Safety and Efficacy Study of Centanafadine Sustained-Release (CTN SR) in Adults With Attention-Deficit Hyperactivity Disorder (ADHD)
Condition: Attention Deficit Disorder With Hyperactivity
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Intervention: CTN SR; Matching placebo
Intervention description: CTN SR tablets, daily, Orally.; Matching-placebo tablets daily, orally.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 85.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: centanafadine sustained-release; Attention-Deficit Hyperactivity Disorder

Summary:

      This was a Phase 2b, randomized, double-blind, multicenter, 2-period, 2-treatment, crossover
      study to evaluate safety and efficacy of CTN SR compared with placebo in adults with ADHD.
      Efficacy was also evaluated in the subgroup of adults with ADHD treated with a target CTN SR
      dose of 400 mg/day.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Participant was 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, defined as, 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-4).
             Note: DSM-5 was used for screening / diagnosis and DSM-4 was used for evaluation
             throughout the study.

          3. Participant had a Baseline score of greater than or equal to 28 using the
             Attention-Deficit Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV).

          4. Participant had a minimum score of 4 on the Clinical Global Impression of Severity at
             Baseline.

          5. Participant was functioning at an age-appropriate level intellectually, as judged by
             the Investigator.

        Exclusion Criteria:

          1. Participant had a current comorbid psychiatric disorder that was either controlled
             with medications prohibited in this study or was uncontrolled and associated with
             significant symptoms. Exclusionary conditions included any severe comorbid Axis II
             disorder or severe Axis I disorder (such as post-traumatic stress disorder, 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, would have contraindicated CTN SR treatment or confound efficacy
             or safety assessments. Specifically, participants with mild to moderate forms of Axis
             I disorders (for example, social phobia and dysthymia) may have been included, whereas
             participants with a lifetime history of psychosis or bipolar disorder were excluded.
             Comorbid psychiatric diagnosis was 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 were currently considered a suicide risk, any participant who had
             previously made a suicide attempt, or those who were 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 was considered
             a suicide risk. Participants who developed suicidal ideation or behavior during the
             study as measured by the C-SSRS were discontinued and followed appropriately.

          3. The participant had a body mass index of less than 18.5 or greater than or equal to 40
             at Baseline.

          4. Participant had a concurrent chronic or acute illness (such as severe allergic
             rhinitis or an infectious process requiring antibiotics), disability, or other
             condition that might have confounded the results of safety assessments administered in
             the study or that might have increased 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 had no episodes greater than
             or equal to 1 year), or a current diagnosis and/or a known family history of
             Tourette's Disorder (that is, first degree relatives).

          6. Participant had 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 have placed them at increased vulnerability to
             potential sympathomimetic effects.

          7. Participant had a known family history of sudden cardiac death or ventricular
             arrhythmia.

          8. Participant had a history of significant bleeding or coagulation disorder and/or low
             platelet levels (less than 130 x 10^9/liter) or increased international normalized
             ratio (greater than 1.3) at Screening.

          9. Participant had a history of cancer (other than noncomplicated basal or squamous cell
             cancer).

         10. Participant had any clinically significant 12-lead electrocardiogram or clinically
             significant laboratory abnormality at Screening and/or Baseline.

         11. Participant had current abnormal thyroid function, as defined as abnormal Screening
             thyroid stimulating hormone (less than 0.34 or greater than 5.6 micro-International
             Units/milliliter). Treatment with a stable dose of thyroid medication for at least 3
             months was permitted.

         12. Participant had a resting sitting systolic blood pressure (SBP) greater than or equal
             to 140 millimeters of mercury (mm Hg) or diastolic blood pressure (DBP) greater than
             or equal to 90 mm Hg. No more than 1 repeat measurement was permitted.

         13. Participant had a history of hyponatremia.

         14. Participant was 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 had a known history of hypertension.

         17. Participant exhibited lifestyle that may have been confounding to safety or efficacy
             assessments per the judgment of the investigator (for example, exercises, diets or
             travels extensively).

         18. Participant had a known history of glaucoma.

         19. Participant had failed to respond to 1 or more adequate courses (for example, adequate
             dose and duration with poor response as judged by the Investigator) of stimulant
             therapy.

         20. Participant had 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 was taking other medications that have central nervous system effects or
             affected performance, such as sedating antihistamines and decongestant
             sympathomimetic, or was recently on monoamine oxidase inhibitors (during or within 14
             days of investigational product administration). Stable use of bronchodilator inhalers
             was not exclusionary. This also included use of any psychoactive prescription
             medication 30 days prior to Screening or psychoactive over-the-counter ) medication or
             herbal products that required more than a 7-day washout. Participants currently
             treated with methylphenidate or amphetamine products were permitted and underwent a
             7-day washout period. Participants who had taken atomoxetine were required to undergo
             a 30-day washout.

         22. Participant required the frequent or regular use of aspirin, ibuprofen, and naproxen
             sodium, or is on any anticoagulant, such as warfarin.

         23. Participant was taking known potent inhibitors or inducers of common cytochrome P450
             enzymes, including herbal products.

         24. Participant had 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 have been eligible for study participation. The
             Investigator, in conjunction with the Medical Monitor, evaluated the potential impact
             of a positive UDS regarding the continued participation of the participant.

         25. Participant had taken an investigational product or taken part in a clinical study
             within 30 days prior to Screening.

         26. Investigational site personnel were not permitted to participate in the study.

         27. Participant had participated previously in a CTN investigational study.

         28. The female participant was pregnant or lactating.

         29. Participant had a documented allergy, hypersensitivity, or intolerance to CTN or to
             any excipients in the reference product.

         30. Participant had a history of allergy or hypersensitivity to medications (for example.,
             monoamine reuptake inhibitors or antibiotics).

         31. Participant did not agree to or was unable to abstain from consuming alcohol during
             the study.

             Reproductive Potential Requirements

         32. All female participants were required to have a negative serum beta human chorionic
             gonadotropin 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
             post-sterilization or, for females of childbearing potential, had a negative pregnancy
             test prior to entering the study and agreed to use acceptable methods of
             contraception.

             Contraceptive Requirements

         33. Condoms were to be used with all forms of contraception (that is., double-barrier
             method). Acceptable contraceptives included 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 were 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 were used, they were to be administered according to the
             package insert.

         36. Females of childbearing potential who were not currently sexually active agreed to use
             acceptable contraception, as defined above, if they became sexually active during
             their study participation and for the defined follow-up time period.