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Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials.
OBJECTIVE: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue.
MATERIALS AND METHODS: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454).
RESULTS: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction ( p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction ( p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators ( p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure ( p = 0.006) but not on at least 50% reduction. Weight loss ( p = 0.002), decreased appetite ( p = 0.04), and all-cause withdrawal ( p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups.
CONCLUSION: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS.
CLINICAL TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.
MATERIALS AND METHODS: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses. The study was registered with PROSPERO (CRD42023392454).
RESULTS: Six hundred and twelve patients from four randomized controlled trials were enrolled. The results demonstrated that FFA at 0.2, 0.4, or 0.7 mg/kg/d showed significantly greater efficacy compared to placebo in terms of at least 50% reduction ( p < 0.001, p < 0.001, p < 0.001) and at least 75% reduction ( p < 0.001, p = 0.007, p < 0.001) in monthly seizure frequency from baseline. Moreover, significantly more patients receiving FFA than placebo were rated as much improved or very much improved in CGI-I by both caregivers/parents and investigators ( p < 0.001). The most common treatment-emergent adverse events were decreased appetite, diarrhea, fatigue, and weight loss, with no valvular heart disease or pulmonary hypertension observed in any participant. For dose comparison, 0.7 mg/kg/d group presented higher efficacy on at least 75% reduction in seizure ( p = 0.006) but not on at least 50% reduction. Weight loss ( p = 0.002), decreased appetite ( p = 0.04), and all-cause withdrawal ( p = 0.036) were more common in 0.7 mg/kg/d group than 0.2 mg/kg/d. There was no statistical difference in other safety parameters between these two groups.
CONCLUSION: The higher range of the licensed dose achieves the optimal balance between efficacy, safety, and tolerability in patients with DS and LGS.
CLINICAL TRIAL REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023392454.
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