TY - JOUR
T1 - Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome
AU - Cross, J. Helen
AU - Galer, Bradley S.
AU - Gil-Nagel, Antonio
AU - Devinsky, Orrin
AU - Ceulemans, Berten
AU - Lagae, Lieven
AU - Schoonjans, An Sofie
AU - Donner, Elizabeth
AU - Wirrell, Elaine
AU - Kothare, Sanjeev
AU - Agarwal, Anupam
AU - Lock, Michael
AU - Gammaitoni, Arnold R.
N1 - Funding Information:
Dr. Cross has acted as an investigator for studies with GW Pharma, Zogenix, Vitaflo, and Marinus. She has been a speaker and has served on advisory boards for GW Pharma, Zogenix, and Nutricia; all remuneration has been paid to her department. She holds an endowed chair at UCL Great Ormond Street Institute of Child Health, as well as grants from NIHR, EPSRC, GOSH Charity, ERUK, and the Waterloo Foundation. Her research is supported by the National Institute of Health Research (NIHR) Biomedical Research centre at Great Ormond Street Hospital.
Funding Information:
This study was funded by Zogenix, Inc.
Funding Information:
Dr. Ceulemans has received research funding from Brabant and Zogenix and has served as consultant for Brabant and Zogenix. Dr. Ceulemans has a patent for ZX008. Dr. Ceulemans and the KU Leuven University/Antwerp University Hospital may 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:
© 2021
PY - 2021/12
Y1 - 2021/12
N2 - Purpose: To assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). Methods: In this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. Results: A total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43−7) for persons with DS receiving standard-of-care. Conclusion: All-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk. Clinical Trial Registration: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.
AB - Purpose: To assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). Methods: In this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. Results: A total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43−7) for persons with DS receiving standard-of-care. Conclusion: All-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk. Clinical Trial Registration: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127.
KW - Dravet syndrome
KW - Fenfluramine
KW - Mortality
KW - SUDEP
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U2 - 10.1016/j.seizure.2021.10.024
DO - 10.1016/j.seizure.2021.10.024
M3 - Article
C2 - 34768178
AN - SCOPUS:85118823616
SN - 1059-1311
VL - 93
SP - 154
EP - 159
JO - Seizure
JF - Seizure
ER -