Long-term retention rates for antiepileptic drugs: A review of long-term extension studies and comparison with brivaracetam

Toledo, Manuel; Beale, Rebecca; Evans, JS; Steeves, Sara; Elmoufti, Sami; Townsend, Rebecca; Whitesides, John; Borghs, Simon

doi:10.1016/j.eplepsyres.2017.10.008

Cited by 30 publications

(35 citation statements)

References 31 publications

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“…During the follow‐up period, which extended through 2 years for some patients (median treatment duration of 48 weeks), 76% of patients remained on treatment. This retention rate compares favorably to other AED trials in TREs (63%‐72%) . This is possibly due to maintenance of long‐term efficacy and/or adverse events that were generally mild; improvements in quality of life and seizure severity also have been reported with CBD, likely resulting in better retention.…”

Section: Discussionmentioning

confidence: 48%

“…This retention rate compares favorably to other AED trials in TREs (63%-72%). 9,10 This is possibly due to maintenance of long-term efficacy and/or adverse events that were generally mild; improvements in quality of life 11,12 and seizure F I G U R E 2 Percentage reduction from baseline in convulsive and total* seizures for (A) efficacy analysis set and (B) LOCF analysis. *Total seizures included convulsive seizures (ie, clonic, tonic, tonic-clonic, atonic, focal secondary generalized) and nonconvulsive seizures (ie, myoclonic, absence, myoclonic-absence, focal with and without impaired consciousness).…”

Section: Discussionmentioning

confidence: 99%

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Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results

et al. 2018

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SummaryObjectiveSince 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.MethodsTwenty‐five US‐based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4‐week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2‐10 mg/kg/d, titrated to a maximum dose of 25‐50 mg/kg/d. Patient visits were every 2‐4 weeks through 16 weeks and every 2‐12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last‐observation‐carried‐forward method to account for missing data. Adverse events (AEs) were documented at each visit.ResultsOf 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4‐62). Median number of concomitant AEDs was 3 (range, 0‐10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add‐on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).SignificanceResults from this ongoing EAP support previous observational and clinical trial data showing that add‐on CBD may be an efficacious long‐term treatment option for TRE.

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results

et al. 2018

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“…Median CBD exposure in this extension study was approximately 39 weeks, over twice the duration of the parent randomized‐controlled studies, with some patients treated for 73 weeks. When taking into consideration the duration of follow‐up, the withdrawal rate of 28% is not surprising, and within the range of other long‐term AED studies of 20%‐40% at approximately 1 year of follow‐up . Study burden and the addition of new drug trials for DS (fenfluramine [NCT02826863], ataluren [NCT02758626]) likely contributed to the withdrawals in the current study.…”

Section: Discussionmentioning

confidence: 56%

“…When taking into consideration the duration of follow-up, the withdrawal rate of 28% is not surprising, and within the range of other long-term AED studies of 20%-40% at approximately 1 year of follow-up. 26,27 Study burden and the addition of new drug trials for DS (fenfluramine [NCT02826863], ataluren [NCT02758626]) likely contributed to the withdrawals in the current study.…”

Section: Discussionmentioning

confidence: 99%

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Devinsky¹,

et al. 2018

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Summary Objective Add‐on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double‐blind, placebo‐controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo‐controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long‐term open‐label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient‐reported outcomes from GWPCARE5. Methods Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. Results By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open‐label extension. Median treatment duration was 274 days (range 1‐512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty‐two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance This trial shows that long‐term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment‐resistant DS.

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“…17 When taking into consideration the duration of follow-up in the present study at the time of this analysis (median 38 weeks), there was a relatively low withdrawal rate of 18%. Median F I G U R E 2 Reduction from baseline a in (A) drop seizure frequency and (B) total seizure frequency.…”

Section: Discussionmentioning

confidence: 78%

Cannabidiol in patients with Lennox‐Gastaut syndrome: Interim analysis of an open‐label extension study

Thiele

Marsh

Mazurkiewicz‐Bełdzińska

et al. 2019

Epilepsia

108

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SummaryObjectivePatients with Lennox‐Gastaut syndrome (LGS) who completed 1 of 2 randomized, double‐blind, placebo‐controlled trials of add‐on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open‐label extension (OLE) study evaluating the long‐term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient‐reported outcomes from this trial.MethodsPatients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.ResultsThis interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty‐five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12‐week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12‐week periods through week 48. Eighty‐eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale.SignificanceIn this study, long‐term add‐on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

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Long-term retention rates for antiepileptic drugs: A review of long-term extension studies and comparison with brivaracetam

Cited by 30 publications

References 31 publications

Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results

Long‐term safety and treatment effects of cannabidiol in children and adults with treatment‐resistant epilepsies: Expanded access program results

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Cannabidiol in patients with Lennox‐Gastaut syndrome: Interim analysis of an open‐label extension study

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