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This study evaluated the long-term safety and tolerability of centanafadine sustained-release (SR) tablets, administered twice daily (BID) in the treatment of adults with attention deficit hyperactivity disorder (ADHD).
This open-label study assessed the overall safety and tolerability of 400 mg total daily dose centanafadine SR tablets in participants, over the course of approximately 52 weeks. This study has accepted rollover participants from both the 405-201-00013 and 405-201-00014 trials. For individuals that did not participate in one of the studies mentioned above, they will be able to enroll if they meet the inclusion criteria as outlined below.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Centanafadine | Experimental | 400 mg total daily dose |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Centanafadine SR | Drug | 200mg, BID, oral tablets |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | An AE is defined as any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs are defined as AEs with an onset date on or after the first dose of IMP. They are all adverse events that started after the start of centanafadine; or if the event was continuous from baseline and was worsening, serious, study drug-related, or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs were graded on a 3-point scale and the intensity of an adverse experience was defined as follows: 1 = Mild: Discomfort noticed, but no disruption to daily activity, 2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity, and 3 = Severe: Inability to work or perform normal daily activity. | From first dose of study drug up to 30 days after last dose of study drug (Up to approximately Week 56) |
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| Measure | Description | Time Frame |
|---|---|---|
| Adult ADHD Investigator Symptom Rating Scale (AISRS) | 18-item scale with a total score range of 0 to 54 points. Composed of 2 subscales that can range from 0 to 27 points. A higher value represents a worse outcome. Efficacy endpoint. Results will be assessed to determine effectiveness of drug. | Up to 52 weeks or early termination |
De Novo Participants [De Novo Enrollment has ended 20Sep2019].
Inclusion Criteria:
Exclusion Criteria:
Rollover Participants: Rollover Enrollment has ended 28Aug2020.
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| For additional information regarding sites, contact 844-687-8522 | Culver City | California | 90230 | 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 an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
A total of 662 participants were treated in this study, 494 participants from parent studies (405-201-00013 and 405-201-00014) &168 new participants joined in this current study. As pre-specified in Statistical analysis plan (SAP) data was analyzed by the parent studies (405-201-00013 and 405-201-00014) treatment groups for rollover participants and centanafadine SR 400mg for denovo participants. Data from the 2 parent studies was analyzed and reported in combined way for rollover participants.
This study was conducted in the United States from 14 February 2019 to 07 September 2021. A total of 662 participants were enrolled in the study. Out of 662 participants, 653 participants received the study treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Prior Centanafadine SR 200 mg | Participants who received centanafadine sustained release (SR) 200 milligrams (mg) in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received a total daily dose (TDD) of centanafadine SR 400 mg in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, twice daily (BID) at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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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 | Jun 2, 2020 | Sep 5, 2024 |
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| Clinical Global Impression-Severity of Illness Scale (CGI-S) |
An observer-rated scale with a total score range of 0 to 7. A higher score represents a worse outcome.Efficacy endpoint. Results will be assessed to determine effectiveness of drug. |
| Up to 52 weeks or early termination |
| 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. | Up to 52 weeks or early termination |
| FG001 | Prior Centanafadine SR 400 mg | Participants who received centanafadine SR 400 mg in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| FG002 | Prior Placebo | Participants who received placebo in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| FG003 | De Novo Centanafadine SR 400 mg | Participants who did not participate in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], and who were eligible for this study received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| Safety Sample | Safety Sample comprised all participants who received at least 1 dose of investigational medicinal product (IMP). |
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| COMPLETED |
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| NOT COMPLETED |
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|
Enrolled Sample comprised all participants who signed electronic informed consent form (ICF) for the trial.As prespecified in the SAP,data was analyzed based on the treatments(centanafadine SR 200mg, 400 mg or Placebo)received by the participants in the parent double-blind phase 3 trials(405-201-00013 or 405-201-00014),and the centanafadine SR 400 mg received by de novo participants during this study.Data from 2 parent studies was analyzed and reported in combined way for rollover participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Prior Centanafadine SR 200 mg | Participants who received centanafadine SR 200 mg in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received TDD of centanafadine SR 400 mg in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7 , followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| BG001 | Prior Centanafadine SR 400 mg | Participants who received centanafadine SR 400 mg in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| BG002 | Prior Placebo | Participants who received placebo in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| BG003 | De Novo Centanafadine SR 400 mg | Participants who did not participate in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], and who were eligible for this study received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||
| Sex/Gender, Customized | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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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 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | An AE is defined as any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs are defined as AEs with an onset date on or after the first dose of IMP. They are all adverse events that started after the start of centanafadine; or if the event was continuous from baseline and was worsening, serious, study drug-related, or resulted in death, discontinuation, interruption or reduction of study therapy. TEAEs were graded on a 3-point scale and the intensity of an adverse experience was defined as follows: 1 = Mild: Discomfort noticed, but no disruption to daily activity, 2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity, and 3 = Severe: Inability to work or perform normal daily activity. | Safety Sample comprised all participants who received at least 1 dose of IMP. As prespecified in the SAP, data was analyzed based on the treatments (centanafadine SR 200mg, 400 mg or placebo) received by the participants in the parent double-blind phase 3 trials (405-201-00013 or 405-201-00014), and the centanafadine SR 400 mg received by de novo participants during this current study. Data from 2 parent studies was analyzed and reported in a combined way for rollover participants. | Posted | Count of Participants | Participants | From first dose of study drug up to 30 days after last dose of study drug (Up to approximately Week 56) |
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| |||||||||||||||||||||||||||||||||||
| Other Pre-specified | Adult ADHD Investigator Symptom Rating Scale (AISRS) | 18-item scale with a total score range of 0 to 54 points. Composed of 2 subscales that can range from 0 to 27 points. A higher value represents a worse outcome. Efficacy endpoint. Results will be assessed to determine effectiveness of drug. | Not Posted | Up to 52 weeks or early termination | Participants | ||||||||||||||||||||||||||||||||||||||||
| Other Pre-specified | Clinical Global Impression-Severity of Illness Scale (CGI-S) | An observer-rated scale with a total score range of 0 to 7. A higher score represents a worse outcome.Efficacy endpoint. Results will be assessed to determine effectiveness of drug. | Not Posted | Up to 52 weeks or early termination | 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 52 weeks or early termination | Participants |
From first dose through 30 days after last dose of study drug (Up to approximately Week 56)
Safety Sample comprised of participants who received at least one dose of IMP. As prespecified in the SAP, data was analyzed based on the treatments (centanafadine SR 200mg, 400 mg or placebo) received by the participants in the parent double-blind phase 3 trials (405-201-00013 or 405-201-00014), and the centanafadine SR 400 mg received by de novo participants during this current study. Data from 2 parent studies was analyzed and reported in a combined way for rollover participants.
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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 | Prior Centanafadine SR 200 mg | Participants who received centanafadine SR 200 mg in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. | 0 | 154 | 1 | 154 | 59 | 154 |
| EG001 | Prior Centanafadine SR 400 mg | Participants who received centanafadine SR 400 mg in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. | 0 | 149 | 1 | 149 | 49 | 149 |
| EG002 | Prior Placebo | Participants who received placebo in the parent double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. | 0 | 184 | 7 | 184 | 81 | 184 |
| EG003 | De Novo Centanafadine SR 400 mg | Participants who did not participate in the parents double-blind phase 3 studies 405-201-00013 [NCT03605680] or 405-201-00014 [NCT03605836], and who were eligible for this study received centanafadine SR 400 mg TDD in current study, following a dose-escalation schedule. In the current study, participants received centanafadine SR tablets, orally, BID at a starting dose of 200 mg TDD on Day 1 through Day 7, followed by dose-escalation to 400 mg TDD from Day 8 up to Week 52. | 0 | 166 | 3 | 166 | 61 | 166 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Angina Pectoris | Cardiac disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Vertigo Positional | Ear and labyrinth disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Diverticulitis | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
| |
| Suspected COVID-19 | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
| |
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
| |
| Obesity | Metabolism and nutrition disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Intraductal Proliferative Breast Lesion | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 24.0 | Systematic Assessment |
| |
| Malignant Melanoma In Situ | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 24.0 | Systematic Assessment |
| |
| Intentional Self-Injury | Psychiatric disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Mood Swings | Psychiatric disorders | MedDRA 24.0 | Systematic Assessment |
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| Suicidal Ideation | Psychiatric disorders | MedDRA 24.0 | Systematic Assessment |
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| Nephrolithiasis | Renal and urinary disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Stress Urinary Incontinence | Renal and urinary disorders | MedDRA 24.0 | Systematic Assessment |
| |
| Ureterolithiasis | Renal and urinary disorders | MedDRA 24.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 24.0 | Systematic Assessment |
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| Dry Mouth | Gastrointestinal disorders | MedDRA 24.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 24.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 24.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
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| Upper Respiratory Tract Infection | Infections and infestations | MedDRA 24.0 | Systematic Assessment |
| |
| Decreased Appetite | Metabolism and nutrition disorders | MedDRA 24.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 24.0 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 24.0 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 24.0 | 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 | Sep 15, 2021 | Sep 5, 2024 | 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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| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Unknown |
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| Black or African American |
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| American Indian or Alaska Native |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Other |
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| Unknown |
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| Not Hispanic or Latino |
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| Other |
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| Unknown |
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| Participants With Mild TEAE |
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| Participants With Moderate TEAE |
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| Participants With Severe TEAE |
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