A matching-adjusted indirect comparison of centanafadine versus lisdexamfetamine, methylphenidate and atomoxetine in adults with attention-deficit/hyperactivity disorder: long-term safety and efficacy

Abstract

Aim: To compare long-term safety and efficacy outcomes of centanafadine versus lisdexamfetamine dimesylate (lisdexamfetamine), methylphenidate hydrochloride (methylphenidate) and atomoxetine hydrochloride (atomoxetine), respectively, in adults with attention-deficit/hyperactivity disorder (ADHD) using matching-adjusted indirect comparisons (MAICs). Patients & methods: Patient-level data from a centanafadine trial (NCT03605849) and published aggregate data from a lisdexamfetamine trial (NCT00337285), a methylphenidate trial (NCT00326300) and an atomoxetine trial (NCT00190736) were used. Patient characteristics were matched in each comparison using propensity score weighting. Study outcomes were assessed up to 52 weeks and included safety (rates of adverse events [AEs]) and efficacy (mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale [AISRS] or ADHD Rating Scale [ADHD-RS] score). Results: In all comparisons of matched populations, risks of AEs were statistically significantly lower with centanafadine or non-different between centanafadine and comparator; the largest differences in AE rates included upper respiratory tract infection (risk difference in percentage points: 18.75), insomnia (12.47) and dry mouth (12.33) versus lisdexamfetamine; decreased appetite (20.25), headache (18.53) and insomnia (12.65) versus methylphenidate; and nausea (26.18), dry mouth (25.07) and fatigue (13.95) versus atomoxetine (all p < 0.05). 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). Conclusion: 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.

Keywords: adverse events; attention-deficit/hyperactivity disorder; centanafadine; clinical trials; comparative effectiveness research; efficacy; indirect comparison; propensity score; treatment outcome.

Figure 1.. Comparisons of safety and efficacy between centanafadine and lisdexamfetamine.

Statistical significance was set at the 5% level. Green dots denote significantly in favor of centanafadine. Orange dots denote significantly in favor of lisdexamfetamine. Gray dots denote non-significance. Safety and efficacy outcomes were compared at week 52 (as available in the lisdexamfetamine trial). Analyses were matched on age, sex, race, ethnicity, height, weight, AISRS at baseline and CGI-S at baseline. ADHD-RS: Attention-Deficit/Hyperactivity Disorder Rating Scale; AISRS: Adult ADHD Investigator Symptom Rating Scale; CGI-S: Clinical Global Impression-Severity of Illness Scale.

Figure 2.. Comparisons of safety and efficacy between centanafadine and methylphenidate.

Statistical significance was set at the 5% level. Green dots denote significantly in favor of centanafadine. Gray dots denote non-significance. Safety outcomes were compared for centanafadine at week 52 vs methylphenidate at final observation (week 26 or week 52). Efficacy outcomes were compared between centanafadine at week 26 and methylphenidate at final observation (week 26 or week 52). Analyses were matched on age, sex, AISRS at baseline and CGI-S at baseline. AISRS: Adult ADHD Investigator Symptom Rating Scale; CGI-S: Clinical Global Impression-Severity of Illness Scale.

Figure 3.. Comparisons of safety and efficacy between centanafadine and atomoxetine.

Statistical significance was set at the 5% level. Green dots denote significantly in favor of centanafadine. Gray dots denote non-significance. Safety and efficacy outcomes were compared at week 26 (as available in the atomoxetine trial). Analyses were matched on age, sex, race, AISRS total score at baseline, AISRS inattentive and hyperactive/impulsive subscale score at baseline and CGI-S at baseline. AISRS: Adult ADHD Investigator Symptom Rating Scale; CGI-S: Clinical Global Impression-Severity of Illness Scale.

Figure 4.. Risk of adverse events with centanafadine vs respective comparators.

Adverse events (AEs) for which information was available in both trials in a given comparison. The timepoint for assessment was at week 52 for comparison with lisdexamfetamine, week 26/52 for comparison with methylphenidate, and week 26 for comparison with atomoxetine, as available in the respective comparator trials. The filled circles represent the proportions of people receiving centanafadine or comparator who experienced AEs after matching to adjust for differences in baseline characteristics across trials. The proportions may not match the forest plots due to rounding.