Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.

OBJECTIVE: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.

Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: A critical period for early neurodevelopment.

OBJECTIVE: To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS). METHODS: Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function®-Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p ≤ 0.05) and Cramér's V. RESULTS: Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05). SIGNIFICANCE: In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment.

Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis.

OBJECTIVE: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue. SIGNIFICANCE: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome.

OBJECTIVE: Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use. Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. METHODS: This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5-18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF®) parent form, a questionnaire capturing parents'/caregivers' perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF® were mapped to the current edition, the BRIEF®2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF®2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman's rho correlation coefficients assessed associations between change in BRIEF®2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and ≥50% MCSF reduction. Changes in the distribution of BRIEF®2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as Reliable Change Index (RCI) values ≥95% certainty relative to a reference population of neurotypically developing healthy volunteers, were then assessed by cross-tabulations and Somers' D tests (p ≤ 0.05). When there was a significant meaningful improvement in an index score, post-hoc analyses using the same statistical methods were conducted to evaluate the individual BRIEF®2 scales composing that index. Supplemental analyses examined the proportions of patients in MCSF reduction groups <25% and ≥75% who achieved clinically meaningful improvement or worsening in everyday EF using RCI values ≥95% certainty and ≥80% certainty, respectively, relative to the reference population. RESULTS: At the time of analysis, 58 children and young adults (mean age: 11 ±â€¯4 years) had reached OLE Year 1 of fenfluramine treatment with a 75% median percentage reduction in seizure frequency from pre-randomization baseline. Overall, there was a significant correlation between change in MCSF and change in BRIEF®2 T-scores for ERI (p = 0.008), but not for BRI, CRI, or GEC (p > 0.05). At OLE Year 1, 78% (n = 45) of total children/young adults had ≥50% MCSF reduction (50% [n = 29] achieved ≥75% MCSF reduction) and 22% (n = 13) of total children/young adults had <50% MCSF reduction (12% [n = 7] showed <25% MCSF reduction). The ≥50% MCSF reduction group was significantly more likely to achieve clinically meaningful improvement (RCI ≥ 95% certainty) in ERI (p = 0.002) and in CRI (p = 0.001) than the <50% MCSF reduction group. There were no significant differences in the proportions of children and young adults in the 2 MCSF reduction groups showing clinically meaningful worsening (RCI ≥ 80% certainty) on the BRIEF®2 indexes/composite. SIGNIFICANCE: In children and young adults with DS, the magnitude of reduction in MCSF after long-term treatment with adjunctive fenfluramine was associated with clinically meaningful levels of improvement in everyday EF. Seventy-eight percent (78%) of children and young adults treated with adjunctive fenfluramine for 1 year in the OLE study achieved ≥50% reduction in MCSF, for a magnitude of efficacy associated with a significantly greater likelihood of experiencing clinically meaningful improvement in emotion regulation and cognitive regulation.

Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth.

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.

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.

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.

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study.

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.

Psychosocial impact on siblings of patients with developmental and epileptic encephalopathies.

OBJECTIVE: Caring for children with developmental and epileptic encephalopathies (DEEs) places substantial demands on the entire family unit, including siblings. The Sibling Voices Survey assesses parental and sibling responses to questions designed to assess how children adapt to growing up with siblings with DEE. METHODS: Participants responded to 1 of 4 online, age- and role-specific surveys (9-12, 13-17, and ≥18-year-old [adult] siblings; parents responded with perceptions of their unaffected child's/children's feelings). Survey questions used visual analog scales, categorical responses, and free-form responses. RESULTS: Survey submissions (n = 248) included 128 parents and 120 siblings (9- to 12-year-olds, n = 24; 13- to 17-year-olds, n = 17; adults, n = 79). All groups identified home life as the most substantially affected area of their lives (71%-84%), compared with interactions at school (21%-32%) or with friends (28%-42%). The most difficult aspect across all sibling groups was "feeling worried/scared when their sibling has seizures" (58%-70%). Feeling "overly responsible" for the sibling was reported by most adult siblings (63%), 41% of 13- to 17-year-old siblings, and 34% of parents. Siblings reported more symptoms of depressed mood (e.g., "down/unhappy," 47%-62%) than their parents perceived them feeling (25%). Most sibling groups (29%-49%) reported more symptoms of anxious mood (e.g., "nightmares/bad dreams") than parents perceived (15%). Identification of potential helpful coping mechanisms varied by age group. Most respondents (68%-76%) reported positive aspects, including greater maturity and compassion. SIGNIFICANCE: The Sibling Voices Survey provided important insights into how DEE impacts siblings psychologically and socially. This study highlights the need for increased awareness among parents and healthcare providers to monitor siblings for potential signs of depressed or anxious mood, to provide proper support, and to decrease potential for negative long-term consequences.

Development and validation of the University of Washington caregiver stress and benefit scales for caregivers of children with or without serious health conditions.

PURPOSE: To develop item response theory (IRT)-based item banks and short forms to measure stress and benefit related to caregiving for children, including children with epilepsy or other serious health conditions. METHODS: Items developed with feedback from neurologists and caregivers of children with epilepsy were tested in cognitive interviews and administered to caregivers of children with severe epilepsy (N = 128), down syndrome (N = 143) and muscular dystrophy (N = 129), as well as a community sample of US caregivers (N = 322). IRT was used to analyze the data. Test-retest reliability was assessed using a two-way random effects (2,1) intraclass correlation coefficient (ICC). Validity was assessed by a pattern of correlations with relevant constructs (stress, depression, anxiety, and resilience) and by the pattern of scores by known groups. RESULTS: Caregivers of children with serious health conditions reported more stress and less benefit than the general sample. The final caregiver stress item bank (k = 19) and the caregiver benefit item bank (k = 13) were calibrated using IRT and centered on a sample of community caregivers representative of the US general caregiver population. Short form scores are highly correlated with full bank scores (r ≥ 0.98) and IRT reliability exceed 90% for most levels. Test-retest reliability was high (ICC > 0.92) for banks and short forms. CONCLUSIONS: Results provide strong support for reliability and validity of the caregiver stress and benefit scores. Instruments are publicly available, flexible, brief, and provide reliable and valid scores of caregiver stress and benefit of caregivers of children with and without serious health conditions.

A phase I, randomized, open-label, single-dose, 3-period crossover study to evaluate the drug-drug interaction between ZX008 (fenfluramine HCl oral solution) and a regimen of stiripentol, clobazam, and valproate in healthy subjects
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OBJECTIVE: Phase I, open-label, randomized, single-dose, 3-period crossover study assessing pharmacokinetics (PK) and safety of ZX008, a liquid oral formulation of fenfluramine (FFA) under development for adjunctive treatment of Dravet syndrome and Lennox-Gastaut syndrome, administered with and without a combined antiepileptic drug (AED) regimen of stiripentol (STP), valproate (VPA), and clobazam (CLB) (STP regimen). MATERIALS AND METHODS: 26 healthy adults were administered the following treatments: ZX008 0.8 mg/kg; STP 3,500 mg, CLB 20 mg, VPA 25 mg/kg (max. 1,500 mg); and ZX008 0.8 mg/kg + STP regimen. Dose periods were 17 days apart. Blood samples were obtained for 72 hours after drug administration and used to calculate non-compartmental PK parameters. RESULTS: Statistical bioequivalence-type analysis demonstrated ZX008 had no significant impact on the PK of any drug in the STP regimen, while the STP regimen moderately affected FFA PK. The 3-drug combination increased the geometric mean Cmax, AUC0-t, and AUC0-inf of FFA while reducing the Cmax and AUC0-t of its major metabolite, norfenfluramine (norFFA). Adverse events (AEs) were mild to moderate and resolved spontaneously. ZX008 + STP regimen co-administration to healthy adult subjects modestly impacted the number but not severity of AEs. CONCLUSION: Results show that the STP regimen had a moderate impact on FFA and norFFA PK and ZX008 had no significant impact on the 3 STP regimen drugs. ZX008 would not be expected to alter the clinical response of patients to this regimen by means of an effect on PK. When administering these drugs together, a downward dose adjustment of ZX008 may be warranted.
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A pilot, open-label study of the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut syndrome.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198). METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ≥4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram. RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ≥50% CS reduction; three (23%) patients had a ≥75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ≥50% reduction, and three (33%) patients had a ≥75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. SIGNIFICANCE: ZX008 provided clinically meaningful reduction (≥50%) in CS frequency in the majority of patients with LGS in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.

Life impact of caregiving for severe childhood epilepsy: Results of expert panels and caregiver focus groups.

Severe epilepsy in children and young adults can significantly affect the lives of their caregivers. However, the lack of a reliable and valid measure of caregiver impact has limited our understanding of the scope and correlates of this impact, as well as our ability to measure the effects of treatments that could lessen it. The purpose of this study was to facilitate focus groups and interviews with an international group of clinician experts and caregivers to identify the most important domains that should be assessed in a measure of caregiver impact. Ten specific subdomains emerged from the panel discussions, which could be classified into the four overarching categories of physical health, mental health, social function, and financial resources. The caregivers highlighted the impact on the subdomains of sleep and fatigue as most critical. A review of existing caregiver impact measures confirmed that there is no measure currently available that assesses all of these relevant domains, indicating the need for the development of such a measure. The current findings highlight the significant life effects of caring for a child with severe epilepsy and can be used to inform the development of such a tool.

The humanistic and economic burden of Dravet syndrome on caregivers and families: Implications for future research.

We reviewed the current literature with respect to the humanistic and financial burdens of Dravet Syndrome (DS) on the caregivers of children with DS, in order to (1) identify key unanswered questions or gaps in knowledge that need to be addressed and then, based on these knowledge gaps, (2) propose a research agenda for the scientific community to address in the coming decade. The findings support the conclusion that caring for a child with DS is associated with significant humanistic burden and direct costs. However, due in part to the paucity of studies, as well as the lack of measures of specific burden domains, there remains much that is not known regarding the burden of caregiving for children with DS. To address the significant knowledge gaps in this area, research is needed that will: (1) identify the specific domains of caregivers' lives that are impacted by caring for a child with DS; (2) identify or, if needed, develop measures of caregiving impact in this area; (3) identify the factors that influence DS caregiving burden; (4) develop and evaluate the efficacy of treatments for reducing the negative impact of DS and its comorbidities on DS caregivers; (5) quantify the direct medical costs associated with DS and DS comorbidities and identify the factors that influence these costs; and (6) quantify and fully explore the indirect costs of DS. Research that addresses these goals will provide the empirical foundation needed for improving the quality of life of children with DS and their families.

An Analysis of Rescue Medication Utilization from a 3-Month, Randomized, Double-Blind, Placebo-Controlled Study in Patients with Chronic Low Back Pain Treated with Single-Entity, Twice-Daily, Extended-Release Hydrocodone.

OBJECTIVE: To evaluate the durability of pain relief provided by a new formulation of single-entity, hydrocodone extended-release (ER) (Zohydro(®) ER) throughout the 12-hour dosing interval by examining patterns of rescue medication use. DESIGN: Phase 3, enriched enrollment, randomized withdrawal study with an open-label, conversion/titration phase (≤6 weeks) followed by a placebo-controlled, double-blind treatment phase (12 weeks). SETTING: Fifty-seven study sites in the United States enrolled patients. SUBJECTS: One hundred and fifty-one opioid-experienced subjects with moderate to severe chronic low back pain who were treated with hydrocodone ER once every 12 hours. METHODS: Post hoc analysis of rescue medication use by frequency and distribution of use following the morning and evening dose of hydrocodone ER. RESULTS: No rescue medication was used following the morning or evening dose of hydrocodone ER during 36.0% and 76.7% of the dosing days, respectively. Time distribution of rescue medication use showed that 79.3% of all rescue medication doses were administered following the morning dose, with the highest rate of usage (46.2%) occurring 4-8 hours postdose, followed by 18.7% and 14.4% usage 0-4 and 8-12 hours postdose, respectively. Examination of the three 4-hour intervals following the evening dose of hydrocodone ER revealed similar minimal rescue medication use (5.6-8.2%). CONCLUSIONS: End-of-dose failure was not observed based on the use of rescue medication after administration of single-entity, twice daily, hydrocodone ER capsules (Zohydro ER).

Predicting Response to Subacromial Injections and Lidocaine/Tetracaine Patch from Pretreatment Pain Quality in Patients with Shoulder Impingement Syndrome.

OBJECTIVES: No existing pain treatment is effective for all pain problems, and response to pain treatment is highly variable. Knowledge regarding the patient factors that predict response to different treatments could benefit patients by providing an empirical foundation for patient-treatment matching. This study sought to test the hypothesis that improvements following two treatments thought to operate via similar mechanisms would be predicted by similar baseline pain qualities. DESIGN: Prospective prediction analysis using data from a previously published open label trial comparing a heated lidocaine/tetracaine patch versus subacromial corticosteroid injection for the treatment of pain in individuals with shoulder impingement syndrome. RESULTS: Consistent with the study hypothesis, the response to the two treatments were predicted by similar baseline pain qualities; specifically, higher baseline levels of unpleasant, electric, and sensitive pain predicted subsequent improvements in sleep interference, work/activity interference, and patient global ratings of improvement, respectively. CONCLUSIONS: The findings are consistent with the combined ideas that (1) those who have the most to gain (i.e., those reporting the highest levels of various pain qualities) can expect the best response to effective treatments and (2) different pain qualities may be associated with different types of outcomes. The findings support further research to examine how pain quality measures may be used to improve patient-treatment matching, and therefore, ultimately improve the efficiency, efficacy, and overall benefit-risk of pain treatment.

Predicting response to pregabalin from pretreatment pain quality: clinical applications of the pain quality assessment scale.

OBJECTIVE: The aim of this study is to assess the Pain Quality Assessment Scale (PQAS) in predicting pregabalin in peripheral neuropathic pain (NP). STUDY DESIGN: Post hoc analysis of a double-blind, placebo-controlled, enriched enrollment, randomized withdrawal trial evaluating pregabalin in 99 patients with NP who completed the PQAS, which comprises 20 questions regarding individual pain domains and qualities that are scored into three scales: paroxysmal, deep, and surface. METHODS: Patients rated the average pain intensity and pain quality using the PQAS at baseline; average pain intensity was assessed again after 40 days of treatment with pregabalin. Associations between pretreatment PQAS scores and treatment response were estimated using Pearson's r. Logistic regression was used to identify pretitration PQAS scores contributing unique variance to predicting treatment response. RESULTS: Fifty participants provided baseline PQAS scores and received pregabalin for the entire length of the study. Nine of 23 PQAS baseline scales and items were significantly associated with treatment response to pregabalin: the paroxysmal and deep scales, and the items assessing the following pain domains and qualities: intensity, electric, tingling, cramping, radiating, throbbing, and deep (P values range, 0.002-0.045; rs range, 0.28-0.43). The PQAS items assessing sharp, hot, and unpleasant pain items demonstrated nonsignificant trends (P < 0.10) to be associated with treatment response. In the logistic regression analysis, pretitration PQAS scores had 77% sensitivity and 83% specificity to correctly identify pregabalin responders. Significantly correlated PQAS items had a sensitivity of 85% and specificity of 76%. CONCLUSION: Pretitration PQAS scores reliably predicted pregabalin responders in patients with NP.

The impact of TK2 deficiency syndrome and its treatment by nucleoside therapy on quality of life.

TK2d is an ultrarare autosomal recessive mitochondrial DNA depletion syndrome. Nucleoside therapy improves or stabilizes disease across key outcomes including survival, ambulation, and requirement for mechanical ventilation. However, little is known about the effects of nucleoside therapy treatment of TK2d from the patient's perspective. This study sought to address this knowledge gap. Participants with TK2d and/or their parents/caregivers completed online surveys with standardized health measures and interviews. During interviews, participants rated and described TK2d's impact on 13 quality of life domains, changes since starting nucleoside therapy, and if they would recommend nucleoside therapy. Twenty-five individuals participated (17 adults with TK2d, 4 parent-participant pairs, 4 parents of children with TK2d). Adult participants with TK2d had clinically meaningfully worse scores than the general population on global physical and mental health, physical function, pain interference, fatigue, anxiety, and social function. Children's mobility and pain interference were significantly worse than the general pediatric population. Physical domains most affected by TK2d were: mobility (84%), fatigue (60%), respiratory function (56%), and hospitalizations (55%). Psychosocial domains most affected were: impact on family members (39%), mood (36%), and social life (28%). Most (77%) treated patients reported improvement; whereas, 67% in the untreated group reported worsening. All participants would recommend nucleoside therapy. In summary, TK2d has significant negative impacts on most areas of life and function. Measures of fatigue, sleep, swallowing/eating, speaking, and mood, should be considered as outcomes in clinical trials and research studies. Nucleoside therapy appears to provide meaningful improvements across many health domains affected by TK2d. SYNOPSIS: The consequences of having TK2d are devastating for both those with the disorder and their families; however, nucleoside therapy appears to provide meaningful improvements across many health domains affected by TK2d.

Fenfluramine treatment for dravet syndrome: Real-world benefits on quality of life from the caregiver perspective.

OBJECTIVE: Prior research has demonstrated durable and profound reductions in seizure frequency and improvements in executive functions in individuals with Dravet syndrome (DS) who are treated with fenfluramine (FFA). This study aimed to understand the benefits of FFA from the perspective of the patients' caregivers. METHODS: Caregivers for a child with DS participated in semi-structured interviews to discuss the benefits of FFA treatment on the child with DS, the caregiver, and the family. RESULTS: 65 caregivers participated. Patients were between 2 and 33 years old and had been treated with FFA for an average of 22.7 months. The most commonly reported seizure-related benefits (> 50 % of participants) of FFA treatment included a reduction in seizure activity, fewer seizure triggers, and shorter post-ictal recovery. The most common quality of life (QOL) benefits in patients included improvements in cognitive function, alertness, and academic performance. In addition, the caregivers reported improvements in their sleep quality (74 %) and that they felt less overwhelmed (72 %) and stressed (69 %) after their children began FFA treatment. Many caregivers also reported improved relationships between the child with DS and their siblings (52 %). CONCLUSIONS: The study found that FFA treatment is associated with meaningful improvement in a large number of QOL domains both for the people with DS who received FFA and their families.