Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder
Conditions
Keywords
Centanafadine, ADHD, ADD
Brief summary
This study evaluates the efficacy, safety, and tolerability of centanafadine sustained-release tablets in adults with attention-deficit/hyperactivity disorder (ADHD). Participants will either receive a twice-daily dose of centanafadine sustained-release tablets, or twice-daily placebo.
Detailed description
Screening & Washout Period: up to 28 days Investigational Treatment Period: 49 days Follow-up Period : 7 days or 10 days
Interventions
DRUGCentanafadine SR
100 mg, BID, oral tablets
OTHERPlacebo
BID, oral tablet.
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Participants must meet the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for ADHD (including predominantly inattentive presentation, hyperactive presentation, or combined presentation) as confirmed by the Adult ADHD Clinical Diagnostic Scale (ACDS) Version 1.2. To confirm that ADHD is the primary diagnosis, the Mini International Neuropsychiatric Interview (MINI) will be used to identify and exclude other psychiatric conditions which would preclude enrollment. * Participants who were not receiving any pharmacological treatment for ADHD must have an Adult ADHD Investigator Symptom Rating Scale (AISRS) score of ≥ 28 at screening and baseline. Participants who were receiving pharmacological treatment for ADHD at screening must have a minimum AISRS score of ≥ 22 at screening, and a score of ≥ 28 at baseline. * All participants must be willing to discontinue all prohibited psychotropic medications starting from the time of signing the informed consent through the 7-day follow-up period. Participants that do not rollover into Trial 405-201-00015 (NCT03605849) must be willing to discontinue all prohibited psychotropic medications starting from the time of signing the informed consent until after the follow-up telephone call 10 days after the last dose of investigational medicinal product (IMP). * Participants must have a Clinical Global Impression-Severity of Illness Scale (CGI-S) score of ≥ 4 (≥ moderate impairment) at baseline.
Exclusion criteria
* Participants with a DSM-5 diagnosis of Other Specified or Unspecified Attention Deficit/Hyperactivity Disorder. * Participants has a current comorbid psychiatric disorder that either could be expected to require treatment with medications prohibited in this trial, or to confound efficacy or safety assessments. Examples include, but are not limited to, psychotic disorder, bipolar disorder, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, a current major depressive episode, or posttraumatic stress disorder, as established by the Mini International Neuropsychiatric Interview (MINI). * In the opinion of the investigator, participants has not derived significant therapeutic benefit from 2 or more ADHD therapies of 2 different classes (eg, amphetamine and methylphenidate) given with an acceptable dose and duration during adulthood (aged 18 or older). NOTE: If participants has not derived significant therapeutic benefit due to an inability to tolerate side effects, eligibility can be discussed on case-by-case basis with the medical monitor. * Participants who have a positive alcohol test (via breathalyzer or blood), a positive drug screen assessed prior to the baseline visit for cocaine, other illicit drugs (including marijuana), or prescription or over-the-counter (OTC) ADHD medications will be early terminated. This includes medications such as opioids or benzodiazepines taken without prescription. * In the opinion of the investigator, the participants is unable to adhere to the treatment regimen or other requirements outlined in the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS) | Baseline and Day 42 | The Adult Investigator Symptom Rating Scale (AISRS) is an 18-item clinician rating scale to evaluate individual ADHD symptoms on a scale of 0 (none) to 3 (severe). The total sum ranges from 0 (no ADHD symptoms) to 54 (extremely severe ADHD symptoms). Negative change from Baseline indicates improvement. Mixed-effect model repeated measure (MMRM) was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) | Baseline and Day 42 | CGI-S is an observer-rated scale used to measure symptom severity with a total score range of 0 to 7 where 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. A negative change from Baseline indicates improvement. MMRM was used for the analysis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event Reporting | Up to 59 days | Frequency and severity of treatment-emergent adverse events (TEAEs) will be assessed to determine safety and tolerability of centanafadine SR tablets. |
| ADHD Impact Module - Adult (AIM-A) | Up to 42 days | Scale composed of 3 subscales with a maximum score of 100. A lower score indicates a worse outcome. Exploratory endpoint; comparison of baseline score to other points throughout the study. |
| Adult ADHD Self Report Scale (ASRS) | Up to 42 days | An 18 question report, total score ranges from 0 to 124. A higher score denotes a worse outcome. Exploratory endpoint; comparison of baseline score to other points throughout the study. |
| Adult ADHD Investigator Symptom Rating Scale (AISRS) | Up to 42 days | Change from baseline total score compared to every scheduled visit. Each subscale is composed of 9 items each. Scores can range from 0 to 27, with a higher score representing a worse outcome. Change from baseline scores are compared to every scheduled visit score. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 45 investigative sites in the United States from 16 January 2019 to 11 April 2020.
Pre-assignment details
A total of 604 participants were enrolled in the study, out of which 584 were treated during the placebo Run-in Period. Out of 584, 466 participants were randomized into one of the three treatment groups (centanafadine 200 mg, centanafadine 400 mg, or placebo) in the Double-blind Treatment Period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo: Single-blind Run-in Period Only Placebo-matching tablets BID (twice daily) on Day -7 through Baseline (Day -1) in the Run-in Period only. Participants did not continue to Double-blind Treatment Period. | 138 |
| Double-blind Treatment Period: Placebo + Centanafadine SR 200 mg Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed \>=30% improvement in Adult ASRS at Baseline were early terminated and the remaining participants were randomized to receive centanafadine SR 200 mg tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. | 154 |
| Double-blind Treatment Period: Placebo + Centanafadine SR 400 mg Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed \>=30% improvement in Adult ASRS at Baseline were early terminated and the remaining participants were randomized to receive centanafadine SR 200 mg tablets BID orally on Day 1 through Day 7 and were then escalated to their target TDD of centanafadine 400 mg on Day 8 through Day 42 in the Double-blind Treatment Period. | 156 |
| Double-blind Treatment Period: Placebo + Placebo Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed \>=30% improvement in Adult ASRS at Baseline were early terminated and the remaining participants were randomized to receive centanafadine SR matching placebo tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. | 156 |
| Total | 604 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Treatment Period (6 Weeks) | Adverse Event | 0 | 8 | 8 | 3 |
| Double-blind Treatment Period (6 Weeks) | Lack of Efficacy | 0 | 0 | 0 | 1 |
| Double-blind Treatment Period (6 Weeks) | Lost to Follow-up | 0 | 3 | 4 | 3 |
| Double-blind Treatment Period (6 Weeks) | Non-compliance with Study Drug | 0 | 3 | 1 | 2 |
| Double-blind Treatment Period (6 Weeks) | Physician Decision | 0 | 1 | 2 | 0 |
| Double-blind Treatment Period (6 Weeks) | Protocol Deviation | 0 | 14 | 7 | 5 |
| Double-blind Treatment Period (6 Weeks) | Randomized but Not Treated in Double-Blind Treatment Period | 0 | 5 | 7 | 8 |
| Double-blind Treatment Period (6 Weeks) | Reason due to COVID-19 | 0 | 1 | 2 | 3 |
| Double-blind Treatment Period (6 Weeks) | Reason not Specified | 0 | 5 | 4 | 3 |
| Double-blind Treatment Period (6 Weeks) | Withdrawal by Subject | 0 | 4 | 4 | 7 |
| SB Placebo Run-in Period (1 Week) | Adverse Event | 6 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Lack of Efficacy | 1 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Lost to Follow-up | 9 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Non-compliance With Study Drug | 3 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Physician Decision | 6 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Protocol Deviation | 13 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Reason not Specified | 87 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Site Terminated by Sponsor | 1 | 0 | 0 | 0 |
| SB Placebo Run-in Period (1 Week) | Withdrawal by Subject | 12 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Double-blind Treatment Period: Placebo + Centanafadine SR 200 mg | Double-blind Treatment Period: Placebo + Centanafadine SR 400 mg | Double-blind Treatment Period: Placebo + Placebo | Total | Placebo: Single-blind Run-in Period Only |
|---|---|---|---|---|---|
| Adult Attention-deficit/Hyperactivity Disorder (ADHD) Investigator Symptom Rating Scale (AISRS) | 39.7 score on a scale STANDARD_DEVIATION 6.7 | 39.4 score on a scale STANDARD_DEVIATION 6.8 | 39.4 score on a scale STANDARD_DEVIATION 7.1 | 39.5 score on a scale STANDARD_DEVIATION 6.8 | — |
| Age, Continuous | 36.6 years STANDARD_DEVIATION 9.8 | 35.3 years STANDARD_DEVIATION 10.4 | 35.0 years STANDARD_DEVIATION 9.9 | 35.0 years STANDARD_DEVIATION 9.9 | 33.1 years STANDARD_DEVIATION 9.4 |
| Clinical Global Impression-Severity of Illness Scale (CGI-S) | 4.5 score on a scale STANDARD_DEVIATION 0.6 | 4.5 score on a scale STANDARD_DEVIATION 0.6 | 4.5 score on a scale STANDARD_DEVIATION 0.6 | 4.5 score on a scale STANDARD_DEVIATION 0.6 | — |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 38 Participants | 29 Participants | 129 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 119 Participants | 116 Participants | 124 Participants | 469 Participants | 110 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants | 6 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 4 Participants | 15 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 23 Participants | 21 Participants | 85 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 1 Participants | 11 Participants | 2 Participants |
| Race (NIH/OMB) White | 126 Participants | 123 Participants | 130 Participants | 486 Participants | 107 Participants |
| Sex: Female, Male Female | 76 Participants | 75 Participants | 76 Participants | 284 Participants | 57 Participants |
| Sex: Female, Male Male | 78 Participants | 81 Participants | 80 Participants | 320 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 138 | 0 / 149 | 0 / 149 | 0 / 148 |
| other Total, other adverse events | 2 / 138 | 25 / 149 | 22 / 149 | 18 / 148 |
| serious Total, serious adverse events | 0 / 138 | 2 / 149 | 0 / 149 | 0 / 148 |
Outcome results
Primary
Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS)
The Adult Investigator Symptom Rating Scale (AISRS) is an 18-item clinician rating scale to evaluate individual ADHD symptoms on a scale of 0 (none) to 3 (severe). The total sum ranges from 0 (no ADHD symptoms) to 54 (extremely severe ADHD symptoms). Negative change from Baseline indicates improvement. Mixed-effect model repeated measure (MMRM) was used for analysis.
Time frame: Baseline and Day 42
Population: Efficacy sample FAS included all participants in the safety sample who had a Baseline value and at least one valid post-randomization efficacy evaluation for AISRS total score in the Double-blind Treatment Period. Overall number analysed are the participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Treatment Period: Centanafadine SR 200 mg | Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS) | -10.1 score on a scale | Standard Error 0.99 |
| Double-blind Treatment Period: Centanafadine SR 400 mg | Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS) | -9.73 score on a scale | Standard Error 0.98 |
| Double-blind Treatment Period: Placebo | Change From Baseline in ADHD Investigator Symptom Rating Scale (AISRS) | -6.98 score on a scale | Standard Error 0.98 |
p-value: =0.019395% CI: [-5.79, -0.51]MMRM
p-value: =0.039295% CI: [-5.35, -0.14]MMRM
Secondary
Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S)
CGI-S is an observer-rated scale used to measure symptom severity with a total score range of 0 to 7 where 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. A negative change from Baseline indicates improvement. MMRM was used for the analysis.
Time frame: Baseline and Day 42
Population: Efficacy sample FAS included all participants in the safety sample who had a Baseline value and at least one valid post-randomization efficacy evaluation for AISRS total score in the Double-blind Treatment Period. Overall number analysed are the participants with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Treatment Period: Centanafadine SR 200 mg | Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) | -0.78 score on a scale | Standard Error 0.09 |
| Double-blind Treatment Period: Centanafadine SR 400 mg | Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) | -0.79 score on a scale | Standard Error 0.08 |
| Double-blind Treatment Period: Placebo | Change From Baseline in Clinical Global Impression-Severity of Illness Scale (CGI-S) | -0.52 score on a scale | Standard Error 0.08 |
p-value: =0.023295% CI: [-0.5, -0.04]MMRM
p-value: =0.016295% CI: [-0.51, -0.05]MMRM
Other Pre-specified
ADHD Impact Module - Adult (AIM-A)
Scale composed of 3 subscales with a maximum score of 100. A lower score indicates a worse outcome. Exploratory endpoint; comparison of baseline score to other points throughout the study.
Time frame: Up to 42 days
Other Pre-specified
Adult ADHD Investigator Symptom Rating Scale (AISRS)
Change from baseline total score compared to every scheduled visit. Each subscale is composed of 9 items each. Scores can range from 0 to 27, with a higher score representing a worse outcome. Change from baseline scores are compared to every scheduled visit score.
Time frame: Up to 42 days
Other Pre-specified
Adult ADHD Self Report Scale (ASRS)
An 18 question report, total score ranges from 0 to 124. A higher score denotes a worse outcome. Exploratory endpoint; comparison of baseline score to other points throughout the study.
Time frame: Up to 42 days
Other Pre-specified
Adverse Event Reporting
Frequency and severity of treatment-emergent adverse events (TEAEs) will be assessed to determine safety and tolerability of centanafadine SR tablets.
Time frame: Up to 59 days