Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy : Results from two double-blind, randomized, placebo-controlled trials
© 2022 UCB BioSciences GmbH. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy..
OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials.
METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled.
RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55).
SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
Epilepsia open - 7(2022), 4 vom: 01. Dez., Seite 758-770 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rademacher, Michael [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.12.2022 Date Revised 29.12.2022 published: Print-Electronic ClinicalTrials.gov: NCT03373383, NCT03739840 Citation Status MEDLINE |
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| doi: |
10.1002/epi4.12656 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM34691583X |
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| 100 | 1 | |a Rademacher, Michael |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy |b Results from two double-blind, randomized, placebo-controlled trials |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 02.12.2022 | ||
| 500 | |a Date Revised 29.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT03373383, NCT03739840 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 UCB BioSciences GmbH. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. | ||
| 520 | |a OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials | ||
| 520 | |a METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled | ||
| 520 | |a RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55) | ||
| 520 | |a SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a antiepileptic drug | |
| 650 | 4 | |a antiseizure medication | |
| 650 | 4 | |a dual mechanism of action | |
| 650 | 4 | |a focal seizure | |
| 650 | 4 | |a synaptic vesicle protein 2 | |
| 650 | 4 | |a tolerability | |
| 650 | 7 | |a padsevonil |2 NLM | |
| 650 | 7 | |a 0R1HN52K0N |2 NLM | |
| 650 | 7 | |a Anticonvulsants |2 NLM | |
| 700 | 1 | |a Toledo, Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Van Paesschen, Wim |e verfasserin |4 aut | |
| 700 | 1 | |a Liow, Kore K |e verfasserin |4 aut | |
| 700 | 1 | |a Milanov, Ivan G |e verfasserin |4 aut | |
| 700 | 1 | |a Esch, Maria-Luise |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Nan |e verfasserin |4 aut | |
| 700 | 1 | |a MacPherson, Merran |e verfasserin |4 aut | |
| 700 | 1 | |a Byrnes, William J |e verfasserin |4 aut | |
| 700 | 1 | |a Minh, Timothy D C |e verfasserin |4 aut | |
| 700 | 1 | |a Webster, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Werhahn, Konrad J |e verfasserin |4 aut | |
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