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A pilot, open‐label study of the effectiveness and tolerability of low‐dose ZX 008 (fenfluramine HC l) in Lennox‐Gastaut syndrome
Author(s) -
Lagae Lieven,
Schoonjans AnSofie,
Gammaitoni Arnold R.,
Galer Bradley S.,
Ceulemans Berten
Publication year - 2018
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14540
Subject(s) - lennox–gastaut syndrome , fenfluramine , medicine , dravet syndrome , tolerability , adverse effect , epilepsy syndromes , refractory (planetary science) , anesthesia , epilepsy , pediatrics , gastroenterology , receptor , psychiatry , serotonin , physics , astrobiology
Summary Objective Lennox‐Gastaut syndrome ( LGS ) is a drug‐resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX 008 (fenfluramine HC l oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open‐label, dose‐finding study of add‐on ZX 008 in patients with LGS ( NCT 02655198). 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 ZX 008 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 ZX 008 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 ZX 008 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.