CompletedNCT03605849Updated Oct 1, 2024Results posted

A Trial Evaluating the Long-term Safety and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder

A Phase 3 interventional study of Centanafadine SR in Attention Deficit Disorder and Attention Deficit Hyperactivity Disorder, sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc.. Completed at 1 site in United States. Open to participants aged 18 Years to 55 Years. Per ClinicalTrials.gov, last updated 2024-10-01.

Sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 662
Allocation: Not applicable
Ages: 18 Years to 55 Years
Sex: All

Study 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).

Read the 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.

Conditions studied

Attention Deficit Disorder
Attention Deficit Hyperactivity Disorder

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Keywords

Centanafadine
ADD
ADHD

Who can participate

Ages eligible: 18 Years to 55 Years
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility 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.

Exclusion Criteria:

Participants who, during the double-blind phase 3 trial experienced, in the opinion of the investigator, poor tolerability to trial medication or whose safety assessments resulted in new concerns that would suggest the participant may not be appropriate for a 52-week treatment with trial medication.
Participants who have re-initiated any therapy for adult ADHD during the 7-day follow-up period after the final treatment visit of the double-blind phase 3 trial.
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 test positive for marijuana may not be permitted to rollover into the open label study, and must agree to refrain from use for the duration of the open label trial. Allowance for participants testing positive for marijuana at time of rollover requires explicit approval from the medical monitor.

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 662 participants (actual)

Study arms

Experimental
Centanafadine
400 mg total daily dose
Drug: Centanafadine SR

Interventions

DrugCentanafadine SR
200mg, BID, oral tablets
Also known as: EB-1020

What researchers measure

Primary outcomes

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)

Other outcomes

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
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
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

Results

Posted Oct 1, 2024

Participant flow

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.

Participant flow — Overall Study
Milestone	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg
Started	156	151	187	168
Safety sample	154	149	184	166
Completed	78	72	92	103
Not completed	78	79	95	65
Withdrew: Adverse event	20	21	29	11
Withdrew: Lack of efficacy	4	7	9	2
Withdrew: Lost to follow-up	8	8	14	11
Withdrew: Non-compliance with imp	6	5	2	1
Withdrew: Protocol deviation	1	2	1	3
Withdrew: Withdrawal by subject	33	28	30	28
Withdrew: Site terminated by sponsor	0	0	0	1
Withdrew: Physician decision	2	1	2	1
Withdrew: Enrolled, but not treated	2	2	3	2
Withdrew: Other (covid-19 related)	0	1	1	0
Withdrew: Other (not related to covid-19)	2	4	4	5

Outcome measures

PrimaryNumber 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)
Reported as:: Count of participants · Participants

Number of Participants With Treatment-emergent Adverse Events (TEAEs) Graded by Severity
Participants	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg
Participants With TEAEs	98	89	123	91
Participants With Mild TEAE	73	59	92	70
Participants With Moderate TEAE	58	53	75	50
Participants With Severe TEAE	2	4	7	3

Other pre-specifiedAdult 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

Results for this outcome have not been posted.

Other pre-specifiedClinical 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

Results for this outcome have not been posted.

Other pre-specifiedADHD 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

Results for this outcome have not been posted.

Adverse events

Collected over From first dose through 30 days after last dose of study drug (Up to approximately Week 56). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Prior Centanafadine SR 200 mg	0/154 (0%)	1/154 (0.6%)	59/154 (38.3%)
Prior Centanafadine SR 400 mg	0/149 (0%)	1/149 (0.7%)	49/149 (32.9%)
Prior Placebo	0/184 (0%)	7/184 (3.8%)	81/184 (44%)
De Novo Centanafadine SR 400 mg	0/166 (0%)	3/166 (1.8%)	61/166 (36.7%)

Most frequent serious events

Showing 10 of 15

Most frequent serious events
Event	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg
Upper Respiratory Tract InfectionInfections and infestations	0/154	1/149	0/184	0/166
Mood SwingsPsychiatric disorders	1/154	0/149	0/184	0/166
SepsisInfections and infestations	0/154	0/149	0/184	1/166
Malignant Melanoma In SituNeoplasms benign, malignant and unspecified (incl cysts and polyps)	0/154	0/149	0/184	1/166
Intentional Self-InjuryPsychiatric disorders	0/154	0/149	1/184	1/166
Suicidal IdeationPsychiatric disorders	0/154	0/149	0/184	1/166
NephrolithiasisRenal and urinary disorders	0/154	0/149	0/184	1/166
UreterolithiasisRenal and urinary disorders	0/154	0/149	0/184	1/166
Angina PectorisCardiac disorders	0/154	0/149	1/184	0/166
Vertigo PositionalEar and labyrinth disorders	0/154	0/149	1/184	0/166

Most frequent other events

Most frequent other events
Event	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg
NauseaGastrointestinal disorders	11/154	7/149	19/184	13/166
InsomniaPsychiatric disorders	9/154	10/149	19/184	14/166
DiarrhoeaGastrointestinal disorders	11/154	6/149	13/184	16/166
NasopharyngitisInfections and infestations	8/154	5/149	16/184	4/166
Decreased AppetiteMetabolism and nutrition disorders	6/154	7/149	16/184	14/166
HeadacheNervous system disorders	7/154	11/149	14/184	14/166
AnxietyPsychiatric disorders	8/154	6/149	12/184	11/166
Dry MouthGastrointestinal disorders	7/154	6/149	12/184	3/166
Upper Respiratory Tract InfectionInfections and infestations	6/154	7/149	11/184	5/166
FatigueGeneral disorders	7/154	4/149	6/184	9/166

Baseline characteristics

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.

Age, Categorical
Age, Categorical(Participants)	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg	Total
<=18 years	0	0	0	0	0
Between 18 and 65 years	156	151	187	168	662
>=65 years	0	0	0	0	0

Sex/Gender, Customized
Sex/Gender, Customized(Participants)	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg	Total
Female	76	76	94	92	338
Male	80	75	93	75	323
Unknown	0	0	0	1	1

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg	Total
Race — White	121	122	162	144	549
Race — Black or African American	19	21	16	10	66
Race — American Indian or Alaska Native	0	2	1	1	4
Race — Asian	7	1	6	9	23
Race — Native Hawaiian or Other Pacific Islander	1	0	0	0	1
Race — Other	8	5	2	3	18
Race — Unknown	0	0	0	1	1

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg	Total
Ethnicity — Hispanic or Latino	34	36	35	50	155
Ethnicity — Not Hispanic or Latino	119	112	150	116	497
Ethnicity — Other	3	1	2	1	7
Ethnicity — Unknown	0	2	0	1	3

Region of Enrollment
Region of Enrollment(participants)	Prior Centanafadine SR 200 mg	Prior Centanafadine SR 400 mg	Prior Placebo	De Novo Centanafadine SR 400 mg	Total
United States	156	151	187	168	662

Study locations

1 site

For additional information regarding sites, contact 844-687-8522
Culver City, California 90230, United States

References and documents

Study documents

Study protocol · Jun 2, 2020
Statistical analysis plan · Sep 15, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol, Sap, Csr

Registry details

Key details

Study ID: NCT03605849
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Responsible party: Sponsor
First posted: Jul 30, 2018
Start date: Feb 14, 2019
Primary completion: Sep 7, 2021
Completion: Sep 7, 2021
Results posted: Oct 1, 2024
Last update: Oct 1, 2024

Oversight

FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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