A Trial of Centanafadine Efficacy, Safety, and Tolerability in Adult Subjects With Binge Eating Disorder

Binge eating day was defined as a day with at least one binge eating episode. Least squares (LS) mean was determined by Mixed-effect Model Repeated Measures (MMRM) method with change from baseline in binge eating days per week at scheduled visit as dependent variable and included fixed effect terms for treatment, trial center, visit week, and an interaction term of treatment by visit week.

Time frame: Baseline, Weeks 7 to 8

Population: Efficacy analysis set included all the randomized participants who received at least 1 dose of IMP and had a baseline value and at least 1 valid post-randomization efficacy evaluation within the double-blind treatment period.

The CGI-S is a standardized, clinician-administered global rating scale that measures disease severity on scale with a score range of 0 to 7 where, 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. A higher score on the CGI-S represents a higher severity of disease. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Week 8

Population: Efficacy analysis set included all the randomized participants who received at least 1 dose of IMP and had a baseline value and at least 1 valid post-randomization efficacy evaluation within the double-blind treatment period. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis. 'Number analyzed' is the number of participants with data available for analysis at the specified timepoint.

The HAM-A scale assesses both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). It consists of 14 items to rate the severity of symptoms of anxiety, each scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Total score was calculated as the sum of the 14 individual item scores, ranging from 0 to 56 and categorized as 0-13: normal range, 14-17: mild severity, 18-24: mild to moderate severity, 25-30: moderate to severe, and \>=31: severe. A higher score indicates a more severe anxiety.

Time frame: Baseline, Week 8

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

The MADRS is a diagnostic questionnaire used by clinician to assess the participant's severity of depression. The questionnaire includes questions on ten symptoms: Apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, difficulty concentrating, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each question is scored on a range of 0 to 6 points and the total score was calculated as the sum of the 10 individual item scores, ranging from 0 to 60 categorized as: 0 to 6: normal/symptoms absent, 7 to 19: mild depression, 20 to 34: moderate depression, and 35 to 60: severe depression. Higher scores indicate increased depressive symptoms.

Time frame: Baseline, Week 8

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

An AE is defined as any untoward medical occurrence in a clinical trial participant administered an IMP and which does not necessarily have a causal relationship with this treatment. AESIs were newly acquired skin eruptions that were non-traumatic which included eruptions such as skin rashes, skin irritations, skin reactions, or acneiform lesions. AEs related to abuse included: Feeling abnormal (floaty feeling in the head), euphoric mood (feeling high). MHIs included: IMP accounting errors, not involving suspected abuse nor diversion by participant; Non-compliance with trial procedures, not involving suspected abuse nor diversion by participant; and other cases involving neither suspected abuse nor diversion of trial IMP by participant.

Time frame: From first dose of study drug up to 1 week post last dose (Up to 9 weeks)

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP.

12-lead ECG abnormality criteria included Rhythm: Supraventricular premature beat (not present at baseline and present post baseline); and Conduction: Primary (1°) atrioventricular block (PR ≥200 milliseconds \[msec\] and increase of ≥50 msec).

Time frame: From first dose of study drug up to 1 week post last dose (Up to 9 weeks)

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

Laboratory assessments included hematology, serum chemistry, and urinalysis. Abnormality criteria included: In milligrams per deciliter (mg/dL) \[high bilirubin ≥2.0, low/high calcium ≤8.2/ ≥12, high cholesterol fasting ≥240, high glucose, fasting ≥100, high triglycerides, fasting ≥150, high urate ≥8.5 female / ≥10.5 male, high protein urine ≥2 units increase\]; high creatine kinase (units per liter \[U/L\]) \>3xupper limit of normal (ULN); high eosinophils/leukocytes ≥10%, low neutrophils/leukocytes ≤15%; In 10\^3/microliter (µL) \[low or high leukocytes ≤2.8x10\^9/L or ≥16.0x10\^9/L, low neutrophils ≤1.5x10\^9/L\]. The categories with at least one participant with clinically relevant value are reported here.

Time frame: From first dose of study drug up to 1 week post last dose (Up to 9 weeks)

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis. 'Number analyzed' is the number of participants with data available for analysis of specified parameter.

Vital sign measurements included heart rate in supine and standing positions (low: \<50 beats per minute \[bpm\] and decrease ≥10 bpm; High: \>100 bpm and increase ≥10 bpm), systolic blood pressure (BP) in supine and standing positions (low: \<90 millimeters of mercury \[mmHg\] and decrease ≥20 mmHg; High: ≥140 mmHg and increase ≥20 mmHg), diastolic BP in supine and standing positions (low: \<60 mmHg and decrease ≥10 mmHg; High: ≥90 mmHg and increase ≥10 mmHg), weight in kilograms (kg) (low: ≥7% decrease; High: ≥7% increase), orthostatic hypotension, (≥30mmHg decrease is systolic BP or ≥20 mmHg in diastolic BP after at least 3 minutes of standing compared to the previous supine BP), and orthostatic tachycardia (≥25 bpm increase in heart rate from supine to standing). The categories with at least one participant with clinically relevant value are reported here.

Time frame: From first dose of study drug up to 1 week post last dose (Up to 9 weeks)

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

The C-SSRS is a clinician-administered instrument that systematically assess suicidal ideation (SI) and suicidal behavior rating scale. It rates an individual's degree of SI on a scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent. The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). The scale identifies specific behaviors ranging from preparatory acts or behavior to suicide which may be indicative of an individual's intent to complete suicide. Suicidality was reported in this outcome measure, defined as at least 1 occurrence of suicidal ideation or at least 1 occurrence of suicidal behavior for each assessment period.

Time frame: Week 8

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

SMWQ is a questionnaire to assess withdrawal symptoms subsequent to completion of dosing with IMP. The SMWQ is a modification of the Amphetamine Withdrawal Questionnaire, in which in which the terms amphetamines and methamphetamine are replaced with the term the study medication. This change was intended to prevent bias by implying that the trial medication might be an amphetamine or amphetamine-like stimulant when presented with the survey. This questionnaire comprises of 13 items which describe symptoms associated with the cessation of study medication use for which participants indicate severity on a scale with scores ranging from 0 (no withdrawal symptoms) to 4 (most severe withdrawal symptom). The total score is calculated as the sum of all the scores for the 13 items, ranging from 0 to 52. Lower scores indicate less withdrawal symptoms.

Time frame: Week 8

Population: Safety analysis set included all the randomized participants who received at least 1 dose of IMP. 'Overall number of participants analyzed' is the number of participants with data available for outcome measure analysis.

The SF-36 is a health-related survey that assesses participant's health status and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to emotional problems, general health, mental health, social functioning, and vitality. The 8 domains are combined to form 2 component scores: PCS and MCS. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. MCS consisted of social functioning, vitality, mental health, and role-emotional scales. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale with higher scores indicating better health-related quality of life. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Week 8

The CGI-S is a standardized, clinician-administered global rating scale that measures disease severity on scale with a score range of 0 to 7 where, 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. A higher score on the CGI-S represents a higher severity of disease. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Weeks 1, 2, 3, 4, and 6

The EDE-Q7 is a self-report version of the eating disorder examination (EDE) and measures eating-disorder psychopathology in the past 28 days and over longer intervals. It comprises of 3 subscale scores (dietary restraint, shape/weight overvaluation, and body dissatisfaction). An EDE-Q global (total) score is calculated as average of 3 subscale scores and ranges from 0 (absence of the feature) to 6 (extreme degree). A higher score indicates a more severe outcome. LS mean was determined by ANCOVA model with treatment and trial center as fixed factors and baseline value as covariate.

Time frame: Baseline, Week 8

All binge eating episodes were recorded daily by the participant in a binge eating diary. At each visit, the investigator reviewed the completed diary and assessed the number of binges for each day. Number of binge episodes per week are reported. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Weeks 7 to 8

The PGI-S is a single-item self-report of the participant's severity of symptoms. Severity is rated on a 7-point scale: 1 = no symptoms; 2 = minimal; 3 = mild; 4 = moderate; 5 = marked; 6 = severe; 7 = very severe. A higher score indicates more severe symptoms. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Week 8

The Y-BOCS-BE is a clinician-rated scale that assesses obsession with binge eating thoughts and compulsiveness of binge eating behaviors. The Y-BOCS-BE is a 10-item scale, divided into 2 subscales with 5 items each: obsessions and compulsions. Each item is rated from 0 (no symptoms) to 4 (extreme symptoms) and total scores range from 0 to 40. A score of 0 to 7 is considered sub-clinical; 8 to 15 as mild; 16 to 23 as moderate; 24 to 31 as severe; and 32 to 40 as extreme obsession and compulsiveness of binge eating. LS mean was determined by MMRM method with change from baseline value as dependent variable and included treatment, trial center, visit week, treatment-by-week interaction as fixed effects and baseline-by-week interaction as covariates.

Time frame: Baseline, Week 8

The CGI-C is a single-item, 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to their baseline state at the beginning of treatment, rated as: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. A higher score on the CGI-C represents a greater disease progression.

Time frame: Week 8

The PGI-C is a single-item, self-report that requires the participant to assess how much his/her illness has improved or worsened relative to baseline and rate on a 7-point scale: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. A higher score indicates a greater disease progression.

Time frame: Week 8

Percentages are rounded off to the nearest single decimal point.

Time frame: Week 8