Study of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 Sustained Release (SR) in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder

Phase 2CompletedNCT01939353

Otsuka Pharmaceutical Development & Commercialization, Inc.45 enrolled

Overview

This was a Phase 2 exploratory study to evaluate the efficacy and safety of EB-1020 SR (centanafadine sustained release \[CTN SR\]) in treating participants who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for Attention-Deficit Hyperactivity Disorder (ADHD) on the Mini International Neuropsychiatric Interview Plus, Version 6.0 (M.I.N.I.-Plus). Evaluations included determining an effectiveness signal for ADHD and related symptoms and exploring dosing, tolerability, onset of action, and duration of effect. Dose-response/tolerability relationships with CTN SR were also explored. The 1-week placebo run-in \[single-blind (SB)\] was also used for informal safety comparison purposes.

This Phase 2, flexible-dosage, single-blind exploratory study of CTN SR in adult male participants with ADHD consisted of a 1-week placebo run-in (SB), 4 weeks of treatment with CTN SR, and 2 weeks of follow-up. At the placebo run-in, participants must have had a score of greater than or equal to 28 on the Adult Attention-Deficit Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) to be eligible to continue participation in the study. At the end of single-blind placebo run-in treatment (that is, beginning of CTN SR treatment), the ADHD-RS-IV with adult prompts was re-administered. Participants who showed an improvement greater than or equal to 30% over baseline values or who had a score of less than 28 on the ADHD-RS-IV were withdrawn from the study prior to receiving any active drug. Those who showed less than 30% improvement from the placebo run-in to the beginning of CTN SR treatment continued the study. The consent form was phrased such that participants were not informed of the exact timing of CTN SR versus placebo treatment in order to maintain the blinded nature of the placebo treatment and reduce potential placebo effects. Dosing was flexible, with a target maximum dosage of 500 milligrams (mg) daily in divided doses (morning and afternoon, approximately 5 hours later) to be achieved if possible during Week 2 of CTN SR treatment. The participants took a starting dose of 100 mg of CTN SR daily; the dose was titrated in 100 mg increments up to the maximum dosage of 500 mg daily. The treating physician escalated the dose to the maximum dose if participants had not achieved remission of ADHD in his/her judgment, and CTN SR was still well tolerated. If in the physician's judgment the participant could not tolerate further dose escalation, or was not tolerating the current dose well, the dose was maintained or reduced, with the goal of re-assessing dose and response at the subsequent visit for a possible increase in dose, until study completion.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 55 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participants had to be able to understand the nature of the study, agree to comply with the prescribed dosage regimens, report for regularly scheduled office visits, and communicate to study personnel about adverse events and concomitant medication use. 2. Participants must have met DSM-IV-TR diagnostic criteria for ADHD (Combined, Predominantly Inattentive or Predominantly Hyperactive-Impulsive Types) on the M.I.N.I.-Plus. 3. Participants must have had an ADHD-RS-IV score of greater than or equal to 28 at the placebo run-in baseline and CTN SR treatment baseline. 4. Participants must have had a Clinical Global Impression of Severity (ADHD version) score of greater than or equal to 4. 5. Participants must be able to read well enough to understand the informed consent form and other participant materials. 6. Participants must have been able to be reliably rated on the psychiatric scales required by the protocol based on investigator's judgment. 7. Participants must have been able to read and understand English. 8. Participants must have had a body mass index of approximately 18 to 35 kilograms/meter squared. 9. Sexually active, fertile males must have used effective birth control if their partners were women of childbearing potential. Women of childbearing potential (if a partner of a male participant) included any female who had experienced menarche and who had not undergone successful surgical sterilization or women on hormone replacement therapy with documented serum follicle stimulating hormone level greater than 35 milli-international units/milliliter. Even women who were using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or were practicing abstinence or where the partner was sterile (for example, vasectomy), should have been considered to be of childbearing potential. Exclusion Criteria: 1. Participant had a DSM-IV-TR diagnosis of ADHD not otherwise specified. 2. Participants rated as having a greater than or equal to 30% improvement in ADHD symptoms or a score of less than 28 on the ADHD-RS-IV after Week 1 (placebo run-in). Such participants were withdrawn from the study prior to receiving any active drug. 3. Participant had a current or lifetime history of bipolar disorder or any psychotic disorder as established by M.I.N.I.-Plus. 4. Participant had a current history (past 90 days) of major depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder or post-traumatic stress disorder as established by the M.I.N.I.-Plus. 5. History in the past 20 years of electroconvulsive therapy or lifetime history of vagal nerve stimulation or deep brain stimulation for the treatment of depression. 6. Participants with a history of drug or alcohol use disorders (abuse or dependence) must have been free of the diagnosis and of substance use for at least 6 months prior to the Screening visit. 7. Participant had a history of epilepsy, seizures, syncope, unexplained blackout spell(s), head trauma with clinically significant loss of consciousness or noninfantile febrile seizures. 8. Participant had a currently active medical condition (other than ADHD) that, in the opinion of the investigator, could have interfered with the ability of the participant to participate in the study safely. 9. Participant had a history of clinically significant, diagnosed cardiovascular disease of any kind, including uncontrolled hypertension. Participant had newly diagnosed cardiovascular disease of any kind in the investigator's judgment. 10. The participant had an intelligence quotient less than 80. 11. In the opinion of the investigator, the participant had not derived significant therapeutic benefit from 2 or more ADHD therapies given with an adequate dose and duration in adulthood (age 18 or older); that is, 1 failed course of treatment was acceptable, but 2 failed courses of treatment were not acceptable. 12. Participant taking medication specifically for treatment of ADHD symptoms (for example, stimulants, atomoxetine, tricyclic antidepressants, bupropion, modafinil) must have been off stimulants for 2 weeks and off nonstimulant ADHD therapies for 3 weeks prior to the placebo run-in visit and must have returned to the baseline level of ADHD symptoms in the opinion of the investigator. Participants must not have had evidence of a discontinuation or withdrawal reaction. 13. Participant was currently taking any antidepressant medication for any condition. 14. Participant was currently taking antipsychotic medication or an anticonvulsant medication (for example, phenytoin, carbamazepine, lamotrigine, or valproic acid) at anticonvulsant doses. 15. Participant had a known history of allergy to CTN. 16. Participant was unwilling to refrain from taking medications that may have interfered with the assessment of cognitive function and the assessment of sleep. Examples included benzodiazepines, sedating antihistamines, zolpidem, eszopiclone, and zaleplon. Herbal preparations with effects on the central nervous system also were prohibited throughout the study (for example, St. John's Wort or melatonin). 17. Participant had a history of sleep problems in the last 3 months. 18. Participant was unwilling to refrain from taking more than 1 unit of alcohol within 24 hours of the investigational center visits. 19. Participant was unwilling to restrict caffeine to no more than 500 mg/day (5 cups of coffee). 20. Participant was actively using any drugs with potential for abuse (for example, marijuana, cocaine, amphetamines). 21. Participant reported passive or active suicidal ideation or intent. 22. Participant was concurrently participating in another clinical research study or investigational drug study or had participated in such a study within the past 1 month. 23. Participant was at high risk of nonadherence to investigational product and the protocol regimen in the investigator's opinion. 24. Participant could not have begun psychotherapy during the study, but may have continued therapy at the same intensity and frequency, if begun at least 3 months prior to placebo run-in. Exclusion Criteria, Physical and Laboratory Test Findings 1. Participants who had a positive urine drug screen, which could not be explained by prescribed medications. The urine drug screen may have been repeated based on investigator judgment. 2. Participants with clinically significantly abnormal thyroid-stimulating hormone or a positive result on a standard hepatitis-screening panel or human immunodeficiency virus screen. Note: Adequate thyroid replacement for a previously diagnosed thyroid deficiency, which had been stable for 3 months or more, was acceptable. 3. Participants with clinically significant laboratory abnormalities or with clinical laboratory values of potential clinical concern. 4. Diastolic blood pressure greater than 85 millimeters of mercury (mmHg) at placebo run-in. 5. Systolic blood pressure greater than 135 mmHg at placebo run-in. 6. Participant had a QT interval of greater than 450 milliseconds on 2 or more electrocardiogram tracings taken within 15 minutes, assessed with the participant in a supine position for 3 minutes. Other Exclusion Criteria 1. Prisoners or participants who were involuntarily incarcerated. 2. Participants who had a compulsory detainment for treatment of either a psychiatric or a physical illness. 3. Participants who planned to have elective surgeries during the course of the study. 4. Participants with a history of antidepressant-induced hypomania or dysphoria.

Outcomes

Primary Outcomes

Change From Baseline-2 in ADHD Symptoms to Week 4 as Assessed by the Adult Attention-Deficit Hyperactivity Disorder Rating Scale (AD HD-RS-IV)

The ADHD-RS-IV consists of 18 items with first 9 items assessing inattentive symptoms and the last 9 items assessing hyperactive-impulsive symptoms scored on a 4-point Likert-type severity scale with 0 (none), 1 (mild), 2 (moderate), and 3 (severe) with a total score ranging from 0 to 54. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR. A negative change from Baseline indicates improvement.

Time frame: Baseline, Week 4

Secondary Outcomes

Change From Baseline-2 in ADHD Symptoms as Assessed by the Adult ADHD-RS-IV

Time frame: Baseline-2, Weeks 1, 2, 3, and 6 (Follow-up Visit)

Change From Baseline-2 to Week 4 on the Behavior Rating Inventory of Executive Function, Adult Version (BRIEF-A) Scale

BRIEF-A is a standardized self-administered scale that captures an adult's executive functions or self-regulation in their everyday environment, composed of 75 items within 9 nonoverlapping derived clinical scales and measures various aspects of executive functioning, including the following: inhibit, self-monitor shift, emotional control, initiate, working memory, plan/organize, monitor, and organization of materials. Items are rated 1=never, 2=sometimes, and 3=often; total raw scale score ranges from 75-225, higher total scores=more problems with executive functioning. Raw scale scores are used to generate T-scores. Total T-scores range from 30 to 90, with broader composite indexes including Behavioral Regulation Index(BRI) and Metacognition Index(Ml). These indexes form overall summary score, the Global Executive Composite(GEC). Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR. A negative change from Baseline indicates improvement.

Time frame: Baseline-2 and Week 4

Percentage of Participants Who Are Responders for ADHD Symptoms as Measured by the ADHD-RS-IV

Responders are defined as participants with ≥30% improvement in ADHD symptoms compared with Baseline-2, as measured by the ADHD-RS-IV. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR.

Time frame: Baseline-2, Weeks 1, 2, 3, and 4

Percentage of Participants Who Are High Responders for ADHD Symptoms as Measured by the ADHD-RS-IV

High responders are defined as participants with ≥50% improvement in ADHD symptoms compared with Baseline-2, as measured by the ADHD-RS-IV. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR.

Time frame: Baseline-2, Weeks 1, 2, 3, and 4

Change From Baseline-2 on the Inattentiveness and Hyperactivity/Impulsivity Subscales of ADHD-RS-IV

The ADHD-RS-IV consists of 18 items with first 9 items assessing inattentive symptoms and the last 9 items assessing hyperactive-impulsive symptoms scored on a 4-point Likert-type severity scale with 0=none, 1=mild, 2=moderate, and 3=severe, with a total score ranging from 0 to 54. Inattention and hyperactivity/impulsivity subscales consist of 9 items each, for total subscale scores ranging from 0 to 27. Higher scores are indicative of more severe symptoms. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR. A negative change from Baseline indicates improvement.

Time frame: Baseline-2, Weeks 1, 2, 3 and 4

Change From Baseline-2 in the Clinical Global Impression of Severity (CGI-S) [ADHD Version] Scale Score

CGI-S is an observer-rated scale that is used to assess the severity of the participants condition on a 7-point scale ranging from 1 to 7, where 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill. This rating is based upon observed and reported symptoms, behavior, and function in the past 7 days with a minimum score of 1 and maximum score of 7. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR. A negative change from Baseline indicates improvement.

Time frame: Baseline-2, Weeks 1, 2, 3, 4 and 6 (Follow-up Visit)

Change From Baseline-2 in the Clinical Global Impression of Improvement (CGl-I) [ADHD Version] Scale Score

CGl-I is an observer-rated scale to assess how much the participant's illness has improved or worsened relative to a Baseline state, with scores ranging from 1 to 7. It consists of a 7-point scale ranging from 1 to 7, where 1=very much improved; 2=much improved; 3=minimally improved; 4=no change from Baseline-2 (the initiation of treatment); 5=minimally worse; 6=much worse; and 7=very much worse since the initiation of treatment. Improvement is defined as a score of 1=very much improved or 2=much improved on the scale. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR.

Time frame: Baseline-2, Weeks 1, 2, 3, 4 and 6 (Follow-up)

Percentage of Responders to the CGl-I (ADHD Version) Scale

CGl-I is an observer-rated scale to assess how much the participant's illness has improved or worsened relative to a Baseline state, with scores ranging from 1 to 7. It consists of a 7-point scale ranging from 1 to 7, where 1=very much improved; 2=much improved; 3=minimally improved; 4=no change from Baseline-2 (the initiation of treatment); 5=minimally worse; 6=much worse; and 7=very much worse since the initiation of treatment. Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale. Responders are defined as those who had CGI-I (ADHD version) scores of much or very much improved.

Time frame: Weeks 4 and 6 (Follow-up Visit)

Change From Baseline-2 in the Columbia-Suicide Severity Rating Scale (C-SSRS)

C-SSRS is a brief method of assessing both behavior and ideation that tracks all suicidal events, and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation, and deterrents), all of which are significantly predictive of completed suicide. Severity of suicidal ideation is rated on a 6-point scale from 0=no ideation present to 5=active ideation with plan and intent. Suicidal behavior was collected as presence/absence of actual attempts, non-suicidal self-injurious behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal behavior.

Time frame: Baseline-2, Weeks 1, 4, and 6 (Follow-up Visit)

Change From Baseline-2 on the Profile of Mood States, Second Edition, Short Version 2A (POMS 2-A Short) at Week 4

POMS 2-A Short version consists of a subset of 35 items from the full-length version of 72 mood adjectives assessing 7 mood domains namely, anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, tension-anxiety, vigor-activity, and friendliness. High scores indicate better vigor-activity and friendliness, but more severe symptoms for the five other domains. In addition, the Total Mood Disturbance (TMD) score is calculated from anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, tension-anxiety, and vigor-activity. Participants rated each of the 35 items using 4-point Likert-type scale (0=much unlike this; 3=much like this). Items from each domain are summed T-score such that total scores were in the negative-mood direction (i.e., higher scores indicate greater experience of negative moods). Total scores range from 0 to 100. TMD is calculated based on a standard value (mean of 50 and standard deviation of 10).

Time frame: Baseline-2 and Week 4

Change From Baseline-2 on the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) at Week 4

WRAADDS is used to measure the severity of symptoms in adults with ADHD. This structured interview consists of 28 items in 7 psychopathologic domains, which were rated by a clinical expert on a 0 to 2-point Likert scale. The psychopathologic 7 domains are inattention, hyperactivity, affective lability, hot temper, stress intolerance, disorganization, and impulsivity. The scale rated individual items from 0 to 2 (0=not present, 1=mild, 2=clearly present) and summarized each of the 7 categories on a 0-to-4 scale (0=none, 1=mild, 2=moderate, 3=quite a bit, 4=very much). The WRAADDS total score is defined as sum of all 28 item sub scores (range 0 to 56), higher scores indicate worsening of symptoms. Baseline-2 is defined as an end of 1-week SB placebo run-in and beginning of treatment with CTN SR. A negative change from Baseline indicates improvement. Change from Baseline-2 for the WRAADDS scale is calculated using total scores.

Time frame: Baseline-2 and Week 4

Change From Baseline-2 on the Weiss Functional Impairment Rating Scale - Self Report (WFIRS-S) at Week 4

The WFIRS-S is a validated rating scale used to capture functional difficulties in the lives of individuals with ADHD. It investigates emotional or behavioral problems and is comprised of 69 items grouped into six domains: family (8 items), work (11 items), school (10 items, includes learning \[4 items\] and behavior \[6 items\]), life skills (12 items), self-concept (5 items), social (9 items), and risky (14 items). It uses a 4-point Likert scale where 0=never or not at all, 1=sometimes or somewhat, 2=often or much, and 3=very often or very much. Any item rating of 2 or 3 was considered in the clinically impaired range. A total score was derived by summing all scores from every domain, ranging from 0 to 207 with higher scores=greater ADHD-related functional impairment.

Time frame: Baseline and Week 4

Change From Week 4 to End of Discontinuation Phase (Follow-up) on the ADHD-RS-IV

The change on the ADHD-RS-IV was used to assess relapse of symptoms after end of investigational product administration.

Time frame: Week 4 and end of Discontinuation Phase (Week 6)

Study of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 Sustained Release (SR) in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder

Overview

Conditions

Interventions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes