14 research outputs found
Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial
IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in
patients with Dravet syndrome who have poor seizure control with their current
stiripentol-containing antiepileptic drug regimens.
OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure
frequency relative to placebo in patients with Dravet syndrome who were taking
stiripentol-inclusive regimens.
DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group
randomized clinical trial was conducted in multiple centers. Eligible patients were children
aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving
stable, stiripentol-inclusive antiepileptic drug regimens.
INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline
period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d),
or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for
12 additional weeks. Caregivers recorded seizures via a daily electronic diary.
MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean
monthly convulsive seizure frequency between fenfluramine and placebo during the
combined titration and maintenance periods relative to baseline.
RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age
9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately
25 convulsive seizures per month) were enrolled and randomized to fenfluramine,
0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a
54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive
seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients
demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure
frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval
was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004).
The most common adverse events were decreased appetite (19 patients taking fenfluramine
[44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]),
and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or
echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.
CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in
monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions
were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens.
Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment
option for Dravet syndrome.
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT0292689
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Clinical studies and anti-inflammatory mechanisms of treatments.
In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both "conventional, broad spectrum" anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain
Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens A Randomized Clinical Trial
IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in
patients with Dravet syndrome who have poor seizure control with their current
stiripentol-containing antiepileptic drug regimens.
OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure
frequency relative to placebo in patients with Dravet syndrome who were taking
stiripentol-inclusive regimens.
DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group
randomized clinical trial was conducted in multiple centers. Eligible patients were children
aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving
stable, stiripentol-inclusive antiepileptic drug regimens.
INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline
period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d),
or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for
12 additional weeks. Caregivers recorded seizures via a daily electronic diary.
MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean
monthly convulsive seizure frequency between fenfluramine and placebo during the
combined titration and maintenance periods relative to baseline.
RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age
9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately
25 convulsive seizures per month) were enrolled and randomized to fenfluramine,
0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a
54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive
seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients
demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure
frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval
was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004).
The most common adverse events were decreased appetite (19 patients taking fenfluramine
[44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]),
and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or
echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.
CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in
monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions
were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens.
Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment
option for Dravet syndrome.
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT0292689
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Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.
Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10Â years