centanafadine SR (EB-1020) / Otsuka - LARVOL DELTA

Improvement in Caregiver-Rated Executive Functioning Following Centanafadine Treatment in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder (PAS 2025) - "In patients treated with high-dose CTN, a greater difference than placebo in the mean change from baseline at Week 6 in Executive Functioning T-score was observed for both children (mean change [standard error]: CTN, −11.3 [1.12]; placebo, −6.8 [1.11], P=0.0026) and adolescents (CTN, −13.0 [1.01]; placebo, −8.1 [0.99], P=0.0003). Significant improvements with high-dose CTN versus placebo were observed as early as Week 1 in children (P=0.0073) and Week 2 in adolescents (P=0.0047), with effects sustained or further improved with continued treatment. Adverse events were generally mild to moderate."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Mental Retardation • Pediatrics • Psychiatry

Efficacy of Centanafadine on the Conners 3 Learning Problems Content Scale in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder (PAS 2025) - "Overall, 76.5% (367/480) of children (mean age 9.2y, 58.3% male) and 80.8% (371/459) of adolescents (mean age 14.7y, 59.3% male) completed their respective studies. At Week 6 a significant mean change from baseline in Learning Problems Content Scale T-scores was observed with high-dose CTN compared to placebo in children (mean change [standard error]: −8.2 [0.95] vs placebo −2.8 [0.93], P< 0.0001) and in adolescents (PS: −8.0 [0.92] vs placebo −3.1 [0.90], P< 0.0001; SRS: −6.1 [0.86] vs placebo −2.5 [0.85], P=0.0023). Low-dose CTN also demonstrated a significant effect compared to placebo at Week 6 in children (−5.47 [0.97] vs placebo −2.81 [0.93], P=0.0393)."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Mental Retardation • Pediatrics • Psychiatry

Evaluation of the Efficacy and Safety of EB-1020 in Adult ADHD Patients (clinicaltrials.gov) - P2/3 | N=630 | Recruiting | Sponsor: Otsuka Pharmaceutical Co., Ltd.

New P2/3 trial • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

A Trial of Centanafadine Long-term Safety in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD) (clinicaltrials.gov) - P3 | N=680 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Jan 2027 ➔ Mar 2026 | Trial primary completion date: Jan 2027 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

A Long-term Trial of EB-1020 in Adult Patients With ADHD (clinicaltrials.gov) - P3 | N=180 | Recruiting | Sponsor: Otsuka Pharmaceutical Co., Ltd.

New P3 trial • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

A Trial of Centanafadine Efficacy and Safety in Children With Attention-deficit/ Hyperactivity Disorder (ADHD) (clinicaltrials.gov) - P3 | N=574 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

A Trial of Centanafadine Efficacy and Safety in Children With Attention-deficit/ Hyperactivity Disorder (ADHD) (clinicaltrials.gov) - P3 | N=574 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2025 ➔ Mar 2025 | Trial primary completion date: Oct 2025 ➔ Mar 2025

Enrollment closed • Trial completion date • Trial primary completion date • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Conducting clinical trials with self-collection of pharmacokinetic samples: Experience from an exploratory, phase 1, open-label trial of centanafadine SR in healthy individuals. (PubMed, Contemp Clin Trials Commun) - "Participants favored self-collection over staff collection, having visits in their own location, and would consider participation in similar future research. Results from this decentralized PK trial, with remote, in-home sample collection and monitoring, demonstrated the potential feasibility of this study design."

Journal • P1 data • PK/PD data • Infectious Disease • Novel Coronavirus Disease

At-Home Self-Collection of Pharmacokinetic Data: Design and Results From a Phase 1 Open-Label Feasibility Trial. (PubMed, Clin Pharmacol Drug Dev) - "We present the design of a Phase 1, open-label, fixed-sequence, PK trial that aimed to compare the timing accuracy of participant- versus staff-collected data, and we provide safety and tolerability outcomes for centanafadine treatment...No adverse events were related to treatment. Overall, results support the feasibility of at-home collection of PK samples, ECGs, and vital signs."

Journal • P1 data • PK/PD data • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Treatment Preferences of Physicians Treating Adult Patients with Attention-Deficit/Hyperactivity Disorder in the United States and Canada: A Discrete Choice Experiment. (PubMed, Neurol Ther) - "Efficacy was the most important single attribute for physicians treating adult patients with ADHD in both the US and Canada; however, the risks of AEs taken together had greater relative importance than efficacy alone among US but not Canadian physicians. These findings highlight potential discrepancies in physician and patient preferences based on existing evidence and underscore the importance of shared decision-making, which may in turn increase patients' treatment satisfaction."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Xerostomia

Conners 3-Parent and -Self-Report Short Hyperactivity/Impulsivity and Inattention Content Scales in Adolescents With ADHD Treated With Centanafadine (AACAP 2024) - P3 | "High-dose CTN (328.8 mg) showed an early and sustained impact on improving core H/I and I symptoms in adolescents vs placebo for both caregiver and adolescent perceptions of symptom improvement.ADHD, RCT, SAC"

ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Efficacy and Safety of Once-Daily Extended-Release Centanafadine for the Treatment of ADHD in Children Aged 6–12 Years (CADDRA ADHD 2024) - P3 | "Overall, 367/480 (76.5%) randomized patients completed the study (mean age 9.2 years; 58% male). Change from baseline in ADHD-RS-5 symptoms total raw score at Week 6 was ‒16.3 for CTN high dose versus ‒10.8 for placebo (P=0.0008), with improvement seen from Week 1 (P=0.0009). Low-dose CTN did not meet the primary endpoint."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Pediatrics • Psychiatry

Efficacy and Safety of Once-Daily Extended-Release Centanafadine for the Treatment of ADHD in Adolescents Aged 13–17 Years (CADDRA ADHD 2024) - P3 | "Overall, 371/459 (80.8%) randomized patients completed the study (mean age 14.7 years; 59% male). The change from baseline in ADHD-RS-5 symptoms total raw score at Week 6 was ‒18.5 for CTN 328.8mg versus ‒14.2 for placebo (P=0.0006), with benefit seen from Week 1 (P=0.001). CTN 164.4mg did not meet the primary endpoint."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Pediatrics • Psychiatry

A matching-adjusted indirect comparison of centanafadine versus lisdexamfetamine, methylphenidate and atomoxetine in adults with attention-deficit/hyperactivity disorder: long-term safety and efficacy. (PubMed, J Comp Eff Res) - P3, P4 | "Centanafadine had a smaller reduction in the AISRS/ADHD-RS score versus lisdexamfetamine (6.15-point difference; p < 0.05) and no statistically significant difference in the change in AISRS score versus methylphenidate (1.75-point difference; p = 0.13) and versus atomoxetine (1.60-point difference; p = 0.21). At up to 52 weeks, centanafadine showed significantly lower incidence of several AEs than lisdexamfetamine, methylphenidate and atomoxetine; efficacy was lower than lisdexamfetamine and non-different from methylphenidate and atomoxetine."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Fatigue • Infectious Disease • Insomnia • Pain • Psychiatry • Respiratory Diseases • Sleep Disorder • Xerostomia

Treatment Preferences of Adult Patients with Attention-Deficit/Hyperactivity Disorder - A Discrete Choice Experiment. (PubMed, Patient Prefer Adherence) - "Overall preferences for treatment profiles approximating centanafadine, lisdexamfetamine, atomoxetine, and viloxazine were estimated using adjusted total utilities...Accordingly, a profile resembling that of centanafadine would be preferred by an average patient compared to key competitors due to its favorable safety profile. These findings may help improve treatment decision-making, enhance treatment satisfaction, and foster adherence."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Xerostomia

A Trial of Centanafadine Long-term Safety in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD) (clinicaltrials.gov) - P3 | N=700 | Enrolling by invitation | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Enrolling by invitation | Trial completion date: Nov 2024 ➔ Jan 2027 | Trial primary completion date: Nov 2024 ➔ Jan 2027

Enrollment status • Trial completion date • Trial primary completion date • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Assessment of centanafadine in adults with ADHD: a matching adjusted indirect comparison versus methylphenidate hydrochloride extended release (Concerta). (PubMed, Curr Med Res Opin) - P3, P4 | "While the safety results were robust across analyses, there was no difference in efficacy between centanafadine and methylphenidate hydrochloride ER in the sensitivity analysis. Considering its favorable safety profile, centanafadine may be preferred among patients for whom treatment-related adverse events are a concern."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Xerostomia

Efficacy and safety of monoamine reuptake inhibitors in attention deficit hyperactivity disorder: A Bayesian network meta-analysis. (PubMed, J Psychiatr Res) - "The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD...Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence."

Journal • Retrospective data • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Treatments in the pipeline for attention-deficit/hyperactivity disorder (ADHD) in adults. (PubMed, Neurosci Biobehav Rev) - "While several pharmacological and non-pharmacological interventions had evidence of superiority compared to the control condition from a single RCT, centanafadine (norepinephrine, dopamine, and serotonin re-uptake inhibitor) was the only treatment with evidence of efficacy on ADHD core symptoms (small effect size=0.28-0.40) replicated in at least one additional RCT, alongside reasonable tolerability. Overall, the body of ongoing RCTs in adults with ADHD is insufficient, without any intervention on the horizon to match the efficacy of stimulant treatment or atomoxetine and with better tolerability profile. Additional effective and well tolerated treatments for adults with ADHD require development and testing."

Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium. (PubMed, Expert Opin Pharmacother) - "The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor..."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Substance Abuse • Tic Disorders • Tourette Syndrome

Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release. (PubMed, J Manag Care Spec Pharm) - P3, P4 | "Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779."

Clinical • Journal • ADHD (Impulsive Aggression) • Anorexia • Attention Deficit Hyperactivity Disorder • CNS Disorders • Constipation • Erectile Dysfunction • Fatigue • Gastroenterology • Gastrointestinal Disorder • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Xerostomia

Recent advances in pharmacological management of attention-deficit/hyperactivity disorder: moving beyond stimulants. (PubMed, Expert Opin Pharmacother) - "Stimulants, such as amphetamine and methylphenidate, are available in more than two dozen formulations, but all have similar adverse effects and carry a risk of misuse and dependence...Two, including atomoxetine and viloxazine extended-release (ER), are approved by the Food and Drug Administration for the treatment of ADHD in children and adults. Two others, clonidine ER and guanfacine ER, are only approved for children and adolescents in the U.S. Several other compounds are under investigation. Drugs in Phase 3 trials include centanafadine, solriamfetol, and L-threonic acid magnesium salt...Lack of individual drug response and tolerability are reasons many stop treatment. Development of new nonstimulants may offer hope for patients who need medication alternatives."

Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Behavior Disorders • CNS Disorders • Mental Retardation • Psychiatry

A Trial of Centanafadine Efficacy and Safety in Children With Attention-deficit/ Hyperactivity Disorder (ADHD) (clinicaltrials.gov) - P3 | N=570 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Recruiting | Trial completion date: Oct 2023 ➔ Oct 2025 | Trial primary completion date: Oct 2023 ➔ Oct 2025

Enrollment open • Trial completion date • Trial primary completion date • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

A Matching-Adjusted Indirect Comparison of Centanafadine Vs Lisdexamfetamine, Methylphenidate, and Atomoxetine in Adults With Attention-Deficit/Hyperactivity Disorder: Long-Term Safety and Efficacy Outcomes (ISPOR 2024) - P3, P4 | "At up to 52 weeks, centanafadine showed significantly lower incidence of several AEs than lisdexamfetamine, methylphenidate, and atomoxetine; efficacy was lower than lisdexamfetamine and non-different from methylphenidate and atomoxetine. Future studies should evaluate patients’ and physicians’ valuations on treatment attributes and how tradeoff between safety and efficacy affects ADHD management."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Fatigue • Infectious Disease • Insomnia • Pain • Psychiatry • Respiratory Diseases • Sleep Disorder • Xerostomia

Treatment Preferences of Adult Patients With Attention-Deficit/Hyperactivity Disorder in Canada: A Discrete Choice Experiment (ISPOR 2024) - "Overall preferences for treatment profiles approximating centanafadine, lisdexamfetamine, atomoxetine, and viloxazine were estimated using adjusted total utilities... While efficacy was highly valued by patients when making treatment decisions, safety attributes together had a greater relative importance than efficacy alone. Accordingly, ADHD treatments with favorable safety profiles may be preferred by patients. A better understanding of attributes of ADHD treatments valued by patients may help improve shared decision-making, enhance treatment satisfaction, and foster adherence."

Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Xerostomia