Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)

Phase 2

Completed

Conditions: Attention Deficit Disorder With Hyperactivity

Interventions: Drug: CTN SR
Drug: Matching placebo

Registration Number: NCT02547428

Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary: This was a Phase 2b, randomized, double-blind, multicenter, 2-period, 2-treatment, crossover study to evaluate safety and efficacy of CTN SR compared with placebo in adults with ADHD. Efficacy was also evaluated in the subgroup of adults with ADHD treated with a target CTN SR dose of 400 mg/day.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 85

Inclusion Criteria

Participant was 18 to 60 years of age, inclusive, at the time of consent.
Participant meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD, defined as, established by a comprehensive psychiatric evaluation based on DSM-5 criteria with at least 5 of the 9 subtype criteria met, as determined by the Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4). Note: DSM-5 was used for screening / diagnosis and DSM-4 was used for evaluation throughout the study.
Participant had a Baseline score of greater than or equal to 28 using the Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV).
Participant had a minimum score of 4 on the Clinical Global Impression of Severity at Baseline.
Participant was functioning at an age-appropriate level intellectually, as judged by the Investigator.

Exclusion Criteria

Participant had a current comorbid psychiatric disorder that was either controlled with medications prohibited in this study or was uncontrolled and associated with significant symptoms. Exclusionary conditions included any severe comorbid Axis II disorder or severe Axis I disorder (such as post-traumatic stress disorder, psychosis, bipolar illness, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder) or other symptomatic manifestations that, in the opinion of the examining physician, would have contraindicated CTN SR treatment or confound efficacy or safety assessments. Specifically, participants with mild to moderate forms of Axis I disorders (for example, social phobia and dysthymia) may have been included, whereas participants with a lifetime history of psychosis or bipolar disorder were excluded. Comorbid psychiatric diagnosis was established by a Semi-Structured Clinical Interview for DSM-5 Axis I Disorders (the Mini lnternational Neuropsychiatric lnterview, Version 6.0 [M.I.N.I. 6.0]).
Participants who were currently considered a suicide risk, any participant who had previously made a suicide attempt, or those who were currently demonstrating active suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening, or if in the opinion of the investigator the participant was considered a suicide risk. Participants who developed suicidal ideation or behavior during the study as measured by the C-SSRS were discontinued and followed appropriately.
The participant had a body mass index of less than 18.5 or greater than or equal to 40 at Baseline.
Participant had a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might have confounded the results of safety assessments administered in the study or that might have increased risk to the participant.
Participant had a history of seizures (other than infantile febrile seizures), any tic disorder (except transient tic disorder and participant had no episodes greater than or equal to 1 year), or a current diagnosis and/or a known family history of Tourette's Disorder (that is, first degree relatives).
Participant had a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke or other serious cardiac problems that may have placed them at increased vulnerability to potential sympathomimetic effects.
Participant had a known family history of sudden cardiac death or ventricular arrhythmia.
Participant had a history of significant bleeding or coagulation disorder and/or low platelet levels (less than 130 x 10^9/liter) or increased international normalized ratio (greater than 1.3) at Screening.
Participant had a history of cancer (other than noncomplicated basal or squamous cell cancer).
Participant had any clinically significant 12-lead electrocardiogram or clinically significant laboratory abnormality at Screening and/or Baseline.
Participant had current abnormal thyroid function, as defined as abnormal Screening thyroid stimulating hormone (less than 0.34 or greater than 5.6 micro-International Units/milliliter). Treatment with a stable dose of thyroid medication for at least 3 months was permitted.
Participant had a resting sitting systolic blood pressure (SBP) greater than or equal to 140 millimeters of mercury (mm Hg) or diastolic blood pressure (DBP) greater than or equal to 90 mm Hg. No more than 1 repeat measurement was permitted.
Participant had a history of hyponatremia.
Participant was on an antihypertensive medication of any kind.
Participant has a known history of orthostatic hypotension or has an orthostatic blood pressure drop of greater than or equal to 20 mm Hg (based on the drop between sitting and standing [3 minutes] SBP) at Screening or Baseline.
Participant had a known history of hypertension.
Participant exhibited lifestyle that may have been confounding to safety or efficacy assessments per the judgment of the investigator (for example, exercises, diets or travels extensively).
Participant had a known history of glaucoma.
Participant had failed to respond to 1 or more adequate courses (for example, adequate dose and duration with poor response as judged by the Investigator) of stimulant therapy.
Participant had a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-5 criteria.
Participant was taking other medications that have central nervous system effects or affected performance, such as sedating antihistamines and decongestant sympathomimetic, or was recently on monoamine oxidase inhibitors (during or within 14 days of investigational product administration). Stable use of bronchodilator inhalers was not exclusionary. This also included use of any psychoactive prescription medication 30 days prior to Screening or psychoactive over-the-counter ) medication or herbal products that required more than a 7-day washout. Participants currently treated with methylphenidate or amphetamine products were permitted and underwent a 7-day washout period. Participants who had taken atomoxetine were required to undergo a 30-day washout.
Participant required the frequent or regular use of aspirin, ibuprofen, and naproxen sodium, or is on any anticoagulant, such as warfarin.
Participant was taking known potent inhibitors or inducers of common cytochrome P450 enzymes, including herbal products.
Participant had a positive urine drug screen (UDS) result at Screening or Baseline. Note: The UDS must be negative at Screening (with the exception of the participant's current ADHD psychostimulant, if applicable) or Baseline, if applicable, for the participant to potentially have been eligible for study participation. The Investigator, in conjunction with the Medical Monitor, evaluated the potential impact of a positive UDS regarding the continued participation of the participant.
Participant had taken an investigational product or taken part in a clinical study within 30 days prior to Screening.
Investigational site personnel were not permitted to participate in the study.
Participant had participated previously in a CTN investigational study.
The female participant was pregnant or lactating.
Participant had a documented allergy, hypersensitivity, or intolerance to CTN or to any excipients in the reference product.
Participant had a history of allergy or hypersensitivity to medications (for example., monoamine reuptake inhibitors or antibiotics).
Participant did not agree to or was unable to abstain from consuming alcohol during the study.

Reproductive Potential Requirements
All female participants were required to have a negative serum beta human chorionic gonadotropin pregnancy test at Screening, a negative urine pregnancy test at Baseline, and be either postmenopausal (12 consecutive months of spontaneous amenorrhea and greater than or equal to 51 years of age), surgically sterile and at least 6 weeks post-sterilization or, for females of childbearing potential, had a negative pregnancy test prior to entering the study and agreed to use acceptable methods of contraception.

Contraceptive Requirements
Condoms were to be used with all forms of contraception (that is., double-barrier method). Acceptable contraceptives included the following:
1. Intrauterine devices
2. Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring)
3. Diaphragms with spermicidal gel or foam
Females of childbearing potential were advised to use acceptable contraceptives from the date of informed consent throughout the study period and for the defined follow-up period.
If hormonal contraceptives were used, they were to be administered according to the package insert.
Females of childbearing potential who were not currently sexually active agreed to use acceptable contraception, as defined above, if they became sexually active during their study participation and for the defined follow-up time period.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
CTN SR First, Then Placebo	CTN SR	Participants received CTN SR tablets starting at a dose of 100 or 200 milligrams (mg) on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 1. The dose was decreased based on safety and tolerability based on Investigator's discretion, followed by a washout Period of 1 week followed by matching-placebo for up to 3 weeks in Period 2. The most common total daily dose (TDD) was 400 mg/day.
CTN SR First, Then Placebo	Matching placebo	Participants received CTN SR tablets starting at a dose of 100 or 200 milligrams (mg) on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 1. The dose was decreased based on safety and tolerability based on Investigator's discretion, followed by a washout Period of 1 week followed by matching-placebo for up to 3 weeks in Period 2. The most common total daily dose (TDD) was 400 mg/day.
Placebo First, Then CTN SR	CTN SR	Participants received matching-placebo for up to 3 weeks in Period 1, followed by a washout Period of 1 week, followed by CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 2. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.
Placebo First, Then CTN SR	Matching placebo	Participants received matching-placebo for up to 3 weeks in Period 1, followed by a washout Period of 1 week, followed by CTN SR tablets starting at a dose of 100 or 200 mg on Day 1. Dose was up titrated up to 800 mg daily dose for up to 3 weeks in Period 2. The dose was decreased based on safety and tolerability based on Investigator's discretion. The most common TDD was 400 mg/day.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score	Baseline and Week 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
Change From Baseline in ADHD-RS-IV Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Baseline and Week 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment	Baseline, Weeks 1, 2 and 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
Number of Participants With CGI-I Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Weeks 1, 2, and 3	The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worse. The CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline.
Cmax: Maximum Concentration	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
Tmax: Time to Maximum Concentration	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
t½: Elimination Phase Half-Life	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment	Baseline, Weeks 1, and 2	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
Change From Baseline in ADHD-RS-IV Score Total Score After 1 and 2 Weeks of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Baseline, Weeks 1, and 2	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
Change From Baseline in ADHD-RS-IV Hyperactivity/Impulsivity Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Baseline, Weeks 1, 2 and 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
PERMP Score for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8	The PERMP is a skill-adjusted math test consisting of 400 problems. The PERMP total score is the sum of the number of math problems attempted plus the number of math problems answered correctly in a 10-minute session. The score range of number of math problems attempted and number of math problems answered correctly is 0-400 and the total score range from 0-800. The higher scores indicate better performance. Higher scores mean higher performance and less severe ADHD symptoms.
Permanent Product Measure of Performance (PERMP) Score	Predose -0.5 hour and post-dose 1, 3, 5, 7, 9, 11 and 13 hours at Weeks 4 and 8	The Permanent Product Measure of Performance (PERMP) is a skill-adjusted math test consisting of 400 problems. The PERMP total score is the sum of the number of math problems attempted plus the number of math problems answered correctly in a 10-minute session. The score range of number of math problems attempted and number of math problems answered correctly is 0-400 and the total score range from 0-800. The higher scores indicate better performance. Higher scores mean higher performance and less severe ADHD symptoms.
Number of Participants With at Least One Treatment-Emergent Adverse Events (TEAEs)	From signing of informed consent up to approximately Week 9	An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any AE with onset post study drug treatment in the two crossover treatment periods. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Clast: Last Measurable Concentration	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
ke: Elimination Phase Rate Constant	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	Baseline, Weeks 1, 2 and 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
AUC0-t: Area Under the Concentration-Time Curve During the Steady-State 24-hour Dosing Interval	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
Change From Baseline in ADHD-RS-IV Inattention Subscale Score of Double-blind Treatment	Baseline, Weeks 1, 2 and 3	The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items are grouped into 2 subscales of 9 symptoms each: Hyperactivity/Impulsivity (even numbered items 2-18) and Inattentiveness (odd numbered items 1-17). Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The possible sub-scale score range is from 0 to 27. Higher scores indicate more severe disease. A negative change from Baseline indicates improvement.
Number of Participants With Clinical Global Impressions of Improvement (CGI-I) Score	Weeks 1, 2, and 3	The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 8-point scale ranging from 0 to 7 where 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse and 7=very much worse. The CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline.
Number of Participants With at Least One TEAEs for Subgroup of Participants With Target CTN SR Dose of 400 mg/Day	From signing of informed consent up to approximately Week 9	An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any AE with onset post study drug treatment in the two crossover treatment periods. As prespecified in the protocol, data for safety is reported by the treatment group (CTN SR and placebo).
Tlast: Time Point of the Last Measurable Concentration	Predose 90 minutes and 2, 4, 6, 8,10, 11 to 12 and 24 hours post-dose at Weeks 4 and 8
Number of Participants With Clinical Global Impressions of Severity (CGI-S) Score	Baseline	The CGI-S is performed to rate the severity of a participant's condition on a 8- point scale ranging from 0 to 7 where 0=not assessed, 1=normal, not at all ill, 2=borderline mentally ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7 = among the most extremely ill participants.