<p>Safety and Efficacy of Centanafadine Sustained-Release in Adults With Attention-Deficit Hyperactivity Disorder: Results of Phase 2 Studies</p>

Abstract

Purpose: Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD). Patients and Methods: In a phase 2a, flexible-dose, single-blind study, 41 male patients (aged 18-55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200-300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18-60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score. Results: In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (P<0.001). In the phase 2b study, centanafadine-SR treatment resulted in a statistically significant improvement in ADHD-RS-IV from baseline to week 3 compared with placebo (least-squares mean −16.5 vs −8.4; P<0.001; effect size 0.66), with significant efficacy demonstrated as early as week 1. Centanafadine-SR was generally well tolerated at doses ≤400 mg. Most treatmentemergent adverse events (TEAEs) were mild or moderate; decreased appetite, headache, and nausea were the most frequently reported. In the 2 studies, 13 of 120 patients discontinued centanafadine-SR due to TEAEs; however, only 1 patient who received ≤400 mg discontinued due to a TEAE. No serious TEAEs were reported at any dose. Conclusion: These results support the continued development of centanafadine-SR at doses up to 400 mg/d.

Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents

“…CTN-SR was significantly superior to placebo (effect size, 0.66). 30 The most frequently reported treatmentrelated AEs were decreased appetite (24%), headache (23%), and nausea (20%); 10% of subjects discontinued CTN-SR due to AEs. Clinically significant ECG changes were not observed.…”

“…dosing in ADHD. 29,30 In a microdialysis study in conscious rats, CTN increased extracellular NE, DA, and serotonin (5-HT) concentrations from baseline by approximately twofold in the prefrontal cortex; striatal extracellular DA was also increased nearly twofold. 29 A study in healthy volunteers supported dose-related brain occupancy of CTN-SR on NET, SERT, and DAT.…”

“…In light of the ability of CTN-SR to increase DA, the drug's abuse potential was evaluated in an exploratory crossover-design study in healthy recreational stimulant users, comparing an immediate-release (IR) formulation of CTN with d-amphetamine and lisdexamfetamine. 29,30 The subjective effects profile of CTN-IR was different from that of the stimulants. With CTN-IR, aversive effects (dislike) during the initial period when CTN exposure was rapidly increasing were followed by increased "like" mean scores that were numerically lower vs stimulants.…”

“…Results of two Phase 2 studies have been published 30 . In a pilot, single-blind, flexible-dose (target dose, 500 mg/day), 4-week study in adults with ADHD (N = 41), CTN-SR was associated with significant reductions in ADHD symptoms vs baseline 30 .…”

“…Results of two Phase 2 studies have been published 30 . In a pilot, single-blind, flexible-dose (target dose, 500 mg/day), 4-week study in adults with ADHD (N = 41), CTN-SR was associated with significant reductions in ADHD symptoms vs baseline 30 . A Phase 2b double-blind, crossover study (3-week treatment period; 1-week washout) in 85 adults compared CTN-SR (target dose, 400–800 mg/day) and placebo.…”