evaluating pediatric and adult patients with DS or LGS who were continuing fenfluramine treatment from a previous open‐label study, fenfluramine had a low discontinuation rate, was associated with prolonged treatment exposure, and was well tolerated. Importantly, global and subdomain CGI–I ratings (cognition, behavior, motor abilities) indicated stable or improved response to fenfluramine treatment over time.

The low discontinuation rate, prolonged treatment duration in this study, and overall exposure across all feeder studies (7+ years) suggest sustained clinical benefit with fenfluramine use. Overall, 12.6% of patients discontinued this study. Notably, the discontinuation rate observed in the OLE studies of cannabidiol in patients with DS was 45% (median duration = 444 days [range = 18–1535]) ²¹ and in patients with LGS was 33% (median duration = 1090 days [range = 3–1421]) ²² ; the discontinuation rate in a study of clobazam in patients with LGS was 30%, based on a 6‐year interim report. ²³ Median exposure in our OLE study was 2 years (range = 8–1544 days) and was highest in pediatric patients with LGS. Because patients with DS may have been eligible to receive commercial fenfluramine due to an earlier licensed indication, patients with LGS remained in this OLE study longer. Conversely, overall exposure (including fenfluramine treatment while participating in feeder studies) was longer in patients with DS because the DS clinical trial program began earlier than the LGS program.

Due to the lifelong nature of these DEE syndromes, evaluation of long‐term tolerability and safety of therapies is important to clinicians and patients with DS or LGS and their families. In this OLE study, fenfluramine was well tolerated, and AEs were consistent with those previously reported in the literature and prescribing information. Overall, AEs were the reason for treatment discontinuation in only three of 412 (.7%) patients. In this OLE study, 16.3% of patients reported serious AEs, which is consistent with rates reported in previous fenfluramine OLE publications (DS: 26.5%, ¹⁷ LGS: 16.6% ¹⁹ ). In other OLE studies, 42% and 43% of patients reported serious AEs while on cannabidiol ²¹ , ²² and clobazam, ²³ respectively. Of the four TEAEs reported in ≥10% of all patients in this OLE study, three were related to common childhood illnesses (Table 2). The incidence of decreased appetite was >15% in the DS and LGS OLE feeder studies, but decreased appetite was reported in <10% of all patients in this OLE study. Although there have been postmarketing cases of VHD and PAH reported since fenfluramine became commercially available, albeit infrequent and often involving confounding factors, there were no cases of VHD or PAH observed in this OLE study. Overall, there were no major differences in incidence of TEAEs by age group.

For treatment of DS and LGS, seizure control is one of the primary goals, but a holistic approach is needed that addresses non‐seizure‐related outcomes and ensures the patient is comprehensively and sustainably managed. ⁵ , ²⁴ , ²⁵ Studies have demonstrated that nonseizure symptoms impact the quality of life of caregivers and patients with DS and LGS, ²⁵ and due to the lifelong nature of these DEEs, nonseizure symptoms often become primary concerns for caregivers and families. Thus, data to describe treatment impact on patient global functioning and individual subdomains are of great relevance. ²⁶ The multimodal mechanism of action of fenfluramine involving serotonergic activity and modulation of sigma‐1 receptor signaling contributes to its efficacy in both seizure and nonseizure outcomes. ²⁷ Because patients entered this OLE study already receiving fenfluramine from a previous fenfluramine study, CGI–I ratings by caregiver and investigator of “improved or no change” from baseline of this study should be interpreted as reassuring and positive. In the parent DS and LGS OLE studies, 80% and >50% of patients, respectively, were rated as demonstrating any improvement at last visit ¹⁷ , ¹⁹ ; subsequently, in this study, >90% of patients were noted as “improved” or demonstrating “no change.” Additionally, >30% of patients were rated as experiencing clinically meaningful improvement (ratings of “very much improved” or “much improved”) by caregiver and investigator, suggesting continued long‐term effectiveness of fenfluramine in patients who had already been receiving fenfluramine for >1 year in the previous OLE studies. ¹⁷ , ¹⁹ In the DS and LGS cannabidiol OLE studies, >80% of patients/caregivers reported overall improvement of patients at Week 156 on Clinical Global Impression of Change (CGI–C). ²¹ , ²² Clinically meaningful improvement on CGI–C was reported by physicians and caregivers in 80% of 137 patients assessed at 3 years of clobazam treatment (evaluated over 2005–2012) for patients with LGS. ²³ Due to different study designs (follow‐up periods, schedules of assessment, etc.), data from these OLE studies cannot be compared directly. Aside from the cannabidiol and clobazam LGS OLEs, other OLE studies for ASMs used to treat seizures in patients with LGS have not evaluated global functioning. ²⁸ , ²⁹

As in the clinical trials, CGI–I ratings have also been used to describe patient global functioning in fenfluramine real‐world studies. In the post hoc secondary analysis of fenfluramine use in patients with DS participating in European expanded access programs (specifically, in Germany, Italy, Spain, and the United Kingdom), 149 patients received fenfluramine over a median duration of 11.3 months (range = 1–22.9). ³⁰ Overall, 61.5% were rated as demonstrating clinically meaningful improvement: 63.2% of pediatric patients and 54.1% of adults. Real‐world studies also support the improvement in CGI–I subdomains observed in this OLE study, especially cognition. A Spanish real‐world study evaluated effectiveness and tolerability of fenfluramine use in a mixed population of patients with DS or other DEEs (n = 54) and 14 patients with LGS. ³¹ Over a median follow‐up period of >2 years, caregiver‐perceived cognitive and motor improvements (as assessed by CGI) were reported in 70.7% (41/58) and 36.2% (21/58) of patients, respectively. Similar results were described in another retrospective study from Spain, noting that 56%–91% of fenfluramine responders (reduction in seizure frequency of ≥50% from baseline) with DS or LGS showed improvements in CGI–I subdomains (cognition, behavior, and sleep), as assessed by physicians. ³² Additionally, improvements in cognition in patients with DS receiving fenfluramine in the United States as reported by caregivers ³³ and patients with DS living in Germany, Spain, Italy, and the United Kingdom as reported by caregivers and clinicians have also been described. ³⁴ Among the patients in the United States (n = 65), the most commonly cited quality of life benefits included improvements in cognition, alertness, and academic performance in 79%, 71%, and 64% of patients with DS, respectively. ³³ Similar findings were reported in patients in the European Union/United Kingdom, with cognitive function noted as the domain with the highest proportion of non‐seizure‐related improvement in patients with DS by both caregivers and clinicians. ³⁴ In this OLE study, as with the global CGI–I ratings but not in line with the natural cognitive decline associated with aging in DS and LGS, ³⁵ , ³⁶ >90% of patients were rated as “improved or no change” and approximately 20% as demonstrating clinically meaningful improvement on the cognition subdomain by both caregiver and investigator (Figure 2). Preliminary fenfluramine analyses have demonstrated improvements in aspects of everyday executive function (as evaluated by Behavior Rating Inventory of Executive Function) in different age groups among patients with DS and LGS. ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ In some cases, this was partially independent of antiseizure clinical response, although we recognize improvements could be multifactorial, including lower seizure burden, changes in concomitant ASMs, and fewer epileptiform discharges. A recent single‐center, cross‐sectional study also described functional improvements (communication, attention, behavior) in 21 patients with DS treated with fenfluramine. There was a trend toward higher global improvement ratings in patients with better seizure outcomes, and functional improvements were noted even in some patients who achieved only partial seizure control. ⁴² This positive effect of fenfluramine on cognition and behavior is particularly relevant because many ASMs and treatments for DEEs can cause worsening of cognition and behavior. ⁴³ , ⁴⁴

On the overall global CGI–I assessment and three subdomains (cognition, behavior, and motor abilities), compared with investigators, caregivers were more likely to rate patients as still demonstrating clinically meaningful improvement, suggesting caregivers may recognize, prioritize, and/or evaluate nonseizure benefits differently from clinicians.

Due to the long‐term clinical benefit and safety profile, fenfluramine may decrease the need for frequent ASM changes, potentially offering patients and their families peace of mind and reducing an important factor in the burden of illness associated with DS and LGS.

4.1. Study limitations

This study is limited by its open‐label design and lack of control group, which could introduce performance or detection bias. Additionally, the patients in this OLE study represent a cohort who had already demonstrated tolerability and effectiveness in the previous open‐label studies, which could limit generalizability to broader populations of patients with DEEs. Use of CGI–I, although clinically meaningful, could be perceived as introducing subjectivity and observer bias. This study did not account for changes in concomitant ASMs, which could confound the findings and specifically influence rates of TEAEs and overall global functioning, making it difficult to pinpoint the contribution of fenfluramine to the observed outcomes.

Lastly, this OLE study was not designed to report robust seizure efficacy data. “Change in seizure burden” from the previous visit (and not prefenfluramine baseline) was collected. Additionally, investigators were asked to select a level of improvement in seizure burden from the previous visit, where the lowest category (“<25% improvement”) could be interpreted to encompass slight improvement, stable findings, and/or worsening of seizures; therefore, these data would not provide any meaningful conclusions and have not been included here.

5. CONCLUSIONS

To our knowledge, this large, international, multicenter OLE study is the first to describe long‐term results in a combined population of pediatric and adult patients (30% of the total population was aged ≥18 years) with DS and LGS with prolonged treatment exposure. As observed in prior studies, data from this OLE study (up to 4 years of fenfluramine exposure) support the sustained clinical benefit of fenfluramine as demonstrated by global and subdomain (cognitive, behavior, and motor) assessments. These data confirm the favorable risk/benefit profile of fenfluramine in pediatric and adult patients with DS or LGS, adding to the growing body of evidence that fenfluramine results in sustained, stable, or further improved outcomes over extended periods of time for patients with these DEEs. Future real‐world studies evaluating the impact of long‐term fenfluramine use with indirect measures of overall health status (e.g., health care resource utilization) are needed and could provide additional objective data.

AUTHOR CONTRIBUTIONS

Study design: Anne‐Liv Schulz, Mélanie Langlois, Najla Dickson, and Amélie Lothe. Data acquisition: Antonio Gil‐Nagel, Kelly G. Knupp, Boudewijn Gunning, Domenica Immacolata Battaglia, Elizabeth A. Thiele, Ingrid E. Scheffer, An‐Sofie Schoonjans, Rima Nabbout, Nathalie Villeneuve, Kerstin Alexandra Klotz, Rocio Sanchez‐Carpintero, Marta Zolnowska, and Joseph Sullivan. Data analysis: Lily Perrin. Data interpretation: Antonio Gil‐Nagel, Kelly G. Knupp, Boudewijn Gunning, Domenica Immacolata Battaglia, Elizabeth A. Thiele, Ingrid E. Scheffer, An‐Sofie Schoonjans, Rima Nabbout, Nathalie Villeneuve, Kerstin Alexandra Klotz, Nicola Specchio, Rocio Sanchez‐Carpintero, Marta Zolnowska, and Joseph Sullivan. All authors were involved in the methodology of this analysis, critically revised the drafts, and approved the final version for publication.

FUNDING INFORMATION

This study was funded by UCB.

CONFLICT OF INTEREST STATEMENT

A.G.‐N. has received personal fees or research grants from Arvelle/Angelini, Bial, Biocodex, Eisai, Esteve, GW Pharma (now Jazz Pharmaceuticals), GW Research, PTC Therapeutics, Sanofi, Stoke, UCB, and Zogenix (now part of UCB). K.G.K. has received research grants from Encoded Therapeutics, Stoke, and Zogenix (now part of UCB); consulting fees from Biocodex, BioMarin, and Epygenix; and other support as a data and safety monitoring board member from Epygenix and GW Pharma (now Jazz Pharmaceuticals). B.G. has received consultancy fees from GW Pharma (now Jazz Pharmaceuticals), Ovid/Takeda, and Zogenix (now part of UCB), and has been a principal investigator for GW Research and Zogenix (now part of UCB). D.I.B. has served on scientific advisory boards for Biocodex, Ethypharm, and UCB. E.A.T. has been a paid consultant for Biocodex, GW Pharma (now Jazz Pharmaceuticals), LivaNova, Nobelpharma, Noema Pharma, Stoke Therapeutics, and Zogenix (now part of UCB); has received research funding from Biocodex and GW Pharma (now Jazz Pharmaceuticals); and has served as clinical trial site principal investigator for GW Pharma (now Jazz Pharmaceuticals), Neurelis, SK Life Sciences, Stoke Therapeutics, and Zogenix (now part of UCB). I.E.S. has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Longboard Pharmaceuticals, Nutricia, Takeda Pharmaceuticals, UCB, and Xenon Pharmaceuticals; has received speaker honoraria from Akumentis, Biocodex, BioMarin, Chiesi, Eisai, GlaxoSmithKline, LivaNova, Nutricia, Praxis, Stoke Therapeutics, UCB, and Zuellig Pharma; has received funding for travel from Biocodex, BioMarin, Eisai, Encoded Therapeutics, GlaxoSmithKline, Longboard Pharmaceuticals, Stoke Therapeutics, and UCB; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder, Epygenyx, ES‐Therapeutics, GW Pharma (now Jazz Pharmaceuticals), Longboard Pharmaceuticals, Marinus, Neurocrine BioSciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix (now a part of UCB), and Zynerba; has consulted for Atheneum Partners, BioMarin, Biohaven Pharmaceuticals, Care Beyond Diagnosis, Encoded Therapeutics, Epilepsy Consortium, Ovid Therapeutics, Praxis, Stoke Therapeutics, UCB, and Zynerba Pharmaceuticals; and is a Non‐Executive Director of Bellberry and a Director of the Australian Academy of Health and Medical Sciences. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; and has a patent on a molecular diagnostic/theragnostic target for benign familial infantile epilepsy [PRRT2] 2011904493 & 2 012 900 190 and PCT/AU2012/001321 (TECH ID:2012–009). A.S.‐S. has received research support from Zogenix (now part of UCB) and has been a consultant for Brabant and Zogenix (now part of UCB). R.N. has received research funding from Eisai, GW Pharma (now Jazz Pharmaceuticals), Novartis, Shire, UCB, and Zogenix (now part of UCB); has been a consultant/advisor for Eisai, Biogen, GW Pharma (now Jazz Pharmaceuticals), Takeda, Novartis, Shire, and Zogenix (now part of UCB); and has been a speaker for Advicenne, Eisai, BioMarin, GW Pharma (now Jazz Pharmaceuticals), Novartis, Nutricia, Neuraxpharm, Zogenix (now part of UCB), and UCB. N.V. has nothing to disclose. K.A.K. has received personal fees from Biocodex, Desitin, Eisai, GW Pharma (now Jazz Pharmaceuticals), and Zogenix (now part of UCB). N.S. has served on scientific advisory boards for Arvelle, BioMarin, GW Pharma (now Jazz Pharmaceuticals), Marinus, and Takeda; has received speaker honoraria from Eisai, BioMarin, LivaNova, and Sanofi; and has served as an investigator for BioMarin, Marinus, Roche, and UCB. R.S.‐C. has received honoraria and/or research funds from Biocodex, Jazz Pharmaceuticals, and Zogenix (now part of UCB). M.Z. has been a principal investigator for Emalex Biosciences, GW Research, Ovid/Takeda, Marinus, and Zogenix (now part of UCB). A.‐L.S., N.D., M.L., and A.L. are employees of UCB with stock ownership. L.P. has been a consultant/advisor for UCB. J.S. has received research grants from Biopharm, Marinus, Stoke, and Zogenix (now part of UCB); has been a consultant/advisor for Asceneuron, Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharma (now Jazz Pharmaceuticals), Knopp Biosciences, Longboard Pharmaceuticals, and Neurocrine; has held stock options from Epygenix; has received travel support from Zogenix (now part of UCB); and has been a reviewer for the Epilepsy Study Consortium. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

CONSENT

All patients, their parents, or legal representatives provided written informed consent before enrolling in the study.

CONSENT

All patients, their parents, or legal representatives provided written informed consent before enrolling in the study.

Supporting information

TABLE S1. Overview of Clinical Global Impression of Improvement ratings.

TABLE S2. Baseline Clinical Global Impression of Severity global and subdomain ratings by caregiver and investigator by developmental and epileptic encephalopathy cohort and age group.

FIGURE S1. Enrollment and patient disposition.

EPI-67-5227-s001.docx^{(133.4KB, docx)}

ACKNOWLEDGMENTS

The authors thank the patients and families for participating in the fenfluramine trials. The authors acknowledge Katerina Kumpan, PhD (UCB), for managing the development of the manuscript, as well as professional medical writing and editorial assistance from Sandra M Aguero, PharmD, BCPS, and Courtney Breuel, ELS, of the Sensified Division of Woven Health Collective, which were funded by UCB. This manuscript was prepared according to the International Society for Medical Publication Professionals' Good Publication (GPP) Guidelines for Company‐Sponsored Biomedical Research: 2022 Update.

DATA AVAILABILITY STATEMENT

Underlying data from this article may be requested by qualified researchers 6 months after product approval in the United States 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 the following: 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 prespecified time, typically 12 months, on a password‐protected portal.

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38. Bishop KI, Isquith PK, Gioia GA, et al. Fenfluramine treatment is associated with improvement in everyday executive function in preschool‐aged children (<5 years) with Dravet syndrome. Epilepsy Behav. 2023;138:108994. [DOI] [PubMed] [Google Scholar]
39. Bishop KI, Isquith PK, Gioia GA, Knupp KG, Sullivan J, Nabbout R, et al. Fenfluramine improves everyday executive functioning in patients with Lennox‐Gastaut syndrome: analysis of phase 3 data (P12‐8.004). Neurology. 2022;98(18_supplement):3017. [Google Scholar]
40. Bishop KI, Isquith PK, Gioia GA, et al. Fenfluramine (Fintepla®) treatment improves everyday executive functioning in patients with Lennox‐Gastaut syndrome: analysis from a phase 3 clinical trial [poster]. Presented at: American Academy of Neurology annual meeting. Seattle, WA; 2022. [Google Scholar]
41. Bishop KI, Isquith PK, Roth RM, Gioia GA, Knupp KG, Sullivan J, et al. Adults with Lennox‐Gastaut syndrome (LGS) have improved everyday executive functioning (EF) with fenfluramine (Fintepla®). Epilepsia. 2022;63(Suppl 2):79. [Google Scholar]
42. Massaroni V, Ascione F, Porto C, Gambardella ML, Quintiliani M, Perulli M, et al. Beyond seizure control: functional and caregiver‐reported outcomes of long‐term fenfluramine treatment in Dravet syndrome. Epilepsy Behav. 2026;180:111059. [DOI] [PubMed] [Google Scholar]
43. Strzelczyk A, Schubert‐Bast S. Psychobehavioural and cognitive adverse events of anti‐seizure medications for the treatment of developmental and epileptic encephalopathies. CNS Drugs. 2022;36(10):1079–1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Samanta D. Cognitive and behavioral impact of antiseizure medications, neuromodulation, ketogenic diet, and surgery in Lennox‐Gastaut syndrome: a comprehensive review. Epilepsy Behav. 2025;164:110272. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

TABLE S1. Overview of Clinical Global Impression of Improvement ratings.

TABLE S2. Baseline Clinical Global Impression of Severity global and subdomain ratings by caregiver and investigator by developmental and epileptic encephalopathy cohort and age group.

FIGURE S1. Enrollment and patient disposition.

EPI-67-5227-s001.docx^{(133.4KB, docx)}

Data Availability Statement

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[epi70371-bib-0043] 43. Strzelczyk A, Schubert‐Bast S. Psychobehavioural and cognitive adverse events of anti‐seizure medications for the treatment of developmental and epileptic encephalopathies. CNS Drugs. 2022;36(10):1079–1111. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Prolonged fenfluramine use in open‐label studies of Dravet or Lennox–Gastaut syndromes: Long‐term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness

Antonio Gil‐Nagel

Kelly G Knupp

Boudewijn Gunning

Domenica Immacolata Battaglia

Elizabeth A Thiele

Ingrid E Scheffer

An‐Sofie Schoonjans

Rima Nabbout

Nathalie Villeneuve

Kerstin Alexandra Klotz

Nicola Specchio

Rocio Sanchez‐Carpintero

Marta Zolnowska

Anne‐Liv Schulz

Lily Perrin

Najla Dickson

Mélanie Langlois

Amélie Lothe

Joseph Sullivan

Abstract

Objective

Methods

Results

Significance

Key points.

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Study design and participants

2.2. Study interventions

2.3. Study outcomes

2.4. Definitions and statistical analysis

3. RESULTS

3.1. Patients

TABLE 1.

3.2. Safety

TABLE 2.

3.3. Effectiveness

FIGURE 1.

FIGURE 2.

FIGURE 3.

FIGURE 4.

4. DISCUSSION

4.1. Study limitations

5. CONCLUSIONS

AUTHOR CONTRIBUTIONS

FUNDING INFORMATION

CONFLICT OF INTEREST STATEMENT

CONSENT

CONSENT

Supporting information

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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