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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.
Screening & Washout Period: up to 28 days Investigational Treatment Period: 49 days Follow-up Period : 7 days or 10 days
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Single-blind Run-in Period: Placebo | Experimental | Placebo-matching tablets BID (twice daily) on Day -7 through Baseline (Day -1). |
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| Double-blind Treatment Period: Centanafadine SR 200 mg | Experimental | Following Single-blind Run-in Period, participants with <30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine 200 mg SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. |
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| Double-blind Treatment Period: Centanafadine SR 400 mg | Experimental | Following Single-blind Run-in Period, participants with <30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine 400 mg SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. |
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| Double-blind Treatment Period: Placebo | Placebo Comparator | Following Single-blind Run-in Period, participants with <30% improvement on Adult ADHD Self Report Scale (ASRS) scale score were randomized to receive centanafadine SR matching placebo tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Centanafadine SR | Drug | 100 mg, BID, oral tablets |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and Day 42 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Event Reporting | Frequency and severity of treatment-emergent adverse events (TEAEs) will be assessed to determine safety and tolerability of centanafadine SR tablets. | Up to 59 days |
| ADHD Impact Module - Adult (AIM-A) |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| For additional information regarding sites, contact 844-687-8522 | New York | New York | 10022 | United States |
Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
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 took part in the study at 45 investigative sites in the United States from 16 January 2019 to 11 April 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | Single-blind (SB) Run-in Period: Placebo | Placebo-matching tablets BID (twice daily) on Day -7 through Baseline (Day -1). |
| FG001 | Double-blind Treatment Period: Centanafadine SR 200 mg |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| SB Placebo Run-in Period (1 Week) |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 15, 2020 | Apr 8, 2021 |
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| Placebo | Other | BID, oral tablet. |
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| Centanafadine SR | Drug | 200 mg, BID, oral tablets |
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| Baseline and Day 42 |
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.
| Up to 42 days |
| 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. | Up to 42 days |
| 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. | Up to 42 days |
Following Single-blind Run-in Period, participants with <30% improvement on Adult ASRS scale score were randomized to receive centanafadine 200 mg SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period.
| FG002 | Double-blind Treatment Period: Centanafadine SR 400 mg | Following Single-blind Run-in Period, participants with <30% improvement on Adult ASRS scale score were randomized to receive centanafadine SR 200 mg tablets BID orally on Day 1 through Day 7 and were then escalated to their target total daily dose (TDD) of centanafadine 400 mg on Day 8 through Day 42 in the Double-blind Treatment Period. |
| FG003 | Double-blind Treatment Period: Placebo | Following Single-blind Run-in Period, participants with <30% improvement on ASRS scale score were randomized to receive centanafadine matching placebo SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. |
| Treated |
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| COMPLETED |
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| NOT COMPLETED |
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| Double-blind Treatment Period (6 Weeks) |
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Participants who participated only in the Run-in Period and Full Analysis Set (FAS) including all participants in the safety sample who had a Baseline value and at least one valid post-randomization efficacy evaluation for adult ADHD investigator symptom rating scale (AISRS) total score in the Double-blind Treatment Period.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Adult Attention-deficit/Hyperactivity Disorder (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). | Data for ADHD AISRS scale was collected only for Double-blind Treatment Period arms. | Mean | Standard Deviation | score on a scale |
| ||||||||
| 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. | Data for CGI-S scale was collected only for Double-blind Treatment Period arms. Number analyzed is the number of participants with data available for analyses. | Mean | Standard Deviation | score on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Day 42 |
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | score on a scale | Baseline and Day 42 |
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| 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. | Not Posted | Up to 59 days | Participants | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Not Posted | Up to 42 days | Participants | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Not Posted | Up to 42 days | Participants | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. | Not Posted | Up to 42 days | Participants |
Up to 59 days
Safety sample included randomized participants who received at least 1 dose of study drug. The Placebo: Single-blind Run-in Period Only arm includes AEs that occurred during single-blind run-in period for participants who received at least 1 dose of study drug but did not participate in DB period. As pre-specified in SAP, AEs that occurred in Single-blind Placebo Run-In period for participants who received treatment in DB period was reported in DB treatment arms based on DB treatment received.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo: SB Run-in Period Only | Placebo-matching tablets BID (twice daily) on Day -7 through Baseline (Day -1) in the Single-blind Run-in Period only. Participants did not continue to Double-blind Treatment Period. | 0 | 138 | 0 | 138 | 2 | 138 |
| EG001 | Placebo + Centanafadine SR 200 mg | Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed >=30% improvement in 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. | 0 | 149 | 2 | 149 | 25 | 149 |
| EG002 | Placebo + Centanafadine SR 400 mg | Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed >=30% improvement in 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. | 0 | 149 | 0 | 149 | 22 | 149 |
| EG003 | Placebo + Placebo | Participants received centanafadine SR matching placebo tablets in Single-blind Run-in Period. Participants who showed >=30% improvement in 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. | 0 | 148 | 0 | 148 | 18 | 148 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastroenteritis viral | Infections and infestations | MedDra 23.0 | Systematic Assessment |
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| Influenza | Infections and infestations | MedDra 23.0 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDra 23.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry Mouth | Gastrointestinal disorders | Select 0 | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 23.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Clinical Development | Otsuka Pharmaceutical Development & Commercialization, Inc. | 1-609-524-6788 | clinicaltransparency@otsuka-us.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 27, 2020 | Apr 8, 2021 | SAP_001.pdf |
| ID | Term |
|---|---|
| D001289 | Attention Deficit Disorder with Hyperactivity |
| ID | Term |
|---|---|
| D019958 | Attention Deficit and Disruptive Behavior Disorders |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C574080 | 1-(naphthalen-2-yl)-3-azabicyclo(3.1.0)hexane |
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| Adverse Event |
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| Lack of Efficacy |
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| Lost to Follow-up |
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| Non-compliance with Study Drug |
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| Protocol Deviation |
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| Withdrawal by Subject |
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| Physician Decision |
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| Reason not Specified |
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| Reason due to COVID-19 |
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| =0.0392 |
| LS Mean Difference |
| -2.74 |
| 2-Sided |
| 95 |
| -5.35 |
| -0.14 |
| Superiority |
| OG002 | Double-blind Treatment Period: Placebo | Following Single-blind Run-in Period, participants with <30% improvement on Adult ASRS scale score were randomized to receive centanafadine matching placebo SR tablets BID orally on Day 1 through Day 42 in the Double-blind Treatment Period. |
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