title: Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures.
abstract: To evaluate the efficacy and safety of ganaxolone as adjunctive therapy in adults with uncontrolled partial-onset seizures despite taking up to three concomitant antiepileptic drugs (AEDs).
  
  
  
  Adults aged 18-69 years and refractory to conventional AEDs were enrolled in a multicenter, double-blind, placebo-controlled trial. After an 8-week baseline period, patients were randomized 2:1 to ganaxolone 1,500 mg/day or placebo for a 10-week treatment period (2-week forced titration and 8-week maintenance) followed by either tapering or entry into an open-label extension study. The primary endpoint was mean weekly seizure frequency. Secondary endpoints included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate), percent change in mean weekly seizure frequency, seizure-free days, and quality of life. Safety and tolerability assessments included adverse events (AEs), treatment discontinuation, and clinical laboratory evaluations. Efficacy analyses were performed on the intent-to-treat population.
  
  
  
  Of 147 randomized patients (98 ganaxolone, 49 placebo), 131 completed the study; 95% of participants titrated up to 1,500 mg/day and 78% maintained this dose. From baseline to endpoint, mean weekly seizure frequency decreased with ganaxolone (6.5-5.2) versus placebo (9.2-10.8), representing an 11.4% decrease versus placebo (p = 0.0489, analysis of covariance [ANCOVA]). Mean percent change from baseline was -17.6% with ganaxolone versus 2.0% with placebo (p = 0.0144, Kruskal-Wallis test). Responder rates were 24% with ganaxolone versus 15% with placebo (p = 0.19). Discontinuation due to adverse events was similar with ganaxolone (7.1%) and placebo (6.1%). Common adverse events were mild to moderate in severity and included dizziness (16.3% vs. 8.2%), fatigue (16.3% vs. 8.2%), and somnolence (13.3% vs. 2.0%).
  
  
  
  Ganaxolone 1,500 mg/day reduced partial-onset seizure frequency and was generally safe and well tolerated in this phase 2 study. These results support continued development of ganaxolone for adult patients with refractory partial-onset seizures.
authors.affiliation: Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sperling
authors.affiliation: Mid-Atlantic Epilepsy and Sleep Center, Bethesda, Maryland, U.S.A.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klein
authors.affiliation: Marinus Pharmaceuticals, Radnor, Pennsylvania, U.S.A.
authors.forename: Julia
authors.initials: J
authors.lastname: Tsai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011280:Pregnanolone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C105051:ganaxolone; D011280:Pregnanolone
keywords: Adjunctive therapy; Ganaxolone; Neurosteroid; Partial-onset seizures