VANCOUVER, BC—An extended-release formulation of molindone shows promise as an adjunctive treatment for refractory impulsive aggression among children administered stimulant monotherapy for ADHD, according to authors of a multicenter, double-blind, placebo-controlled, parallel-group, Phase 2b dose-ranging study presented in a poster session at the 68th Annual AAN Meeting.
“Addition of SPN-810 to optimized ADHD therapy significantly reduced persistent impulsive aggressive behavior in children with ADHD,” reported lead study author Scott T. Brittain, PhD, of Supernus Pharmaceuticals, Inc., in Rockville, MD, and coauthors. “Preliminary data suggest that SPN-810 may be better tolerated than similar total daily dosage of molindone administered as an immediate-release formulation.”
The findings “support development of SPN-810 as adjunctive therapy targeting impulsive aggression in children with ADHD,” the authors wrote.
Impulsive aggression is common among children with ADHD, the researchers noted. Defined as “angry, immediate, and maladaptive retaliatory reaction arising out of frustration, annoyance, or hostility to real or perceived provocations,” impulsive aggression is a common clinical phenotype, “occurring in ~80% of aggressive children and more than half of preadolescent children with ADHD Combined subtype,” they reported. Parents rate patients’ impulsive aggression as a greater source of ADHD impairment than core symptoms, the authors noted.
However, the FDA has not approved any medication specifically for managing refractory impulsive aggression in children with ADHD.
Extended-release formulations of neurmodulators “can significantly reduce side effects such as sedation vs. immediate-release (IR) counterparts,” the authors wrote. “SPN-810 is designed to deliver more constant plasma drug concentrations with longer dosing intervals vs. IR molindone,” they reported.
The researchers enrolled preadolescents (age 6 to 12 years) with ADHD who were receiving stimulant monotherapy for more than 1 month, who exhibited refractory impulsive aggression, as assessed using the Vitiello Aggression Scale (scoring -2 to -5) or Retrospective Modified Aggression Scale (R-MOAS; scoring at least 24 after initial screening and at least 20 after a 3-week open-label baseline period). The open-label phase allowed optimization of stimulant monotherapy and initiation of parent training.
A total of 118 study participants were randomly assigned to receive placebo or one of three dosing groups, stratified by patient body weight (<30kg or ≥30kg). For children <30kg, these doses were: Dose I group: 12mg/day (n=12); Dose II group: 24mg/day (n=15); and Dose III: 36 mg/day (n=14). For participants ≥30kg, the Dose I, II, and III group doses were: 18, 36 and 54mg/day (n=15, 15, and 17, respectively). There were 12 children <30kg in the placebo group and 18 placebo-group participants ≥30kg.
The double-blind component was 39 days, including a 9- to 18-day titration period and a 21- to 30-day maintenance period.
At Dose I and II, the intent-to-treat population’s median change from baseline in R-MOAS scores were -32.0 and -28.5, respectively (P values = 0.03 and 0.02, respectively), the authors reported. “Across doses, efficacy exhibited nonlinear dose-response profiles in which Dose II (24 or 36mg/day) produced maximum observed treatment effect, whereas mean score changes in placebo and Dose III groups were similar,” they wrote.
“SPN-810 exhibited no unexpected life-threatening or dose-limiting safety issues,” the coauthors reported. One child in the Dose III group exhibited suicidal ideation, a serious adverse event, but the investigator considered this unrelated to the study medication. No safety signals emerged from laboratory tests, vital signs, or ECG findings, the researchers reported.
Increases in weight and body-mass index (BMI) were “slightly larger with SPN-810 vs. placebo,” but this effect did not appear dose-related, they reported.
Dr. Brittain and other coauthors are employees of Supernus Pharmaceuticals, Inc.