52-Week Open-Label Safety and Tolerability Study of Centanafadine Sustained Release in Adults With Attention-Deficit/Hyperactivity Disorder

Abstract

Background:

Centanafadine (CTN) is a potential first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) currently in development for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. Safety, tolerability, and exploratory efficacy of CTN sustained release (SR) in adults were assessed over 52 weeks.

Methods:

Adults were enrolled after completing a phase 3 pivotal trial or de novo. The monitoring schedule employed a screening (up to 28 d for de novo group only), 52-week open-label, and 10-day safety follow-up periods. Participants received CTN SR 400 mg total daily dose, twice daily. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratories, vital signs, electrocardiogram measures, the Study Medication Withdrawal Questionnaire, and the Columbia-Suicide Severity Rating Scale. Exploratory efficacy was assessed using the Adult Investigator Symptom Rating Scale (AISRS) and the Clinical Global Impression of Severity (CGI-S). Safety was analyzed with a mixed-effect model; efficacy was reported using summary statistics.

Results:

Of 662 adults enrolled [mean (SD) age, 36.7 (10.1) y; 51.1% female; 82.9% white], 653 received CTN SR, and 345 completed the trial. Altogether, 61.4% reported ≥1 TEAE, mostly mild or moderate in severity; insomnia (8.0%), nausea (7.7%), diarrhea and headache (7.0% each) were most common. Eighty (12.3%) discontinued because of TEAEs. Serious adverse events occurred in 12 (1.8%) participants; none were CTN SR–related per investigators. AISRS total scores improved up to 57% and CGI-S by 1.5 points from baseline.

Conclusions:

Results from this trial demonstrate that CTN SR 400 mg is safe and effective for long-term treatment of adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a widespread neurodevelopmental disorder characterized by symptoms of pervasive inattention and/or hyperactivity/impulsivity that usually persist throughout a patient’s lifetime.^1–3 ADHD is associated with a multitude of mental health, behavioral, functional, and safety impairments.² Worldwide, the prevalence of ADHD in adults is estimated to be 3% to 5%. Although many cases of ADHD are diagnosed in school-aged children, research suggests that up to 75% of adults with ADHD remain undiagnosed during their youth,⁴ with some cases of ADHD surfacing only in adulthood.⁵ Despite growing awareness of ADHD, women and older adults with ADHD are frequently unidentified.⁶ It is estimated that 65% to 78% of children diagnosed with ADHD will continue to exhibit symptoms into adulthood,^7,8 and newer research indicates that over 90% of pediatric patients with ADHD will continue to experience challenges with symptoms at some point in adulthood.⁹

A prospective cohort study in Sweden, which examined data from national registers and identified 86,670 individuals with ADHD, revealed that people with ADHD face a higher risk of premature death compared with those without ADHD. While leading natural causes of death included neoplasms, neurological diseases, and circulatory system–related deaths, ADHD increased the risk of suicide by 8.63 times (95% CI: 6.27, 11.88) and the likelihood of unintentional injury by 3.94 times (95% CI: 2.49, 6.25) compared with those without ADHD. In addition, adults with ADHD often struggle with other comorbid psychiatric diagnoses, such as major depression, substance use disorders, anxiety, and bipolar disorder, with the risk of mortality increasing with each additional psychiatric comorbidity.^10–13 Furthermore, adults with ADHD experience higher unemployment rates, lower credit ratings, prolonged reliance on social welfare benefit receipt, elevated injury-related insurance claims, and greater impairments in mental health and feeling satisfied with their life and relationships when compared with their peers.^5,14

Current treatments for the core symptoms of ADHD include amphetamine and methylphenidate stimulants. These ADHD therapeutics are controlled (schedule II) substances in the United States that carry a bolded, boxed warning because of their high abuse potential. They are also associated with potentially troubling and serious adverse effects, including decreased appetite, insomnia, cardiovascular effects including increases in heart rate and blood pressure, mood lability, and the emergence of psychotic and/or manic symptoms in patients with no prior history of these symptoms.^15–20

Nonstimulants, which are nonscheduled treatments for ADHD, are generally less effective and slower in onset than stimulants,²¹ requiring 4 weeks or more to bring about their maximal effect.²² While nonstimulants are generally considered safe, they are associated with cardiovascular (increased heart rate and blood pressure), gastrointestinal, and psychiatric adverse events (AEs), with one carrying a black box warning for an increased risk of suicidal thoughts in children and adolescents.²²

Given the increased awareness of ADHD in general, and the growing concerns about stimulant misuse, inventory shortages, and lifelong persistence of ADHD symptoms have driven the U.S. Food and Drug Administration to encourage the development of alternative treatment options for the management of ADHD.²³

Centanafadine (CTN), a potential first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI),²⁴ may be one such option. In a prior phase 2 trial in adults with ADHD, twice-daily CTN sustained release (SR) significantly reduced the core symptoms of ADHD as measured by mean ADHD Rating Scale IV total score reduction from baseline to week 3 versus placebo [least squares (LS) mean, −16.5 vs −8.4, respectively; P < 0.001; effect size, 0.66], with significant efficacy demonstrated as early as week 1 and a favorable tolerability profile.²⁵ In 2 pivotal phase 3, randomized, double-blind, placebo-controlled clinical trials of 6 weeks’ duration (NCT03605680 and NCT03605836), CTN SR, at 200 and 400 mg total daily dose (TDD) administered twice daily, significantly improved mean AISRS total scores from baseline at week 6, by 25.5% to 32.2% for participants who were treated with CTN 200 mg/d and 24.6% to 32.2% for participants who were treated with CTN 400 mg/d, versus 17.7% to 24.2% for participants who received placebo.²⁶

The primary objective of this phase 3, 52-week open-label, multicenter study (clinicaltrials.gov identifier NCT03605849) was to assess the long-term safety and tolerability of CTN SR, at 400 mg TDD administered twice daily for 1 year, in the treatment of adults with ADHD. Exploratory efficacy findings are also reported.

METHODS

Ethics

This phase 3, 52-week, open-label, multicenter trial was conducted from February 2019 to September 2021 at 98 sites across the United States. The Institutional Review Board or independent ethics committee at each trial site approved the research protocol before patient enrollment. The study adhered to Good Clinical Practice Guidelines and ethical principles outlined in the Declaration of Helsinki. All participants provided written informed consent before engaging in any trial procedures.

Study Design

The primary endpoint of this trial was the long-term safety and tolerability of CTN SR 400 mg TDD, administered twice daily. This trial enrolled adults who had either rolled over from 1 of 2 previously conducted randomized, double-blind, placebo-controlled phase 3 pivotal trials or were enrolled de novo (Fig. 1).

FIGURE 1.

Study design. CTN SR indicates centanafadine sustained release; ET, end of treatment; TDD, total daily dose.

For adults who rolled over, this trial had 2 periods: 52-week open-label treatment, and 10-day safety follow-up. Assessments from the 7-day follow-up visit of the antecedent double-blind trials were used as baseline assessments for participating rollover patients. Participants who discontinued from either of the prior 2 phase 3 pivotal trials were ineligible for enrollment.

Participants who enrolled de novo went through a screening period (up to 28 d) before study entry during which the Mini International Neuropsychiatric Interview was used to confirm that ADHD was the primary diagnosis and to identify and exclude other psychiatric conditions. A medication washout period ranging from 7 to 28 days was used to discontinue disallowed drugs, including a washout of ≥7 days for stimulants and ≥21 days for nonstimulants. After screening and washout, de novo participants returned to the clinic for reassessment of eligibility criteria and establishment of baseline measures. Thereafter, de novo participants went through the same open-label treatment and follow-up periods as described for the rollover participants.

During open-label treatment, all rollover and de novo participants returned to the clinic for evaluation at the end of weeks 1, 2, 4, 8, 12, 16, 20, 26, 32, 38, 44, and 52/early termination. All participants (completers and early withdrawals) were evaluated for safety during a follow-up period lasting 10 days (follow-up telephone call on days 1, 3, and 5, in-clinic visit on days 2 and 7, and a follow-up telephone call on day 10) after the last dose of study drug was received.

Participants

Full inclusion and exclusion criteria are provided as supplemental material for participants eligible to rollover from prior phase 3 pivotal trials, and for those who could enroll de novo (Supplemental Tables S1–S4, http://links.lww.com/JCP/A957). In brief, adults (18–55 y of age) from both groups met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for ADHD² and, in the opinion of the investigator, could potentially benefit from CTN treatment. Any uncontrolled comorbid psychiatric disorder, no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medicine(s), and positive alcohol or drug screen were exclusionary.

Treatments

After the completion of baseline evaluations on day −1, all participants began treatment with twice-daily (ie, in the morning and 4 to 6 h later) CTN SR 200 mg TDD on days 1 to 7, with up-titration to the target 400 mg TDD of CTN SR on day 8. The dose was to remain fixed thereafter through week 52. If any tolerability issues occurred with CTN SR 400 mg TDD, a temporary decrease to CTN SR 200 mg TDD could be considered based on clinical judgment of the investigator.

Outcomes and Assessments

The primary endpoint in this trial was the long-term safety and tolerability of CTN SR 400 mg TDD, administered twice daily. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), quantified by amount and severity, including relevant TEAEs resulting in study discontinuation and serious TEAEs. Additional safety assessments included standard clinical laboratory investigations (hematology, serum chemistry, and urinalysis), physical examinations (clinically relevant abnormal changes were reported as TEAEs), vital signs, and electrocardiograms (ECGs). Suicidal ideation and behavior were measured using the Columbia-Suicide Severity Rating Scale (C-SSRS), a semistructured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors.²⁷

The Study Medication Withdrawal Questionnaire (SMWQ) was used to measure symptoms of withdrawal after the end of the treatment period. The SMWQ is a modification of the Amphetamine Withdrawal Questionnaire, in which the terms “amphetamine” and “methamphetamine” are replaced with “study medication.”²⁸ SMWQ scores range from 0 to 40; higher scores indicate greater severity of withdrawal symptoms.

All efficacy assessments were exploratory in nature and included measurements of the Adult ADHD Investigator Symptom Rating Scale (AISRS) and Clinical Global Impression–Severity of Illness (CGI-S) scale.²⁹ The AISRS, a modified version of the ADHD Rating Scale IV, assesses the impact and severity of adult symptoms of ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, through a semistructured interview method. The rating scale measures the presence of 9 inattentive items and 9 hyperactive/impulsive items, evaluated on a scale of 0 to 3 (0 = none, 1 = mild, 2 = moderate, and 3 = severe); maximum total score is 54 points, 27 points for each subscale.³⁰ The CGI-S scale is a clinician-rated assessment of mental illness severity scored from 1 (normal, not at all ill) to 7 (most extremely ill).³¹ Discontinuation for lack of efficacy was also assessed.

Statistical Methods

The sample size required for this trial was not based on statistical power considerations but on International Conference on Harmonization and Good Clinical Practice requirements. It was expected that ∼560 rollover participants from the previous double-blind phase 3 trials and ∼145 de novo participants would be enrolled.

Safety analyses were conducted on the safety sample (ie, all participants who received ≥1 dose of study drug); summary statistics are categorized by the parent study treatment group for rollover participants, for de novo participants, and overall.

Descriptive statistics for exploratory efficacy assessments were summarized for each measure (ie, AISRS, CGI-S, and discontinuation for lack of efficacy). These summaries are presented by the parent study treatment group for rollover participants, de novo participants, and overall. Baseline was defined as the last available measurement before the first dose of open-label CTN SR in the open-label treatment period. The mixed-effect model for repeated measures with an unstructured variance–covariance structure was fitted to the change from baseline in AISRS total and subscale scores and in CGI-S score at each visit based on the observed-cases data set. The model included fixed class-effect terms for treatment, trial center, and visit day and an interaction term for treatment by visit day. The model also included baseline values of AISRS total score for the open-label treatment period and the interaction term of baseline AISRS total scores by visit day as covariates. If the model was not converged, the alternative structured covariance matrix was sequentially explored with an empirical estimate of SE to accommodate potential model misspecification. Least squares means with 95% CIs will be reported to summarize efficacy. The last observation carried forward (LOCF) data set at last visit will be analyzed using analysis of covariance (ANCOVA) with treatment, trial center and baseline score as covariates as sensitivity analysis.

RESULTS

Patient Disposition

A total of 662 participants enrolled in the trial (prior 200 mg CTN SR, n = 156; prior 400 mg CTN SR, n = 151; prior placebo, n = 187; de novo, n = 168); 653 (98.6%) participants were treated with twice-daily CTN SR (400 mg TDD; Table 1). In total, 345 (52.1%) participants completed the trial, and 308 (46.5%) discontinued. The most commonly reported reasons for discontinuation were participant withdrawal [n = 119 (18.0%)], TEAEs [n = 80 (12.3%)], and being lost to follow-up [n = 41 (6.2%)]; 22 (3.3%) discontinued for lack of efficacy. The safety population included 653 participants [prior CTN SR 200 mg, n = 154 (98.7%); prior CTN SR 400 mg, n = 149 (98.7%); prior placebo, n = 184 (98.4); de novo, n = 166 (98.8%)].

TABLE 1.

Patient Demographics and Baseline Characteristics

Characteristic	Prior CTN SR 200 mg (n = 156)	Prior CTN SR 400 mg (n = 151)	Prior Placebo (n = 187)	De Novo (n = 168)	Total (N = 662)
Age (y),* mean (SD)	36.9 (10.2)	37.2 (10.7)	36.0 (9.8)	36.8 (9.7)	36.7 (10.1)
Sex,* n (%)
Male	80 (51.3)	75 (49.7)	93 (49.7)	75 (44.6)	323 (48.8)
Female	76 (48.7)	76 (50.3)	94 (50.3)	92 (54.8)	338 (51.1)
Race,* n (%)
White	121 (77.6)	122 (80.8)	162 (86.6)	144 (85.7)	549 (82.9)
Black	19 (12.2)	21 (13.9)	16 (8.6)	10 (6.0)	66 (10.0)
Asian	7 (4.5)	1 (0.7)	6 (3.2)	9 (5.4)	23 (3.5)
American Indian or Alaska Native	0	2 (1.3)	1 (0.5)	1 (0.6)	4 (0.6)
Native Hawaiian or Other Pacific Islander	1 (0.6)	0	0	0	1 (0.2)
Other	8 (5.1)	5 (3.3)	2 (1.1)	3 (1.8)	18 (2.7)
Ethnicity,* n (%)
Hispanic or Latino	34 (21.8)	36 (23.8)	35 (18.7)	50 (29.8)	155 (23.4)
BMI (kg/m2), mean (SD)	29.1 (7.3)	29.1 (6.4)	28.5 (7.8)	28.6 (5.0)	28.8 (6.7)
AISRS score, mean (SD)	32.6 (10.8)	32.6 (11.2)	34.9 (10.2)	37.1 (8.5)	34.4 (10.3)

^*n = 661.

AISRS indicates Adult ADHD Investigator Symptom Rating Scale; BMI, body mass index; CTN SR, centanafadine sustained release.

Demographic and Baseline Characteristics

Participant demographics and baseline clinical characteristics were similar across groups (Table 1). Most enrolled participants were female, white, and of non-Hispanic ethnicity. Enrollees were 18 to 56 years of age (mean age, 36.7 y) and had a mean body mass index of 28.8 kg/m². The overall mean (SD) baseline AISRS score was 34.4 (10.3).

Safety and Tolerability

Treatment-Emergent Adverse Events

A total of 401 (61.4%) participants in the safety population experienced a TEAE (Table 2). Most TEAEs were mild (n = 294; 45.0%) or moderate (n = 236; 36.1%) in severity; 16 (2.5%) TEAEs were considered severe. The most commonly reported TEAEs were insomnia (n = 52; 8.0%), nausea (n = 50; 7.7%), and diarrhea and headache (n = 46; 7.0% for each). The most commonly reported treatment-related TEAEs were decreased appetite (n = 40; 6.1%), nausea (n = 38; 5.8%), and insomnia (n = 35; 5.4%). In total, 80 (12.3%) participants discontinued CTN SR because of a TEAE. Only nausea (n = 12; 1.8%), anxiety (n = 10; 1.5%), and diarrhea (n = 8; 1.2%) resulted in discontinuation of ≥1% of participants.

TABLE 2.

Treatment-Emergent Adverse Events

Event, n (%)	Prior CTN SR 200 mg (n = 154)	Prior CTN SR 400 mg (n = 149)	Prior Placebo (n = 184)	De Novo (n = 166)	Total (N = 653)
Any TEAE	98 (63.6)	89 (59.7)	123 (66.8)	91 (54.8)	401 (61.4)
Serious TEAEs	1 (0.6)	1 (0.7)	7 (3.8)	3 (1.8)	12 (1.8)
TEAEs leading to discontinuation	20 (13.0)	21 (14.1)	29 (15.8)	10 (6.0)	80 (12.3)
Possibly abuse potential–related TEAEs	9 (5.8)	5 (3.4)	7 (3.8)	10 (6.0)	31 (4.7)
TEAEs with incidence ≥5%
Insomnia	9 (5.8)	10 (6.7)	19 (10.3)	14 (8.4)	52 (8.0)
Nausea	11 (7.1)	7 (4.7)	19 (10.3)	13 (7.8)	50 (7.7)
Diarrhea	11 (7.1)	6 (4.0)	13 (7.1)	16 (9.6)	46 (7.0)
Headache	7 (4.5)	11 (7.4)	14 (7.6)	14 (8.4)	46 (7.0)
Decreased appetite	6 (3.9)	7 (4.7)	16 (8.7)	14 (8.4)	43 (6.6)
Anxiety	8 (5.2)	6 (4.0)	12 (6.5)	11 (6.6)	37 (5.7)
Nasopharyngitis	8 (5.2)	5 (3.4)	16 (8.7)	4 (2.4)	33 (5.1)
Upper respiratory tract infection	6 (3.9)	8 (5.4)	11 (6.0)	5 (3.0)	30 (4.6)

CTN SR indicates centanafadine sustained release; TEAE, treatment-emergent adverse event.

In total, there were 16 serious TEAEs reported in 12 (1.8%) participants, with 7 (3.8%) of these occurring in participants who previously received placebo and 3 (1.8%) in those who enrolled de novo. Participants who had previously received placebo reported serious AEs (SAEs) of angina pectoris and suspected COVID-19, stress urinary incontinence, intraductal proliferative breast lesion, diverticulitis, upper respiratory tract infection, vertigo positional, intentional self-injury, mood swings, and obesity. SAEs of intentional self-injury and suicidal ideation, ureterolithiasis and sepsis, and malignant melanoma in situ were reported in participants who had enrolled de novo. SAEs were assessed by the investigators and the sponsor independently and deemed not related to CTN SR treatment. No deaths were reported during the study.

There were no reports of euphoric mood, a symptom that may be indicative of the potential for abuse, over the 52-week open-label treatment period, as was also the case in each of the antecedent pivotal phase 3 trials. Likewise, there were no reports of other abuse potential–related TEAEs, including disorientation, hallucinations of any kind, dissociation, confusional state, or craving.

Clinical Laboratory Measures

No trends were observed for changes in serum chemistry, hematology, or urinalysis values during the trial. Fifteen (2.3%) participants had laboratory test abnormalities recorded as TEAEs, including 4 (2.7%) and 3 (1.9%) participants with prior exposure to CTN SR 400 or 200 mg TDD, respectively, 5 (2.7%) participants previously exposed to placebo, and 3 (1.8%) who enrolled de novo. None were considered SAEs. Only 1 TEAE, pollakiuria, was considered related to study drug, but it resolved with no dosage change. There were no potential liver injury–related laboratory test abnormalities. Six (0.9%) participants had a TEAE of increased blood creatine phosphokinase of mild to moderate severity and were considered not related to CTN SR by the investigator.

Vital Signs

Occasional changes from baseline in vital sign parameters were reported; however, no trends were observed. Forty-four participants [10 (6.5%) with prior exposure to CTN SR 200 mg, 11 (7.4%) with prior exposure to CTN SR 400 mg, 14 (7.6%) with prior exposure to placebo, and 9 (5.4%) de novo participants] had an abnormality in their vital sign parameters recorded as a TEAE; none were considered SAEs. These TEAEs included 16 instances of increased blood pressure, 9 of increased heart rate, 7 of increased temperature, and 16 focused on weight (weight decreased, n = 11; weight increased, n = 5). One (0.2%) mild case of increased blood pressure was observed in a participant who was discharged from the study for noncompliance; 2 (0.3%) cases of moderate hypertension led to discontinuation.

Electrocardiograms

No trends were observed in ECG parameter changes. Ten (1.5%) participants had an ECG abnormality recorded as a TEAE: 1 (0.6%) and 3 (2.0%) participants with prior exposure to CTN SR 200 mg or 400 mg TDD, respectively; 1 (0.5%) participant with prior placebo exposure, and 5 (3.0%) de novo participants. None of the abnormalities were SAEs, and all of them were considered unrelated to the study drug. Tachycardia was observed in 6 (0.9%) participants 3 instances were considered drug related and resolved during the trial, 1 after a dose reduction and 2 without a dose change. The 3 other instances of tachycardia were considered unrelated to the study drug, including 1 case that led to discontinuation from the trial and was ongoing at the time of discontinuation.

Columbia Suicide Severity Rating Scale

Thirteen (2.0%) participants reported suicidality during the trial, as assessed by the C-SSRS. This included 12 (1.8%) with suicidal ideation (expressing a “wish to be dead” in each case) and 1 (0.2%) instance initially recorded as suicidal behavior. However, upon investigator review, the instance of suicidal behavior was reclassified as nonsuicidal self-injurious behavior, as the participant reported cutting to “relieve the pain, not to take life.” Four (0.6%) incidents of suicidal ideation were recorded as TEAEs during the trial, with none considered severe. No participants had emergent suicidal behavior or worsening of suicidal ideation during treatment with CTN SR.

Study Medication Withdrawal Questionnaire

SMWQ scores were assessed for 10 days after the last dose of study drug. The mean (SD) SMWQ score at week 52 was 5.6 (5.8) and remained <10 throughout the follow-up period, providing no signal of drug withdrawal symptoms with CTN SR.

Efficacy

Adult Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale Scores

In total, 642 (98.3%) adults received ≥1 dose of CTN SR and had ≥1 postbaseline AISRS total score assessment. The mean (SD) AISRS total scores were 32.6 (10.8), 32.6 (11.3), 34.9 (10.2), and 37.1 (8.5) in the prior treatment of CTN SR 200 mg/d, CTN SR 400 mg/d, placebo, and de novo groups, respectively, at baseline. At week 52, respective mean (SD) AISRS total scores were 14.6 (11.3), 11.7 (9.5), 14.3 (11.5), and 14.5 (9.2). These scores reflect LS mean (SE) changes from baseline of −17.6 (1.1), −18.5 (1.2), −18.7 (1.1), and −18.2 (1.8), among the respective treatment groups (Fig. 2A), representing a 49.1% to 56.7% improvement in AISRS total scores from baseline.

FIGURE 2.

Least squares mean change in AISRS total (A), hyperactive/impulsive subscale (B), and inattentive subscale (C) score changes over 52 weeks of open-label CTN SR therapy by prior treatment. ADHD indicates attention-deficit/hyperactivity disorder; AISRS, Adult ADHD Investigator Symptom Rating Scale; BL, baseline; CI, confidence interval; CTN SR, centanafadine sustained release; LS, least squares.

The mean (SD) AISRS hyperactive/impulsive subscale scores for participants in the prior treatment of CTN SR 200 mg/d, CTN SR 400 mg/d, placebo, and de novo groups were 14.5 (5.9), 14.7 (6.3), 15.3 (6.1), and 16.3 (5.5), respectively, at baseline. At week 52, LS mean (SE) changes from baseline for the AISRS hyperactive/impulsive subscale score were −8.1 (0.6), −8.8 (0.6), −8.7 (0.5), and −7.4 (0.8), respectively (Fig. 2B), representing an improvement of 45.4% to 59.8% in AISRS hyperactive/impulsive subscale scores from baseline.

The mean (SD) AISRS inattentive subscale scores were 18.1 (6.0), 17.9 (6.3), 19.6 (5.5), and 20.9 (4.4) in the prior treatment of CTN SR 200 mg/d, CTN SR 400 mg/d, placebo, and de novo groups, respectively, at baseline. At week 52, the LS mean (SE) changes from baseline for the AISRS inattentive subscale score were −9.7 (0.7), −10.0 (0.7), −10.0 (0.6), and −10.8 (1.1), respectively (Fig. 2C), representing a 51.3% to 55.6% improvement in AISRS inattentive subscale scores from baseline.

Using LOCF data set for prior treatment of CTN SR 200 mg/d, CTN SR 400 mg/d, placebo, and de novo groups, the LS mean (SE) changes at last visit were: −15.7 (1.2), −15.9 (1.2), −15.6 (1.1) and −12.2 (2.5) for AISRS total scores; −7.2 (0.6), −7.3 (0.6), −7.2 (0.6) and −4.6 (1.2) for AISRS hyperactive/impulsive subscale scores; −8.4 (0.7), −8.6 (0.7), −8.3 (0.7) and −7.6 (1.4) for AISRS inattentive subscale scores. All 95% CIs do not span zero, indicating improvement from baseline for all prior treatment and de novo groups.

Clinical Global Impression–Severity of Illness Scale Scores

The overall mean (SD) baseline CGI-S score for participants was 4.2 (0.9). Mean (SD) CGI-S score decreased (ie, improved) by 1.5 (1.1) points at week 52 with CTN SR treatment—a decrease that is considered clinically meaningful (Fig. 3).

FIGURE 3.

Mean CGI-S modified for ADHD scores decreased during CTN SR treatment. CGI-S scores progressively decreased (ie, improved) over the 52-week treatment period. Mean decreases were numerically similar between patients in the prior CTN 200 mg group, the prior CTN 400 mg group, the prior placebo group, and de novo patients. ADHD indicates attention-deficit/hyperactivity disorder; BL, baseline; CGI-S, Clinical Global Impression–Severity; CTN SR, centanafadine sustained release.

Discontinuation Due to Lack of Efficacy

Twenty-two (3.4%) participants discontinued from the study for lack of efficacy.

DISCUSSION

In this phase 3, 52-week open-label, multicenter trial, the long-term safety and tolerability of CTN SR 400 mg TDD, administered twice daily for the treatment of ADHD in adults, were demonstrated by the overall rate of TEAEs (61.4%) and the rate of associated discontinuations secondary to TEAEs (12.3%), which compare favorably with findings from previous open-label studies of currently approved treatments for ADHD in adults. These studies reported 12-month TEAE rates of 81.3% to 94.2% and associated discontinuation rates due to TEAEs of 8.0% to 19.9%.^32–37 In addition, in this trial, rates of SAEs were low, and none of the SAEs observed (1.8%) were considered by the investigator to be related to CTN SR.

Currently, treatment options available for ADHD include various formulations of methylphenidate and amphetamine, norepinephrine reuptake inhibitors, and α2-agonists.^38,39 A recent systematic review and network meta-analysis of randomized controlled trials emphasized that methylphenidate significantly increases systolic blood pressure compared with placebo in adults with ADHD. In contrast, amphetamines, atomoxetine, and methylphenidate significantly increase diastolic blood pressure compared with placebo in both children and adults with ADHD.³⁸ In addition to blood pressure considerations, several commonly prescribed ADHD medications—including methylphenidate, amphetamines, lisdexamfetamine, atomoxetine, and viloxazine—carry warnings for increased heart rate and potential for serious cardiac events.^{15–19,22,39}

Recognizing the serious implications of untreated ADHD is crucial, as it is associated with a markedly increased risk of premature death from various causes, both from natural and unnatural causes, in patients treated with the current standards of care. Particularly concerning are the associations with an 8-fold to 9-fold increased risk of death by suicide and a nearly 4-fold increased risk of death from unintentional injuries.¹³ Mood disorders and psychiatric adverse reactions, particularly anxiety and agitation, linked to current standards of ADHD care raise concerns for adults living with ADHD.¹⁵

Both atomoxetine and viloxazine are associated with risks for emergent suicidal ideation.^22,39 It is worth noting that during this trial, although 12 (1.8%) participants reported suicidal thoughts on the C-SSRS assessment, none exhibited self-injurious behaviors with suicidal intent or severe ideation during treatment with CTN SR, or had to discontinue the trial. Only 2 TEAEs leading to discontinuation were severe, involving a single case of anxiety and a case of decreased libido. These outcomes suggest that there is a low potential risk of exacerbation or emergence of existing or new psychiatric comorbidities during treatment with CTN SR. Furthermore, the mechanism of action of CTN, including the reuptake inhibition of norepinephrine, dopamine, and serotonin, suggests that CTN might be effective for comorbid depression and anxiety, which are common in adults with ADHD.

In addition, the absence of withdrawal signals in the SMWQ assessment and the lack of emergence of euphoric mood reinforce the notion that CTN SR is unlikely to be misused or be abused, aligning with prior findings from earlier pivotal phase 3 trials in adults.^25,26 Importantly, no new safety concerns emerged during this long-term trial that had not already been acknowledged in the previous pivotal trials in adults with ADHD.

Although findings from this open-label trial should be interpreted with caution due to the absence of a placebo group, the overall observed improvement of 49% to 57% in AISRS total scores and a clinically meaningful improvement of >1 in CGI-S scores over the course of this 52-week trial offer compelling evidence that CTN SR represents an effective treatment option for adults with ADHD.

Limitations

This study had several limitations. The absence of a placebo comparison group limits the conclusions regarding the effects of CTN SR compared with placebo or an active comparator. In addition, there may have been some degree of selection bias in the participants who rolled over from the phase 3 pivotal trials, as participants who, in the opinion of the investigator, were considered unlikely to benefit from CTN SR were unlikely to be enrolled in this study, which may affect the generalizability of our findings in individuals who have failed current stimulant or nonstimulant therapies. Another limitation affecting the generalizability of our findings is the exclusion of participants with comorbid psychiatric conditions, which are commonly reported in adults with ADHD. Women generally have been underdiagnosed and therefore underrepresented in ADHD research. In this trial, our demographics better represent the current ADHD landscape, as women made up 51.1% of the total trial population (range, 48.7% to 54.8% across subgroups).

CONCLUSIONS

Overall, CTN SR 400 mg TDD was safe and well tolerated when administered twice daily to adults with ADHD for up to 52 weeks, as evidenced by the occurrence of no new safety findings, low overall incidence of serious TEAEs and SAEs, and rates of discontinuation attributed to TEAEs. Combined with the results of the pivotal phase 3 trials, CTN has demonstrated persistent effectiveness with continued improvement in the treatment of core ADHD symptoms as early as week 1 after initiation and for up to 52 weeks after. CTN’s relatively quick onset of efficacy and sustained effectiveness highlight its value as a nonstimulant treatment option for the treatment of ADHD in adults.