@ARTICLE{Knupp2022-wb,
  title    = "Efficacy and Safety of Fenfluramine for the Treatment of Seizures
              Associated With Lennox-Gastaut Syndrome: A Randomized Clinical
              Trial",
  author   = "Knupp, Kelly G and Scheffer, Ingrid E and Ceulemans, Berten and
              Sullivan, Joseph E and Nickels, Katherine C and Lagae, Lieven and
              Guerrini, Renzo and Zuberi, Sameer M and Nabbout, Rima and Riney,
              Kate and Shore, Svetlana and Agarwal, Anupam and Lock, Michael and
              Farfel, Gail M and Galer, Bradley S and Gammaitoni, Arnold R and
              Davis, Ronald and Gil-Nagel, Antonio",
  journal  = "JAMA Neurol.",
  address  = "United States",
  volume   =  79,
  number   =  6,
  pages    = "554--564",
  abstract = "IMPORTANCE: New treatment options are needed for patients with
              Lennox-Gastaut syndrome (LGS), a profoundly impairing,
              treatment-resistant, developmental and epileptic encephalopathy.
              OBJECTIVE: To evaluate the efficacy and safety of fenfluramine in
              patients with LGS. DESIGN, SETTING, AND PARTICIPANTS: This
              multicenter, double-blind, placebo-controlled, parallel-group
              randomized clinical trial was conducted from November 27, 2017, to
              October 25, 2019, and had a 20-week trial duration. Patients were
              enrolled at 65 study sites in North America, Europe, and
              Australia. Included patients were aged 2 to 35 years with
              confirmed diagnosis of LGS and experienced 2 or more drop seizures
              per week during the 4-week baseline. Using a modified
              intent-to-treat method, data analysis was performed from November
              27, 2017, to October 25, 2019. The database lock date was January
              30, 2020, and the date of final report was September 11, 2021.
              INTERVENTIONS: Patients were randomized to receive either a
              0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine
              or placebo. After titration (2-week period), patients were taking
              their randomized dose for 12 additional weeks. MAIN OUTCOMES AND
              MEASURES: Primary efficacy end point was percentage change from
              baseline in drop seizure frequency in patients who received 0.7
              mg/kg/d of fenfluramine vs placebo. RESULTS: A total of 263
              patients (median [range] age, 13 [2-35] years; 146 male patients
              [56\%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n =
              87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n
              = 87). The median percentage reduction in frequency of drop
              seizures was 26.5 percentage points in the 0.7-mg/kg/d
              fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d
              fenfluramine group, and 7.6 percentage points in the placebo
              group. The trial met its primary efficacy end point: patients in
              the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage
              points (95\% CI, -31.0 to -8.7 percentage points; P = .001)
              estimated median difference in drop seizures from baseline vs
              placebo. More patients in the 0.7-mg/kg/d fenfluramine group
              achieved a 50\% or greater response (22 of 87 [25\%]; P = .02) vs
              placebo (9 of 87 [10\%]). Site investigators and caregivers gave a
              much improved or very much improved rating on the Clinical Global
              Impression of Improvement scale to more patients in the
              0.7-mg/kg/d fenfluramine group than patients in the placebo group
              (21 [26\%] vs 5 [6\%]; P = .001). The seizure subtype that
              appeared most responsive to fenfluramine was generalized
              tonic-clonic seizure (120 of 263 [46\%]), with a decrease in
              frequency of 45.7\% in the 0.7-mg/kg/d fenfluramine group and
              58.2\% in the 0.2-mg/kg/d fenfluramine group compared with an
              increase of 3.7\% in the placebo group. Most common
              treatment-emergent adverse events included decreased appetite (59
              [22\%]), somnolence (33 [13\%]), and fatigue (33 [13\%]). No cases
              of valvular heart disease or pulmonary arterial hypertension were
              observed. CONCLUSIONS AND RELEVANCE: Results of this trial showed
              that, in patients with LGS, fenfluramine compared with placebo
              provided a significantly greater reduction in drop seizures and
              may be a particularly advantageous choice in patients who
              experience generalized tonic-clonic seizures. TRIAL REGISTRATION:
              ClinicalTrials.gov Identifier: NCT03355209.",
  month    =  jun,
  year     =  2022,
  language = "en"
}

{"_id":"9ajSDRj3SxaKqgeZg","bibbaseid":"knupp-scheffer-ceulemans-sullivan-nickels-lagae-guerrini-zuberi-etal-efficacyandsafetyoffenfluramineforthetreatmentofseizuresassociatedwithlennoxgastautsyndromearandomizedclinicaltrial-2022","author_short":["Knupp, K. G","Scheffer, I. E","Ceulemans, B.","Sullivan, J. E","Nickels, K. C","Lagae, L.","Guerrini, R.","Zuberi, S. M","Nabbout, R.","Riney, K.","Shore, S.","Agarwal, A.","Lock, M.","Farfel, G. M","Galer, B. S","Gammaitoni, A. R","Davis, R.","Gil-Nagel, A."],"bibdata":{"bibtype":"article","type":"article","title":"Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial","author":[{"propositions":[],"lastnames":["Knupp"],"firstnames":["Kelly","G"],"suffixes":[]},{"propositions":[],"lastnames":["Scheffer"],"firstnames":["Ingrid","E"],"suffixes":[]},{"propositions":[],"lastnames":["Ceulemans"],"firstnames":["Berten"],"suffixes":[]},{"propositions":[],"lastnames":["Sullivan"],"firstnames":["Joseph","E"],"suffixes":[]},{"propositions":[],"lastnames":["Nickels"],"firstnames":["Katherine","C"],"suffixes":[]},{"propositions":[],"lastnames":["Lagae"],"firstnames":["Lieven"],"suffixes":[]},{"propositions":[],"lastnames":["Guerrini"],"firstnames":["Renzo"],"suffixes":[]},{"propositions":[],"lastnames":["Zuberi"],"firstnames":["Sameer","M"],"suffixes":[]},{"propositions":[],"lastnames":["Nabbout"],"firstnames":["Rima"],"suffixes":[]},{"propositions":[],"lastnames":["Riney"],"firstnames":["Kate"],"suffixes":[]},{"propositions":[],"lastnames":["Shore"],"firstnames":["Svetlana"],"suffixes":[]},{"propositions":[],"lastnames":["Agarwal"],"firstnames":["Anupam"],"suffixes":[]},{"propositions":[],"lastnames":["Lock"],"firstnames":["Michael"],"suffixes":[]},{"propositions":[],"lastnames":["Farfel"],"firstnames":["Gail","M"],"suffixes":[]},{"propositions":[],"lastnames":["Galer"],"firstnames":["Bradley","S"],"suffixes":[]},{"propositions":[],"lastnames":["Gammaitoni"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Davis"],"firstnames":["Ronald"],"suffixes":[]},{"propositions":[],"lastnames":["Gil-Nagel"],"firstnames":["Antonio"],"suffixes":[]}],"journal":"JAMA Neurol.","address":"United States","volume":"79","number":"6","pages":"554–564","abstract":"IMPORTANCE: New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. OBJECTIVE: To evaluate the efficacy and safety of fenfluramine in patients with LGS. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. INTERVENTIONS: Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. MAIN OUTCOMES AND MEASURES: Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. RESULTS: A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. CONCLUSIONS AND RELEVANCE: Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03355209.","month":"June","year":"2022","language":"en","bibtex":"@ARTICLE{Knupp2022-wb,\n title = \"Efficacy and Safety of Fenfluramine for the Treatment of Seizures\n Associated With Lennox-Gastaut Syndrome: A Randomized Clinical\n Trial\",\n author = \"Knupp, Kelly G and Scheffer, Ingrid E and Ceulemans, Berten and\n Sullivan, Joseph E and Nickels, Katherine C and Lagae, Lieven and\n Guerrini, Renzo and Zuberi, Sameer M and Nabbout, Rima and Riney,\n Kate and Shore, Svetlana and Agarwal, Anupam and Lock, Michael and\n Farfel, Gail M and Galer, Bradley S and Gammaitoni, Arnold R and\n Davis, Ronald and Gil-Nagel, Antonio\",\n journal = \"JAMA Neurol.\",\n address = \"United States\",\n volume = 79,\n number = 6,\n pages = \"554--564\",\n abstract = \"IMPORTANCE: New treatment options are needed for patients with\n Lennox-Gastaut syndrome (LGS), a profoundly impairing,\n treatment-resistant, developmental and epileptic encephalopathy.\n OBJECTIVE: To evaluate the efficacy and safety of fenfluramine in\n patients with LGS. DESIGN, SETTING, AND PARTICIPANTS: This\n multicenter, double-blind, placebo-controlled, parallel-group\n randomized clinical trial was conducted from November 27, 2017, to\n October 25, 2019, and had a 20-week trial duration. Patients were\n enrolled at 65 study sites in North America, Europe, and\n Australia. Included patients were aged 2 to 35 years with\n confirmed diagnosis of LGS and experienced 2 or more drop seizures\n per week during the 4-week baseline. Using a modified\n intent-to-treat method, data analysis was performed from November\n 27, 2017, to October 25, 2019. The database lock date was January\n 30, 2020, and the date of final report was September 11, 2021.\n INTERVENTIONS: Patients were randomized to receive either a\n 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine\n or placebo. After titration (2-week period), patients were taking\n their randomized dose for 12 additional weeks. MAIN OUTCOMES AND\n MEASURES: Primary efficacy end point was percentage change from\n baseline in drop seizure frequency in patients who received 0.7\n mg/kg/d of fenfluramine vs placebo. RESULTS: A total of 263\n patients (median [range] age, 13 [2-35] years; 146 male patients\n [56\\%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n =\n 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n\n = 87). The median percentage reduction in frequency of drop\n seizures was 26.5 percentage points in the 0.7-mg/kg/d\n fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d\n fenfluramine group, and 7.6 percentage points in the placebo\n group. The trial met its primary efficacy end point: patients in\n the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage\n points (95\\% CI, -31.0 to -8.7 percentage points; P = .001)\n estimated median difference in drop seizures from baseline vs\n placebo. More patients in the 0.7-mg/kg/d fenfluramine group\n achieved a 50\\% or greater response (22 of 87 [25\\%]; P = .02) vs\n placebo (9 of 87 [10\\%]). Site investigators and caregivers gave a\n much improved or very much improved rating on the Clinical Global\n Impression of Improvement scale to more patients in the\n 0.7-mg/kg/d fenfluramine group than patients in the placebo group\n (21 [26\\%] vs 5 [6\\%]; P = .001). The seizure subtype that\n appeared most responsive to fenfluramine was generalized\n tonic-clonic seizure (120 of 263 [46\\%]), with a decrease in\n frequency of 45.7\\% in the 0.7-mg/kg/d fenfluramine group and\n 58.2\\% in the 0.2-mg/kg/d fenfluramine group compared with an\n increase of 3.7\\% in the placebo group. Most common\n treatment-emergent adverse events included decreased appetite (59\n [22\\%]), somnolence (33 [13\\%]), and fatigue (33 [13\\%]). No cases\n of valvular heart disease or pulmonary arterial hypertension were\n observed. CONCLUSIONS AND RELEVANCE: Results of this trial showed\n that, in patients with LGS, fenfluramine compared with placebo\n provided a significantly greater reduction in drop seizures and\n may be a particularly advantageous choice in patients who\n experience generalized tonic-clonic seizures. TRIAL REGISTRATION:\n ClinicalTrials.gov Identifier: NCT03355209.\",\n month = jun,\n year = 2022,\n language = \"en\"\n}\n\n","author_short":["Knupp, K. G","Scheffer, I. E","Ceulemans, B.","Sullivan, J. E","Nickels, K. C","Lagae, L.","Guerrini, R.","Zuberi, S. M","Nabbout, R.","Riney, K.","Shore, S.","Agarwal, A.","Lock, M.","Farfel, G. M","Galer, B. S","Gammaitoni, A. R","Davis, R.","Gil-Nagel, A."],"key":"Knupp2022-wb","id":"Knupp2022-wb","bibbaseid":"knupp-scheffer-ceulemans-sullivan-nickels-lagae-guerrini-zuberi-etal-efficacyandsafetyoffenfluramineforthetreatmentofseizuresassociatedwithlennoxgastautsyndromearandomizedclinicaltrial-2022","role":"author","urls":{},"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://bibbase.org/f/5E7ySfNJ4NonWuMQw/uploaded.bib","dataSources":["6Te7a6yS8tCGGz7BR","5Rtay2FDL2hDDEsad"],"keywords":[],"search_terms":["efficacy","safety","fenfluramine","treatment","seizures","associated","lennox","gastaut","syndrome","randomized","clinical","trial","knupp","scheffer","ceulemans","sullivan","nickels","lagae","guerrini","zuberi","nabbout","riney","shore","agarwal","lock","farfel","galer","gammaitoni","davis","gil-nagel"],"title":"Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial","year":2022}