Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2243-2254 |
| Number of pages | 12 |
| Journal | The Lancet |
| Volume | 394 |
| Issue number | 10216 |
| DOIs | |
| State | Published - Dec 21 2019 |
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- Medicine(all)
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In: The Lancet, Vol. 394, No. 10216, 21.12.2019, p. 2243-2254.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome
T2 - a randomised, double-blind, placebo-controlled trial
AU - FAiRE DS Study Group
AU - Lagae, Lieven
AU - Sullivan, Joseph
AU - Knupp, Kelly
AU - Laux, Linda
AU - Polster, Tilman
AU - Nikanorova, Marina
AU - Devinsky, Orrin
AU - Cross, J. Helen
AU - Guerrini, Renzo
AU - Talwar, Dinesh
AU - Miller, Ian
AU - Farfel, Gail
AU - Galer, Bradley S.
AU - Gammaitoni, Arnold
AU - Mistry, Arun
AU - Morrison, Glenn
AU - Lock, Michael
AU - Agarwal, Anupam
AU - Lai, Wyman W.
AU - Ceulemans, Berten
N1 - Funding Information: Zogenix does not have a data sharing policy. Acknowledgments The authors received professional medical writing and editing assistance from Edward Weselcouch and Diana Talag of PharmaWrite (Princeton, NJ, USA), funded by Zogenix. The authors thank Dr Susan Cheng for her important insights on the interpretation of echocardiographic findings. Funding Information: Dravet syndrome is a severe, refractory, disabling, childhood-onset, developmental epileptic encephalopathy characterised by a high seizure burden accompanied by significant comorbid neurodevelopmental, motor, and behavioural abnormalities. 2 In addition, the syndrome is marked by high mortality, most frequently due to status epilepticus and sudden unexpected death in epilepsy (SUDEP). 5 A Dravet-specific SUDEP rate of 9·32 per 1000 person-years has been reported, 5 which is substantially higher than that reported in the general population of patients with epilepsy. 6 Despite the use of multidrug regimens in an attempt to control seizures, 45% of patients continued to have at least four tonic-clonic seizures per month. 3 The combination of a high seizure burden and neurodevelopmental abnormalities imparts a high humanistic and economic impact on caregivers and the broader family unit. 2,25,26 Primary caregivers have reported general health scores on the EQ-5D health questionnaire that are equivalent to someone in the general population living with a major illness (ie, heart disease, diabetes, cancer). 25 These reports illustrate the high unmet need for new and better therapies in Dravet syndrome. In this randomised, double-blind clinical trial, fenfluramine oral solution resulted in a significant reduction in the frequency of convulsive seizures compared with placebo in children and young adults with Dravet syndrome. In addition, significantly higher responder rates were observed compared with placebo, particularly in patients who had at least a 50% or 75% reduction in the frequency of convulsive seizures. Patients included in our trial had a high seizure burden as previously described, with an average of about 1·5 convulsive seizures per day (mean baseline convulsive seizure frequency per 28 days 40·3, SD 64·0). On this background of high seizure burden, 25% of patients in the 0·7 mg/kg per day and 13% of patients in the 0·2 mg/kg per day group had either one or no convulsive seizures for the entire 14-week study, further illustrating the efficacy of fenfluramine. Both the investigators and the parents or caregivers rated a significantly larger proportion of fenfluramine-treated patients as being much improved or very much improved compared with patients in the placebo group. In the primary and all key secondary efficacy outcomes, a dose response was observed for the two fenfluramine doses studied. Improvements on some, but not all, quality-of-life measures were seen at the end of 14 weeks of treatment with fenfluramine compared with placebo. No effect was seen in the Quality of Life in Childhood Epilepsy instrument, but the Pediatric Quality of Life Inventory showed improvement in both fenfluramine groups compared with placebo. The BRIEF assesses executive function, a construct of cognition, and was included as a safety measure to assess whether treatment resulted in any negative effects on cognitive function, as this outcome has previously been reported with other antiepileptic medications. 27 The results showed this was not the case with fenfluramine, but rather, improvements in the BRIEF Behavioral Regulation Index, Metacognition Index, and Global Executive Composite scores were noted, while scores from the placebo group worsened on all three indexes. Both seizure burden and neuronal sodium channel dysfunction caused by SCN1A mutations might contribute to cognitive dysfunction in patients with Dravet syndrome, 28,29 and reports suggest that effective seizure control, even in adults, can result in improvement in cognitive abilities. 29 In addition to the significant reductions in seizure frequency noted with fenfluramine in our study, a direct action of the medication on cognitive function cannot be ruled out. Further analyses of the full phase 3 patient population, including the long-term longitudinal assessment from the safety extension study, will be required to fully characterise the potential for fenfluramine to affect non-seizure endpoints such as quality of life and executive function. The safety and adverse events of fenfluramine with respect to non-cardiovascular events were similar to what has been previously reported for fenfluramine from the Belgian cohorts with Dravet syndrome, 11–13 with lethargy and decreases in appetite reported more often in patients given fenfluramine than with placebo. Fenfluramine was previously marketed as an appetite suppressant and 21–38% of patients in the active treatment groups had decreases in appetite; weight loss above the 7% threshold was observed in 13% of patients in the fenfluramine 0·2 mg/kg per day group, and in 20% of patients in the fenfluramine 0·7 mg/kg per day group. Serious adverse events occurred with similar frequency across all three treatment groups. Cardiovascular safety is an important outcome measure when evaluating the use of fenfluramine to treat patients with Dravet syndrome. 9 Based on reports of cardiac valve disease in adult obese patients given up to 220 mg per day, fenfluramine was withdrawn from worldwide markets beginning in 1997. 30 Both increasing dose and increasing duration of treatment have been reported as risk factors for valvulopathy when fenfluramine was used as a weight loss agent in obese adult patients. Li and colleagues 17 examined the records of the patients in the original FDA report and found that the risk of severe valvulopathy was increased 9·2 times (95% CI 2·1–40·8) in patients given at least 60 mg per day compared with patients given less than 40 mg per day. 31 Others have identified 3 months' use of fenfluramine as a threshold for increased risk of valvulopathy 32 and 6 months' use of fenfluramine as a threshold for increased risk of pulmonary arterial hypertension. 32–35 In the present trial, all patients were given 26 mg per day or less of fenfluramine and were monitored with colour Doppler echocardiographic examinations before and during the trial to identify functional changes in cardiac valves and signs of pulmonary hypertension. During the 14-week treatment period and the 2-week transition period at the end of the maintenance period, all echocardiographic examinations revealed valve function within the normal physiological range, and no pulmonary arterial hypertension was observed in any patient at any time. 21 patients, including five patients in the placebo group, had at least one echocardiographic finding with trace mitral or trace aortic regurgitation during the trial. Trace regurgitation is not considered evidence of valve dysfunction; rather, it is described in current guidelines as a physiological finding seen in healthy children and adults. 24,36,37 Although our observations suggest a dose response for the finding of trace regurgitation, this association disappeared with continued treatment in the long-term extension of this study. None of these patients, or any other patient with Dravet syndrome enrolled in the open-label extension study of fenfluramine, had any grade of valvular regurgitation greater than trace during a median 256 days of observation. 38 The point prevalence of trace mitral valve regurgitation in the extension study was ≤11% at any timepoint, and for nearly all patients this finding was transient or fluctuating between trace and absent in subsequent echocardiographic examinations. Although the prevalence of trace regurgitation in young patients with Dravet syndrome is not known, 23 (13%) of 173 patients who were screened for participation in the present trial were excluded due to trace mitral regurgitation on screening echocardiographic examination. This prevalence is similar to that reported in healthy children aged 10–12 years. Webb and colleagues 39 reported a cross-sectional prevalence of trace or physiological mitral regurgitation of 59 (15%) of 396 in children aged 10–12 years. Our conclusions about the cardiovascular safety of fenfluramine are limited by the short treatment and observation period of 14 weeks in this trial. These findings are consistent with those reported with long-term use of fenfluramine at doses between 0·13–0·69 mg/kg per day in Dravet syndrome in Belgium, 8 where no cases of valve dysfunction or pulmonary hypertension have been reported with up to 30 years of fenfluramine treatment with ongoing echocardiographic examinations. Although we used a double-blind design, one potential limitation is the occurrence of side-effects, especially ones known to be associated with the active treatment, that might cause a patient or caregiver to suspect having received the active treatment and therefore affect the reporting of seizures. In this trial, the most common side-effect in fenfluramine-treated patients was decreased appetite, which occurred in 38% of patients in the 0·7 mg/kg per day dose group. This randomised controlled clinical trial showed that fenfluramine significantly reduced the frequency of convulsive seizures in children and young adults with Dravet syndrome when added to existing antiepileptic treatment; while also showing an apparent dose response effect. Fenfluramine was associated with decreased appetite, diarrhoea, lethargy, and somnolence, without the development of any cardiovascular adverse events. Further study is warranted to assess long-term efficacy and safety of fenfluramine for the treatment of Dravet syndrome, including its effect on cardiac valves. Contributors LLag, JS, BC, AG, BSG, GF, and ML designed the study. LLag, JS, KK, LLau, TP, MN, OD, JHC, RG, DT, IM, and BC collected data. ML analysed the data. All authors contributed equally to the interpretation of the efficacy and non-cardiovascular safety findings. WWL and AA provided the primary interpretation of the cardiovascular safety findings. The authors participated in a preliminary conference to discuss the structure and focus of the manuscript. An outline based on this conference was prepared by AG, LLag, BC, and JS and was reviewed by all authors. GF, BSG, AG, LLag, JS, ML, and BC were the primary writers of the manuscript. All authors contributed equally to the review and revision of the manuscript, and all authors approved the final version. FAiRE Study Group Deepak Gill, Kate Riney, Ingrid Scheffer, Berten Ceulemans, Jeffrey Buchhalter, Lionel Carmant, Mary Connolly, Marina Nikanorova, Rima Nabbout, Ulrich Brandl, Julia Jacobs-LeVan, Thomas Mayer, Axel Panzer, Tilman Polster, Milka Pringsheim, Ulrich Stephani, Markus Wolff, Domenica Battaglia, Francesca Beccaria, Francesca Darra, Tiziana Granata, Renzo Guerrini, Antonio Romeo, Pasquale Striano, Federico Vigevano, Antonio Gil-Nagel, Victoria San Antonio, Rocio Sanchez-Carpintero, J Helen Cross, Archana Desurkar, Elaine Hughes, Anand Iyer, Sunny Philip, Sameer Zuberi, Gregory Sharp, Frank Berenson, Orrin Devinsky, Kelly Knupp, Linda Laux, Eric Marsh, Mark Nespeca, Ian Miller, Robert Nahouraii, Juliann Paolicchi, Steven Phillips, Michael Scott Perry, Annapurna Poduri, Ben Renfroe, Russell Saneto, Asim Shahid, Douglas Smith, Marcio Sotero de Menezes, Joseph Sullivan, Matthew Sweney, Dinesh Talwar, Elizabeth Thiele, James Wheless, Angus Wilfong, Elaine Wirrell, and Mary Zupanc. Declaration of interests LLag received grants, personal fees, and other as a consultant or speaker from Zogenix during the conduct of the study; other as a consultant or speaker from LivaNova, grants and other as a consultant or speaker from UCB, other as a speaker from Shire, and other as a speaker from Eisai outside the submitted work. LLag has a patent for ZX008 for the treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. JS received grants and travel support as an investigator from Zogenix, other as an advisory board member from the Dravet Syndrome Foundation, personal fees as a reviewer from the Epilepsy Study Consortium, and served as a consultant for Epygenix during the conduct of the study. KK received research grants from Zogenix and grants from the Pediatric Epilepsy Research Foundation during the conduct of the study; grants from the Colorado Department of Public Health, grants from West Therapeutics, and other as a DSMB member from Greenwich Pharmaceuticals outside the submitted work. LLau received grants as primary investigator from Zogenix during the conduct of the study and grants as primary investigator from GW Pharma outside the submitted work. TP received personal fees from Zogenix during the conduct of the study and personal fees from Desitin, Shire, Novartis, and UCB outside the submitted work. MN received institutional grants from Zogenix during the conduct of the study. OD received research grants from Zogenix during the conduct of the study and received research grants from Novartis and PTC Therapeutics and has equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings outside the submitted work. JHC received institutional research grants from Zogenix during the conduct of the study and received institutional research grants and other as an investigator, speaker, and adviser from GW Pharma, other as a speaker or adviser from Shire, other as an adviser or speaker from Zogenix, other as speaker from Biomarin, and other as adviser from Eisai outside the submitted work. RG received research grants from Zogenix during the conduct of the study and received personal fees as a speaker or consultant from Zogenix outside the submitted work. DT received grants from Zogenix during the conduct of the study and received personal fees from Sunovion and Eisai outside the submitted work. IM received grants and personal fees (honoraria, travel support) from Zogenix during the conduct of the study and received grants and personal fees (honoraria, travel support) from GW Pharmaceuticals, INSYS Therapeutics, Dravet Syndrome Foundation, Greenwich, INSYS, Neurelis, NeuroPace, Tuberous Sclerosis Alliance, Ultragenyx, and Visualase outside the submitted work. GF, BSG, AG, AM, GM, and AA received personal fees and own stock as employees from Zogenix. ML received personal fees as a consultant from Zogenix during the conduct of the study and received personal fees as a consultant from Zogenix outside the submitted work. WWL received personal fees and non-financial support from Zogenix during the conduct of the study. BC received grants from Zogenix during the conduct of the study and has a patent for ZX008 for the treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. LL, BC, and the KU Leuven University/Antwerp University Hospital might benefit financially from a royalty arrangement that is related to this research if Zogenix is successful in marketing its product, fenfluramine. The terms of this arrangement have been reviewed and approved by the KU Leuven University/Antwerp University Hospital. Publisher Copyright: © 2019 Elsevier Ltd
PY - 2019/12/21
Y1 - 2019/12/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076547518&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076547518&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)32500-0
DO - 10.1016/S0140-6736(19)32500-0
M3 - Article
C2 - 31862249
AN - SCOPUS:85076547518
SN - 0140-6736
VL - 394
SP - 2243
EP - 2254
JO - The Lancet
JF - The Lancet
IS - 10216
ER -