Centanafadine Shows Promise for Pediatric and Adolescent ADHD in Phase 3 Trials
Key Insights
High-dose centanafadine (328.8 mg for adolescents, weight-based for children) demonstrated significant efficacy in reducing ADHD (search) symptoms compared to placebo in two separate phase 3 trials.
The norepinephrine, dopamine, and serotonin reuptake inhibitor showed rapid onset of action as early as week 1 and maintained therapeutic effects throughout the 6-week study periods.
Treatment-emergent adverse events were generally mild to moderate, with decreased appetite, nausea, headache, and rash being the most common side effects reported.
Two phase 3 clinical trials have demonstrated that centanafadine, an investigational norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI), significantly reduces ADHD (search) symptoms in both children and adolescents when administered at higher doses. The studies, published in Pediatrics Open Science and Journal of the American Academy of Child & Adolescent Psychiatry, represent important advances for this once-daily extended-release treatment being developed by Otsuka Pharmaceuticals (search).
Adolescent Trial Results Show Significant Symptom Reduction
The adolescent study, conducted at 48 sites from 2022 to 2023, enrolled 459 participants with a mean age of 14.7 years (59.3% male, 70.4% white). Researchers randomized participants to receive either 164.4 mg centanafadine, 328.8 mg centanafadine, or placebo for 6 weeks.
The higher dose demonstrated clear efficacy, with participants showing a mean reduction of -18.5 points on the ADHD (search) Rating Scale, version 5 (ADHD-RS-5) compared to -14.2 points for placebo (P = .0006). These improvements were evident as early as the first week and maintained throughout the study period (P = .001). The lower 164.4 mg dose showed a -15.5 point reduction but did not reach statistical significance compared to placebo.
"The results of this study demonstrate the general tolerability and clinical benefits of centanafadine, an NDSRI, in the treatment of ADHD (search) in an adolescent population," the researchers wrote.
Pediatric Population Shows Similar Benefits
The pediatric trial included 480 children aged 6 to 12 years, randomized to weight-based low-dose centanafadine (n = 154), high-dose centanafadine (n = 162), or placebo (n = 164). At week 6, the high-dose group achieved a mean change of -16.3 points (SE 1.2) on the ADHD (search)-RS-5 compared to -10.8 points (SE 1.2) for placebo (P < .001).
"High-dose CTN showed separation from placebo as early as week 1, the first postbaseline time point, with the effect maintained throughout the study period," the authors noted.
Secondary Endpoints Demonstrate Broad Therapeutic Impact
Both studies evaluated secondary endpoints that revealed centanafadine's effects beyond core ADHD (search) symptoms. In the adolescent trial, the 328.8 mg dose group showed significant improvements compared to placebo in inattention (mean difference, -6.63; 95% CI, -9.06 to -3.6), hyperactivity/impulsivity (mean difference, -5.52; 95% CI, -8.44 to -2.59), and executive functioning (mean difference, -4.92; 95% CI, -7.56 to -2.28) based on Conners 3-Parent Short content scale T-scores.
The pediatric study similarly found that high-dose centanafadine significantly improved symptoms of inattention, hyperactivity/impulsivity, and executive functioning as measured by the Conners 3-Parent Short content scales.
Safety Profile Shows Manageable Adverse Events
Treatment-emergent adverse events occurred across all groups in both studies but were generally mild to moderate in severity. In the adolescent trial, adverse events affected 31.4% of the 164.4 mg group, 50.3% of the 328.8 mg group, and 23.8% of the placebo group. The most common symptoms included decreased appetite, nausea, headache, and rash.
The pediatric study reported similar findings, with adverse events occurring in 39% of the high-dose group, 35% of the low-dose group, and 25% of the placebo group. The most commonly reported events were decreased appetite (5%), rash (3%), and vomiting (3%).
"The AE profile indicated a low likelihood of abuse," the pediatric study authors noted.
Serious adverse events were rare in both studies. Only one participant in the adolescent trial reported suicidality deemed related to the study drug, which was considered mild to moderate in severity. Severe events related to centanafadine were reported by three participants in the adolescent study, with two from the lower dose group leading to study discontinuation.
Clinical Implications and Future Directions
The completion rates were high in both studies, with 80.8% of adolescent participants and a similar proportion of pediatric participants completing the trials including safety follow-up periods. Response rates based on clinically meaningful reductions in ADHD (search)-RS-5 scores were significantly higher in the high-dose groups compared to placebo.
In the pediatric trial, 34% of participants in the high-dose centanafadine group achieved a ≥18-point reduction in ADHD (search)-RS-5 scores compared with 23% in the placebo group (P < .05).
Both research teams acknowledged study limitations including short duration, lack of active comparators, and limited generalizability beyond North American populations. The adolescent study also excluded teacher ratings on the ADHD (search)-RS-5 scale.
"The NDSRI CTN was found to be safe and well tolerated for the treatment of ADHD (search) in children aged 6 to 12 years," the pediatric study authors concluded. "This study found that the high dose was efficacious for the short-term treatment of ADHD in the population studied."
Future research priorities include long-term treatment outcomes, comparative efficacy studies with existing ADHD (search) treatments, and evaluation of centanafadine's effects in treating ADHD with comorbid conditions.