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Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02547428
Recruitment Status : Completed
First Posted : September 11, 2015
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
This is a Phase IIb, randomized, double-blind, multicenter, 2-period, 2-treatment, crossover study to evaluate safety, efficacy, and duration of efficacy of CTN SR BID target total daily dose (TDD) 400 mg compared with placebo in adults with ADHD.

Condition or disease Intervention/treatment Phase
Attention-Deficit Hyperactivity Disorder Drug: CTN SR Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 85 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase IIb, Randomized, Double-Blind, Multicenter, Placebo-Controlled, Crossover, Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)
Study Start Date : August 2015
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: CTN SR first, then Placebo
Participants will receive CTN SR at a TDD of 400 mg followed by placebo (after washout period). CTN SR will be titrated up from 100 to 400 mg daily, at specified increments, for 3 weeks. Placebo will be titrated in the same manner to protect the blind.
Drug: CTN SR
Participants will receive CTN SR tablets in a 100-mg dose strength, designed for twice-daily (BID) oral (PO) administration.
Other Name: Centanafadine Sustained-Release

Drug: Placebo
Participants will receive CTN SR matching placebo tablets, orally twice daily, titrated in the same manner as CTN SR to protect the blind.

Experimental: Placebo first, then CTN SR
Participants will receive placebo followed by CTN SR at a TDD of 400 mg (after washout period). CTN SR will be titrated up from 100 to 400 mg daily, at specified increments, for 3 weeks. Placebo will be titrated in the same manner to protect the blind.
Drug: CTN SR
Participants will receive CTN SR tablets in a 100-mg dose strength, designed for twice-daily (BID) oral (PO) administration.
Other Name: Centanafadine Sustained-Release

Drug: Placebo
Participants will receive CTN SR matching placebo tablets, orally twice daily, titrated in the same manner as CTN SR to protect the blind.




Primary Outcome Measures :
  1. Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score [ Time Frame: Week 3 ]
    The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items may be grouped into 2 subscales: Hyperactivity/Impulsivity and Inattentiveness. Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The scale is subdivided into 2 subscales of 9 symptoms each: hyperactivity/impulsivity and inattentiveness.

  2. Total Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Score for subgroup of participants with target CTN SR dose of 400 mg/day [ Time Frame: Week 3 ]
    The ADHD-RS-IV consists of 18 items and is designed to reflect the participant's current ADHD symptomatology; the severity, frequency, and impairment are measured for each of the items. The 18 items may be grouped into 2 subscales: Hyperactivity/Impulsivity and Inattentiveness. Each item is scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms), with the total score for the rating scale ranging from 0 to 54. The scale is subdivided into 2 subscales of 9 symptoms each: hyperactivity/impulsivity and inattentiveness.


Secondary Outcome Measures :
  1. ADHD-RS-IV Score total score after 1 and 2 weeks of treatment [ Time Frame: Week 1 (Baseline) and Week 2 ]
  2. ADHD-RS-IV Inattention subscale score [ Time Frame: Week 1 (Baseline), Week 2, and Week 3 ]
  3. ADHD-RS-IV Hyperactivity/Impulsivity subscale score [ Time Frame: Week 1 (Baseline), Week 2, and Week 3 ]
  4. Permanent Product Measure of Performance (PERMP) Score [ Time Frame: Week 4 and Week 8 ]
    The PERMP is a 10-minute, individual performance adjusted, math test that provides an objective measure of performance that is time-sensitive and ADHD medication-sensitive. Participants are given 5 pages of 80 math problems and are instructed to complete as many problems as possible in 10 minutes. Performance is measured by the PERMP, which is a permanent product score (the number of problems worked correctly and number of problems attempted). Total score, number of math problems attempted, and PERMP score for the number of math problems answered correctly will be evaluated.

  5. Clinical Global Impressions of Severity (CGI-S) Score [ Time Frame: Week 1 (Baseline) ]
    The CGI-S is performed to rate the severity of a participant's condition on a 7- point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants).

  6. Evaluate global impressions of ADHD severity as measured by the Clinical Global Impressions of Improvement (CGI-I) [ Time Frame: Week 1 (Baseline), Week 2, Week 3, Week 5, Week 6, Week 7, and Week 9 ]
    The CGI-I permits a global evaluation of the participant's improvement over time. The CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). The CGI-I is completed by the clinician and assesses the participant's improvement relative to the symptoms at Baseline.

  7. The Number of participants with treatment-emergent adverse events (TEAEs) [ Time Frame: From signing of informed consent up to approximately Week 9, or until all safety concerns, in the opinion of the Investigator, are resolved. ]
    Safety measurements also include specific evaluation of blood pressure and pulse rate, 12-lead electrocardiogram (ECG), and physical examination.

  8. Maximum concentration (Cmax) [ Time Frame: Week 4 and Week 8 ]
  9. Time to maximum concentration (tmax) [ Time Frame: Week 4 and Week 8 ]
  10. Area under the concentration-time curve during the steady-state 24-hour dosing interval (AUC0-t) [ Time Frame: Week 4 and Week 8 ]
  11. Elimination phase half-life (t½) [ Time Frame: Week 4 and Week 8 ]
  12. Last measurable concentration (Clast) [ Time Frame: Week 4 and Week 8 ]
  13. Time point of the last measurable concentration (tlast) [ Time Frame: Week 4 and Week 8 ]
  14. Elimination phase rate constant (ke) [ Time Frame: Week 4 and Week 8 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant is 18 to 60 years of age, inclusive, at the time of consent
  2. Participant meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD, any presentation, established by a comprehensive psychiatric evaluation based on DSM-5 criteria with at least 5 of the 9 subtype criteria met, as determined by the Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (CAADID Part II)
  3. Participant has a Baseline score of greater than or equal to 28 using the ADHD-RS-IV
  4. Participant has a minimum score of 4 on the CGI-S at Baseline
  5. Participant is functioning at an age-appropriate level intellectually, as judged by the Investigator

Exclusion Criteria:

  1. Participant has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms. Exclusionary conditions include any severe comorbid Axis II disorder or severe Axis I disorder (such as post-traumatic stress disorder [PTSD], psychosis, bipolar illness, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder) or other symptomatic manifestations that, in the opinion of the examining physician, will contraindicate CTN SR treatment or confound efficacy or safety assessments. Specifically, participants with mild to moderate forms of Axis I disorders (e.g., social phobia and dysthymia) may be included, whereas participants with a lifetime history of psychosis or bipolar disorder will be excluded. Comorbid psychiatric diagnosis will be established by a Semi-Structured Clinical Interview for DSM-5 Axis I Disorders (the Mini lnternational Neuropsychiatric lnterview, Version 6.0 [M.I.N.I. 6.0]).
  2. Participants who are currently considered a suicide risk, any participant who had previously made a suicide attempt, or those who are currently demonstrating active suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening, or if in the opinion of the investigator the participant is considered a suicide risk. Participants who develop suicidal ideation or behavior during the trial as measured by the C-SSRS will be discontinued and followed appropriately.
  3. The participant has a body mass index (BMI) of less than 18.5 or greater than or equal to 40 at Baseline
  4. Participant has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might confound the results of safety assessments administered in the study or that might increase risk to the participant
  5. Participant had a history of seizures (other than infantile febrile seizures), any tic disorder (except transient tic disorder and participant has no episodes greater than or equal to 1 year), or a current diagnosis and/or a known family history of Tourette's Disorder (i.e. first degree relatives)
  6. Participant has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke or other serious cardiac problems that may place them at increased vulnerability to potential sympathomimetic effects
  7. Participant has a known family history of sudden cardiac death or ventricular arrhythmia
  8. Participant has a history of significant bleeding or coagulation disorder and/or low platelet levels (less than 130 X 109/L) or increased international normalized ratio (INR) (greater than 1.3) at Screening
  9. Participant has a history of cancer
  10. Participant has any clinically significant 12-lead ECG or clinically significant laboratory abnormality at Screening and/or Baseline
  11. Participant has current abnormal thyroid function, as defined as abnormal Screening thyroid stimulating hormone (less than 0.34 or greater than 5.6 μIU/mL). Treatment with a stable dose of thyroid medication for at least 3 months is permitted.
  12. Participant has a resting sitting systolic blood pressure (SBP) greater than or equal to 140 mm Hg or diastolic blood pressure (DBP) greater than or equal to 90 mm Hg. No more than 1 repeat measurement will be permitted.
  13. Participant has a history of hyponatremia
  14. Participant is on an antihypertensive medication of any kind
  15. Participant has a known history of orthostatic hypotension or has an orthostatic blood pressure drop of greater than or equal to 20 mm Hg (based on the drop between sitting and standing [3 minutes] SBP) at Screening or Baseline
  16. Participant has a known history of hypertension
  17. Participant exhibits lifestyle that may be confounding to safety or efficacy assessments per the judgment of the investigator (e.g. exercises, diets or travels extensively)
  18. Participant has a known history of glaucoma
  19. Participant has failed to respond to 1 or more adequate courses (e.g., adequate dose and duration with poor response as judged by the Investigator) of stimulant therapy
  20. Participant has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-5 criteria
  21. Participant is taking other medications that have central nervous system (CNS) effects or affect performance, such as sedating antihistamines and decongestant sympathomimetic, or was recently on monoamine oxidase inhibitors (during or within 14 days of investigational product [IP] administration). Stable use of bronchodilator inhalers is not exclusionary. This also includes use of any psychoactive prescription medication within 30 days prior to Screening or psychoactive over-the-counter (OTC) medication or herbal products that require more than a 7-day washout. Participants currently treated with methylphenidate or amphetamine products are permitted and will undergo a 7-day washout period. Participants who have taken atomoxetine will be required to undergo a 30-day washout.
  22. Participant requires the frequent or regular use of aspirin, ibuprofen, and naproxen sodium, or is on any anticoagulant, such as warfarin
  23. Participants taking known potent inhibitors or inducers of common cytochrome P450 (CYP) enzymes, including herbal products
  24. Participant has a positive urine drug screen (UDS) result at Screening or Baseline. NOTE: The UDS must be negative at Screening (with the exception of the participant's current ADHD psychostimulant, if applicable) or Baseline, if applicable, for the participant to potentially be eligible for study participation. The Investigator, in conjunction with the Medical Monitor, will evaluate the potential impact of a positive UDS regarding the continued participation of the participant.
  25. Participant has taken an investigational product or taken part in a clinical study within 30 days prior to Screening
  26. Investigational site personnel are not permitted to participate in the study
  27. Participant has participated previously in a CTN investigational study
  28. The female participant is pregnant or lactating
  29. Participant has a documented allergy, hypersensitivity, or intolerance to CTN or to any excipients in the reference product
  30. Participant has a history of allergy or hypersensitivity to medications (e.g., monoamine reuptake inhibitors or antibiotics)
  31. Participant does not agree to or is unable to abstain from consuming alcohol during the study

    Reproductive Potential Requirements

  32. All female participants are required to have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test at Screening, a negative urine pregnancy test at Baseline, and be either postmenopausal (12 consecutive months of spontaneous amenorrhea and greater than or equal to 51 years of age), surgically sterile and at least 6 weeks poststerilization or, for females of childbearing potential, have a negative pregnancy test prior to entering the study and agree to use acceptable methods of contraception

    Contraceptive Requirements

  33. Condoms are to be used with all forms of contraception (i.e., double-barrier method). Acceptable contraceptives include the following:

    1. Intrauterine devices
    2. Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring)
    3. Diaphragms with spermicidal gel or foam
  34. Females of childbearing potential will be advised to use acceptable contraceptives from the date of informed consent throughout the study period and for the defined follow-up period
  35. If hormonal contraceptives are used, they are to be administered according to the package insert
  36. Females of childbearing potential who are not currently sexually active agree to use acceptable contraception, as defined above, if they became sexually active during their study participation and for the defined follow-up time period

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02547428


Locations
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United States, California
Newport Beach, California, United States
United States, Florida
Bradenton, Florida, United States
Maitland, Florida, United States
United States, Nevada
Las Vegas, Nevada, United States
United States, North Carolina
Durham, North Carolina, United States
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02547428    
Other Study ID Numbers: NVI-EB-1020-202
First Posted: September 11, 2015    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Hyperkinesis
Attention Deficit Disorder with Hyperactivity
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Dyskinesias
Neurologic Manifestations
Nervous System Diseases