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Lieven Lagae - One of the best experts on this subject based on the ideXlab platform.
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Fenfluramine hcl fintepla provides long term clinically meaningful reduction in seizure frequency analysis of an ongoing open label extension study
Epilepsia, 2020Co-Authors: Joseph Sullivan, Lieven Lagae, Bradley S. Galer, Milka Pringsheim, Rima Nabbout, Tilman Polster, Dinesh Talwar, Ingrid E Scheffer, Michael Lock, Anupam AgarwalAbstract:OBJECTIVE Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of Fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS Patients enrolling in the OLE study initiated Fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the Fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE Study results demonstrate that Fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and Fenfluramine was generally well tolerated.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Linda Laux, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Dinesh TalwarAbstract:Summary Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863 . Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p Interpretation In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Funding Zogenix.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Linda C Laux, Dinesh TalwarAbstract:BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); Fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the Fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.
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cardiovascular safety of low dose Fenfluramine in dravet syndrome a review of its benefit risk profile in a new patient population
Current Medical Research and Opinion, 2017Co-Authors: Ansofie Schoonjans, Lieven Lagae, Arnold R. Gammaitoni, F Marchau, Bernard P Paelinck, Milka Pringsheim, Martin G Keane, Berten CeulemansAbstract:AbstractObjective: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, Fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of Fenfluramine when used at lower doses for treatment of DS.Methods: Pubmed was searched for clinical studies of Fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose Fenfluramine for up to 28 years.Results: Nine controlled studies of Fenfluramine and related compounds (dexFenfluramine and/or phentermine)...
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low dose Fenfluramine significantly reduces seizure frequency in dravet syndrome a prospective study of a new cohort of patients
European Journal of Neurology, 2017Co-Authors: Ansofie Schoonjans, Lieven Lagae, Arnold R. Gammaitoni, Bradley S. Galer, F Marchau, Bernard P Paelinck, B Gunning, Berten CeulemansAbstract:Background and purpose Dravet syndrome (DS) is a severe, drug-resistant epilepsy. Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. Methods This prospective, open-label study assessed the safety and effectiveness of low-dose Fenfluramine in a new cohort of patients with DS. Following a 3-month baseline period, Fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25–1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic–clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety. Results Nine patients (aged 1.2–29.8 years) enrolled in the study and were treated with Fenfluramine for a median duration of 1.5 (range, 0.3–5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28–100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. Conclusions The effectiveness and safety of low-dose Fenfluramine as an add-on therapy for DS in this new prospective cohort supports previous findings.
Richard B Rothman - One of the best experts on this subject based on the ideXlab platform.
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OPEN Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates
2016Co-Authors: Michael H. Baumann, Richard B Rothman, John S. Partilla, Mario A Ayestas, Simon Bulling, Tova S Benaderet, Kusumika Saha, Syed F Ali, Thomas Stockner, Walter SAbstract:Serotonin (5-HT) transporter (SERT) substrates like Fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: Fenfluramine, d-Fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [3H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (45-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to Fenfluramine and d-Fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [3H]5-HT from synaptosomes, but d-Fenfluramine and its bioactive metabolite d-norFenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. Thi
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chronic Fenfluramine administration increases plasma serotonin 5 hydroxytryptamine to nontoxic levels
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Dorota Zolkowska, Michael H. Baumann, Richard B RothmanAbstract:Large elevations in blood serotonin (5-hydroxytryptamine; 5-HT) can produce valvular heart disease in humans and laboratory animals. In accordance, one prevailing hypothesis (i.e., the "5-HT hypothesis") suggests that 5-HT transporter substrates like Fenfluramine increase the risk for valvular heart disease by elevating plasma 5-HT, secondary to the release of 5-HT from platelets. The main purpose of this study was to determine whether chronic administration of Fenfluramine increases plasma 5-HT to concentrations that are associated with the development of valvular heart disease. To the best of our knowledge, this is the first study to address this issue using an in vivo microdialysis method that measures plasma 5-HT in nonhypoxic rats. We examined the effects of chronic (+/-)-Fenfluramine and fluoxetine on plasma levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in blood samples from conscious catheterized rats. Plasma indoles were measured by high-performance liquid chromatography with electrochemical detection in the dialysates of whole blood. The baseline plasma 5-HT level was <1.0 nM. Chronic Fenfluramine (14-day minipump infusion) produced small increases in baseline plasma 5-HT ( approximately 2-4-fold), whereas chronic fluoxetine had no effect. Chronic Fenfluramine and fluoxetine markedly decreased whole-blood 5-HT and reduced the ability of acute Fenfluramine to evoke 5-HT release. Elevations in baseline plasma 5-HT produced by chronic Fenfluramine are far below the micromolar levels necessary to produce valvular heart disease. Furthermore, chronic Fenfluramine reduces the ability of acute Fenfluramine to increase plasma 5-HT, suggesting that the 5-HT hypothesis cannot explain the increased risk of valvular heart disease in patients treated with Fenfluramine.
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Fenfluramine and its major metabolite norFenfluramine are potent substrates for norepinephrine transporters
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Richard B Rothman, Robert D. Clark, John S. Partilla, Michael H. BaumannAbstract:(+/-)-Fenfluramine is an amphetamine analog that was once widely prescribed as an appetite suppressant. Although (+/-)-Fenfluramine is no longer clinically available, the mechanisms underlying its anorectic properties are still of interest. Upon peripheral administration, stereoisomers of (+/-)-Fenfluramine are N-deethylated to form the metabolites, (+)- and (-)-norFenfluramine. It is well accepted that isomers of (+/-)-Fenfluramine and (+/-)-norFenfluramine interact with 5-hydroxytryptamine (serotonin, 5-HT) transporters to release 5-HT from neurons. However, the effects of these drugs on other monoamine transporters are not well characterized. In this study, we examined the interaction of stereoisomers of (+/-)-Fenfluramine and (+/-)-norFenfluramine with transporters for 5-HT, norepinephrine (NE), and dopamine (DA). Results from in vitro assays confirmed these drugs are potent substrates for 5-HT transporters: (+)-Fenfluramine, (-)-Fenfluramine, (+)-norFenfluramine, and (-)-norFenfluramine released [3H]5-HT from synaptosomes with EC50 values of 52, 147, 59, and 287 nM, respectively. Importantly, (+)-Fenfluramine and (+)-norFenfluramine released [3H]NE with EC50 values of 302 and 73 nM. Results from in vivo microdialysis experiments showed that intravenous injection of (+)-norFenfluramine elevates extracellular levels of 5-HT, NE, and DA in rat frontal cortex. The effects of (+)-norFenfluramine on NE and DA were antagonized by pretreatment with the NE uptake blocker nisoxetine. In summary, administration of Fenfluramines can increase synaptic levels of 5-HT, NE, and DA in the cortex, and (+)-norFenfluramine likely contributes to these effects. Release of NE and DA evoked by (+)-norFenfluramine is at least partly mediated via NE transporters. Our results emphasize the potential involvement of noradrenergic mechanisms in the actions of Fenfluramines.
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Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with Fenfluramine and other serotonergic medications.
Circulation, 2000Co-Authors: Richard B Rothman, Michael H. Baumann, Jason E. Savage, Laura Rauser, Ace Mcbride, Sandra J. Hufeisen, Bryan L. RothAbstract:Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of Fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that Fenfluramine or its metabolite norFenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-Fenfluramine; (+)-Fenfluramine; (−)-Fenfluramine; its metabolites (±)-norFenfluramine, (+)-norFenfluramine, and (−)-norFenfluramine; ergotamin...
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chronic treatment with phentermine combined with Fenfluramine lowers plasma serotonin
American Journal of Cardiology, 2000Co-Authors: Richard B Rothman, Christine A Kwong, Joyce E Swanson, Susan K Raatz, Bruce J Redmon, John P BantleAbstract:: As expected on the basis of published research in both humans and animals, treatment with phentermine/Fenfluramine lowers plasma 5-hydroxytryptamine [corrected], whereas treatment with phentermine had no significant effect. In light of these findings, future research should focus on mechanisms other than increased plasma 5-hydroxytryptamine [corrected] to explain how Fenfluramine increases the risk of primary pulmonary hypertension and valvular heart disease.
Tilman Polster - One of the best experts on this subject based on the ideXlab platform.
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treatment with Fenfluramine in patients with dravet syndrome has no long term effects on weight and growth
Epilepsy & Behavior, 2021Co-Authors: Antonio Gilnagel, Berten Ceulemans, Rima Nabbout, Elaine C Wirrell, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Orrin Devinsky, Scott M Perry, Ronald DavisAbstract:OBJECTIVE Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, Fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of Fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. METHODS Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117-22). Anthropometric data for Fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2-18 y/o; Fenfluramine dose: 0.2-0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of Fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2-<0.3 mg/kg/day, 0.3-<0.5 mg/kg/day, and 0.5-0.7 mg/kg/day), averaged over time. RESULTS At the time of analysis, 279 patients were treated with Fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, Fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with Fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of -0.056 for height and -0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were -0.025 for height and -0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. SIGNIFICANCE/CONCLUSION Long-term treatment with Fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.
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Fenfluramine hcl fintepla provides long term clinically meaningful reduction in seizure frequency analysis of an ongoing open label extension study
Epilepsia, 2020Co-Authors: Joseph Sullivan, Lieven Lagae, Bradley S. Galer, Milka Pringsheim, Rima Nabbout, Tilman Polster, Dinesh Talwar, Ingrid E Scheffer, Michael Lock, Anupam AgarwalAbstract:OBJECTIVE Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of Fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS Patients enrolling in the OLE study initiated Fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the Fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE Study results demonstrate that Fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and Fenfluramine was generally well tolerated.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Linda Laux, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Dinesh TalwarAbstract:Summary Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863 . Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p Interpretation In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Funding Zogenix.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Linda C Laux, Dinesh TalwarAbstract:BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); Fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the Fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.
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individualized treatment approaches Fenfluramine a novel antiepileptic medication for the treatment of seizures in dravet syndrome
Epilepsy & Behavior, 2019Co-Authors: Tilman PolsterAbstract:Dravet syndrome is a rare and severe encephalopathy that first presents in infancy with seizures refractory to conventional antiepileptic drugs. Forty-five percent of patients report four or more tonic-clonic seizures per month despite multidrug regimens. Fenfluramine, an amphetamine derivative, was initially developed as an appetite suppressant with a serotonergic mechanism of action. Clinical observation of a potential antiepileptic activity in a small homogeneous cohort of patients combined with a genetic workup of these patients led to the hypothesis of Fenfluramine as a treatment for seizures in Dravet syndrome. This concept was successfully evaluated in a zebrafish model and led to a Phase 3 trial of Fenfluramine to treat seizures in children with Dravet syndrome. Preliminary results of the trial suggest that Fenfluramine may be a highly effective, well-tolerated treatment for patients with Dravet syndrome. This short review summarizes the history of use of Fenfluramine from the initial clinical observations followed by preclinical studies and subsequent successful clinical trial. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond."
Kelly G Knupp - One of the best experts on this subject based on the ideXlab platform.
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treatment with Fenfluramine in patients with dravet syndrome has no long term effects on weight and growth
Epilepsy & Behavior, 2021Co-Authors: Antonio Gilnagel, Berten Ceulemans, Rima Nabbout, Elaine C Wirrell, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Orrin Devinsky, Scott M Perry, Ronald DavisAbstract:OBJECTIVE Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, Fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of Fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. METHODS Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117-22). Anthropometric data for Fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2-18 y/o; Fenfluramine dose: 0.2-0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of Fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2-<0.3 mg/kg/day, 0.3-<0.5 mg/kg/day, and 0.5-0.7 mg/kg/day), averaged over time. RESULTS At the time of analysis, 279 patients were treated with Fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, Fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with Fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of -0.056 for height and -0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were -0.025 for height and -0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. SIGNIFICANCE/CONCLUSION Long-term treatment with Fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.
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Fenfluramine for treatment resistant seizures in patients with dravet syndrome receiving stiripentol inclusive regimens a randomized clinical trial
JAMA Neurology, 2020Co-Authors: Rima Nabbout, Arun Mistry, Sameer M Zuberi, Nathalie Villeneuve, Antonio Gilnagel, Rocio Sanchezcarpintero, Ulrich Stephani, Linda Laux, Elaine C Wirrell, Kelly G KnuppAbstract:Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether Fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive Fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between Fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to Fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with Fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%;P Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Trial Registration ClinicalTrials.gov identifier:NCT02926898
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Linda Laux, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Dinesh TalwarAbstract:Summary Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863 . Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p Interpretation In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Funding Zogenix.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Linda C Laux, Dinesh TalwarAbstract:BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); Fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the Fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.
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lorcaserin therapy for severe epilepsy of childhood onset a case series
Neurology, 2018Co-Authors: Patricia Tolete, Kelly G Knupp, Michael Karlovich, Elaine Decarlo, Judith Bluvstein, Erin Conway, Daniel Friedman, Patricia Dugan, Orrin DevinskyAbstract:Childhood-onset refractory epilepsies (e.g., Dravet syndrome [DS]) contribute to developmental delays, impaired quality of life, and increased mortality. We lack safe and effective antiseizure medications (ASMs) for these patients. Fenfluramine, an appetite suppressant, increases serotonin activity by releasing and inhibiting the reuptake of 5-HT and stimulating all 5-HT receptors. Combining Fenfluramine with phentermine (Fen-Phen) led to sustained weight loss in obese patients, but pulmonary hypertension and heart valve lesions led to withdrawal. A small open-label trial with Fenfluramine and a subsequent randomized trial found significant reductions in seizures in children with DS.1,2
Helen J Cross - One of the best experts on this subject based on the ideXlab platform.
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Fenfluramine as antiseizure medication for epilepsy
Developmental Medicine & Child Neurology, 2021Co-Authors: Maria Gogou, Helen J CrossAbstract:Fenfluramine hydrochloride has classically been described as acting pharmacologically through a serotonergic mechanism. Therefore, it was initially used as an anorectic drug, given that impaired serotonin homeostasis may be associated with increased food intake. Although positive results were documented, cardiovascular concerns resulted in its temporary withdrawal. Nevertheless, a novel role in patients with epilepsy was later suggested by isolated clinical observations. The wide application of genetic testing allowed the classification (predominantly as Dravet syndrome) of patients in whom benefit was seen, while with the development of zebrafish models, its antiepileptic properties were confirmed at a molecular level. Data from randomized clinical trials have shown a beneficial effect of Fenfluramine, as an adjunct therapy, on seizure control for children with Dravet syndrome, though there is still uncertainty about the impact on neurodevelopment in these patients. No signs of heart valve disease have been documented to date. Long-term and appropriately designed clinical studies will verify whether Fenfluramine is a therapeutic agent of high importance, living up to the promise shown so far. What this paper adds Fenfluramine is a very promising repurposed therapy specifically for seizures in Dravet syndrome. The long-term effect of Fenfluramine on neurodevelopmental prognosis requires further investigation.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Linda Laux, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Dinesh TalwarAbstract:Summary Background Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863 . Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p Interpretation In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Funding Zogenix.
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Fenfluramine hydrochloride for the treatment of seizures in dravet syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Kelly G Knupp, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Orrin Devinsky, Helen J Cross, Renzo Guerrini, Linda C Laux, Dinesh TalwarAbstract:BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of Fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, Fenfluramine 0·2 mg/kg per day, or Fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either Fenfluramine 0·2 mg/kg per day (39), Fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the Fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the Fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with Fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); Fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the Fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, Fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.