Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder
Conditions
Keywords
Centanafadine, ADD, ADHD
Brief summary
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).
Detailed description
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.
Interventions
DRUGCentanafadine SR
200mg, BID, oral tablets
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
De Novo Participants \[De Novo Enrollment has ended 20Sep2019\]. Inclusion Criteria: * De novo 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 are 18 to 55 years of age, inclusive, at the time of consent. * Participants have BMI of 18 to 40, inclusive * Participants are willing to discontinue all prohibited psychotropic medications starting from the time of signing the informed consent and up to the 10-day safety follow-up period.
Exclusion criteria
* Participants has a DSM-5 diagnosis of Other Specified or Unspecified Attention-Deficit/Hyperactivity Disorder as confirmed by ACDS Version 1.2. * Participant has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this trial or is uncontrolled and associated with significant symptoms, including but not limited to: a current major depressive episode (per DSM-5 criteria), current symptoms (past 90 days) meeting the DSM-5 criteria for a diagnosis of generalized anxiety disorder, obsessive compulsive disorder, panic disorder, or posttraumatic stress disorder, as established by the MINI. NOTE: Participants with mild mood or anxiety symptoms that do not meet criteria for diagnosis, who do not require treatment based on the Investigator's assessment, and do not confound efficacy or safety assessments in the opinion of the examining Investigator, may be included. * Participants that have a positive alcohol test (via breathalyzer or blood), a positive drug screen for cocaine, or other illicit drugs (excluding marijuana). Participants with a positive drug screen for confirmed prescription medications at baseline will not be permitted to continue participation in Trial 405-201-00015. NOTE: Participants that tested positive for marijuana may be permitted to be enrolled if they have no evidence of a substance use disorder, and if they agree to refrain from use for the duration of the trial. Allowance for participants testing positive for marijuana at screening require explicit approval from the medical monitor. Rollover Participants: Rollover Enrollment has ended 28Aug2020. Inclusion Criteria: * Participants who completed the double-blind treatment period and 7-day follow-up after last dose of investigational medicinal product (IMP) in double-blind trials and who, in the opinion of the investigator, could potentially benefit from centanafadine for ADHD.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | From first dose of study drug up to 30 days after last dose of study drug (Up to approximately Week 56) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adult ADHD Investigator Symptom Rating Scale (AISRS) | Up to 52 weeks or early termination | 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. |
| Clinical Global Impression-Severity of Illness Scale (CGI-S) | Up to 52 weeks or early termination | 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. |
| ADHD Impact Module - Adult (AIM-A) | Up to 52 weeks or early termination | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 156 |
| 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. | 151 |
| 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. | 187 |
| 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. | 168 |
| Total | 662 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 20 | 21 | 29 | 11 |
| Overall Study | Enrolled, but not Treated | 2 | 2 | 3 | 2 |
| Overall Study | Lack of Efficacy | 4 | 7 | 9 | 2 |
| Overall Study | Lost to Follow-up | 8 | 8 | 14 | 11 |
| Overall Study | Non-compliance With IMP | 6 | 5 | 2 | 1 |
| Overall Study | Other (COVID-19 Related) | 0 | 1 | 1 | 0 |
| Overall Study | Other (Not Related to COVID-19) | 2 | 4 | 4 | 5 |
| Overall Study | Physician Decision | 2 | 1 | 2 | 1 |
| Overall Study | Protocol Deviation | 1 | 2 | 1 | 3 |
| Overall Study | Site Terminated by Sponsor | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 33 | 28 | 30 | 28 |
Baseline characteristics
| Characteristic | Prior Centanafadine SR 200 mg | Prior Centanafadine SR 400 mg | Prior Placebo | De Novo Centanafadine SR 400 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 156 Participants | 151 Participants | 187 Participants | 168 Participants | 662 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 34 Participants | 36 Participants | 35 Participants | 50 Participants | 155 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 119 Participants | 112 Participants | 150 Participants | 116 Participants | 497 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 7 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Asian | 7 Participants | 1 Participants | 6 Participants | 9 Participants | 23 Participants |
| Race/Ethnicity, Customized Race Black or African American | 19 Participants | 21 Participants | 16 Participants | 10 Participants | 66 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 8 Participants | 5 Participants | 2 Participants | 3 Participants | 18 Participants |
| Race/Ethnicity, Customized Race Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 121 Participants | 122 Participants | 162 Participants | 144 Participants | 549 Participants |
| Region of Enrollment United States | 156 participants | 151 participants | 187 participants | 168 participants | 662 participants |
| Sex/Gender, Customized Female | 76 Participants | 76 Participants | 94 Participants | 92 Participants | 338 Participants |
| Sex/Gender, Customized Male | 80 Participants | 75 Participants | 93 Participants | 75 Participants | 323 Participants |
| Sex/Gender, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 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 / 154 | 0 / 149 | 0 / 184 | 0 / 166 |
| other Total, other adverse events | 59 / 154 | 49 / 149 | 81 / 184 | 61 / 166 |
| serious Total, serious adverse events | 1 / 154 | 1 / 149 | 7 / 184 | 3 / 166 |
Outcome results
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.
Time frame: From first dose of study drug up to 30 days after last dose of study drug (Up to approximately Week 56)
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prior Centanafadine SR 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With TEAEs | 98 Participants |
| Prior Centanafadine SR 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Mild TEAE | 73 Participants |
| Prior Centanafadine SR 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Moderate TEAE | 58 Participants |
| Prior Centanafadine SR 200 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Severe TEAE | 2 Participants |
| Prior Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Mild TEAE | 59 Participants |
| Prior Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Moderate TEAE | 53 Participants |
| Prior Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Severe TEAE | 4 Participants |
| Prior Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With TEAEs | 89 Participants |
| Prior Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Moderate TEAE | 75 Participants |
| Prior Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Mild TEAE | 92 Participants |
| Prior Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Severe TEAE | 7 Participants |
| Prior Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With TEAEs | 123 Participants |
| De Novo Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Severe TEAE | 3 Participants |
| De Novo Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Mild TEAE | 70 Participants |
| De Novo Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With TEAEs | 91 Participants |
| De Novo Centanafadine SR 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity | Participants With Moderate TEAE | 50 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.
Time frame: Up to 52 weeks or early termination
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.
Time frame: Up to 52 weeks or early termination
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.
Time frame: Up to 52 weeks or early termination