Determining the Relationship between Seizure-Free Days and Other Predictors of Quality of Life in Patients with Dravet Syndrome and Their Carers

Objectives Dravet syndrome (DS) is a rare, lifelong epileptic encephalopathy characterised by frequent and severe seizures associated with premature mortality. Typically diagnosed in infancy, patients also experience progressive behavioural, motor-function and cognitive decline. Twenty percent of patients do not reach adulthood. Quality of life (QoL) is impaired for both patients and their carers. Reducing convulsive seizure frequency, increasing seizure free days (SFDs) and improving patient/carer QoL are primary treatment goals in DS. This study explored the relationship between SFDs and patients’ and carers’ QoL to inform a cost-utility analysis of fenfluramine. Methods In fenfluramine registration studies, patients (or their carer proxies) completed the Paediatric Quality of Life inventory (PedsQOL). These data were mapped to EuroQol-5 Dimensions Youth version (EQ-5D-Y) to provide patient utilities. Carer utilities were collected using EQ-5D-5L and mapped to EQ-5D-3L to align patient and carer QoL on the same scale. Linear mixed-effects and panel regression models were tested and Hausman tests identified the most appropriate approach for each group. On this basis, a linear mixed-effects regression model was used to examine the relationships between patient EQ-5D-Y, and clinically relevant variables (age, frequency of SFDs per 28-days, motor impairments and treatment dose). A linear panel regression model examined the relationship between SFDs and carer QoL. Results Adjusting for age and underlying comorbidities, the patient regression model showed that SFDs per 28-days was a significant predictor of QoL. Each additional patient-SFD increased utility by 0.005 ( p <.001). The carer linear panel model also showed that increasing SFDs per 28-days was a significant predictor of improved QoL. Each additional SFD increased carer utility by 0.014 ( p <.001). Significance This regression framework highlights that SFDs are significantly correlated with both patients’ and carers’ QoL. Treatment with effective antiseizure medications that increase SFDs, directly improves QoL for patients and their carers. Short summary DS patients experience daily severe seizures with progressive deterioration in their physical, cognitive and behavioural development (“comorbidities”), which substantially impacts the QoL of patients and their carers. Reducing seizure frequency and increasing Seizure Free Days (SFDs) are key treatment goals. This study examined the relationship between seizures and patients’ and carers’ QoL. Regression analyses were conducted using data from the fenfluramine registration studies and confirmed increasing SFDs directly, and quantifiably, improved patient and carer QoL (utilities per additional SFD per 28-days: patient=0.005 and carer=0.014). These analyses demonstrate that effective antiseizure treatment can directly and profoundly improve patients’ and carers’ QoL. ### Competing Interest Statement TT and WL were employed by Zogenix at the time of the study. TT is a shareholder in Zogenix. EA, GW, AP and CHW were employed by Aquarius Population Health consultancy which received consultancy fees from Zogenix to the organisation to support this study. NH received consultancy fees to support this study to the organisation. MS received research funding from Zogenix via employment institution. ### Funding Statement Award/Grant number is not applicable. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical statement The present study is a secondary data analysis study and we have utilised existing data collected in the previous two FFA registration trial studies (12, 13). The Lagae et al., 2019 trial study protocols were reviewed and approved by the institutional review board or ethics committee for each study site before any study activation. All patients or their legal representatives signed informed consent before enrolling in the trial (12). The protocol of Nabbout et al. study in 2020 was approved by applicable regulatory authorities and an independent ethics committee or institutional review board at each participating institution. All patients or their legal representatives provided written informed consent before enrolment (13). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data relevant to the study are included in the online Supplementary Material. No additional data are available.