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An Exploratory, Single-Blind Pilot Study Of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 SR in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder

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ClinicalTrials.gov Identifier: NCT01939353
Recruitment Status : Completed
First Posted : September 11, 2013
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
This is a Phase 2 exploratory study being conducted to evaluate the efficacy and safety of EB-1020 SR in treating adult male patients who meet DSM-IV-TR diagnostic criteria for ADHD on the M.I.N.I.-Plus. Evaluations include 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 EB-1020 SR will also be explored. The 1-week placebo lead-in also will be used for informal safety comparison purposes.

Condition or disease Intervention/treatment Phase
Adult ADHD Drug: EB-1020 SR Drug: Matching Placebo Phase 2

Detailed Description:
This Phase 2, flexible-dosage, single-blind study consists of a Screening Phase (up to 28 days [Visit 1]), a 5-week Treatment Phase (1 week of treatment with placebo [Baseline-1/Visit 2 to Baseline-2/Visit 3] followed by 4 weeks of treatment with EB-1020 SR [Weeks 1 through 4/Visits 4 through 7]), and a 2-week Discontinuation Phase, which starts at the time of Week 4/Visit 7 and includes a Follow-up Visit (Week 6/Visit 7). Approximately 40 patients are planned to enter the treatment period. At Baseline-1, patients must have a score of greater than or equal to 28 on the ADHD-RS-IV to be eligible to continue participation in the study. At the end of single-blind placebo treatment (i.e., Baseline-2), the ADHD-RS-IV with adult prompts is re-administered. Patients who show an improvement greater than or equal to 30% over baseline values or who have a score of less than 28 on the ADHD-RS-IV are withdrawn from the study prior to receiving any active drug. Those who show less than 30% improvement from Baseline-1 to Baseline-2 scores will continue in the study. The consent form will be phrased such that patients are not informed of the exact timing of EB-1020 SR vs. placebo treatment in order to maintain the blinded nature of the placebo treatment and reduce potential placebo effects. Dosing will be flexible, with a target maximum dosage of 500 mg daily in divided doses (morning and afternoon, approximately 5 hours later) to be achieved if possible during Week 2 of EB-1020 SR treatment. The patient will take a starting dose of 100 mg of EB-1020 SR daily; the dose will be titrated in 100 mg increments up to the maximum dosage of 500 mg daily. The treating physician will escalate the dose to the maximum dose if patients have not achieved remission of ADHD in his/her judgment, and EB-1020 SR is still well tolerated. If in the physician's judgment the patient could not tolerate further dose escalation, or is not tolerating the current dose well, the dose may be 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: An Exploratory, Single-Blind Pilot Study Of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 SR in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder
Study Start Date : September 2013
Actual Primary Completion Date : February 2014
Actual Study Completion Date : February 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: EB-1020 SR
100-500 mg flexible titration
Drug: EB-1020 SR
100-500 mg flexible titration

Placebo Comparator: Placebo
Matching Placebo
Drug: Matching Placebo



Primary Outcome Measures :
  1. Change from Baseline-2 in Attention-Deficit Hyperactivity Disorder (ADHD) symptoms to Week 4 after investigational product administration, as assessed by the adult Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) [ Time Frame: Baseline-2 and Week 4 ]
    Change in ADHD symptoms from Baseline-2 (after one week of placebo treatment) to Week 4 as assessed by the ADHD-RS-IV total score. The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.


Secondary Outcome Measures :
  1. Change from Baseline-2 on the adult ADHD-RS-IV [ Time Frame: Baseline-2, Weeks 1, 2, 3, 4, and 6 (Follow-up) ]
    Change in the ADHD-RS-IV total score from Baseline-2. The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.

  2. Change from Baseline-2 on the Behavior Rating Inventory of Executive Function, Adult Version (BRIEF-A) [ Time Frame: Baseline-2 and Week 4 ]
    BRIEF-A is a validated 75-item questionnaire composed of three indexes (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. Total scores range from 30 to 90, with broader composite indexes including the Behavioral Regulation Index (BRI) and the Metacognition Index (MI). These indexes form the overall summary score, the Global Executive Composite (GEC).

  3. Percentage of participants who are Responders [ Time Frame: Baseline-2, Weeks 1, 2, 3, and 4 ]
    Responders are defined as those who have a greater or equal to 30% improvement in ADHD symptoms compared with Baseline-2, as measured by the ADHD-RS-IV.

  4. Percentage of participants who are High Responders [ Time Frame: Baseline-2, Weeks 1, 2, 3, and 4 ]
    High responders are defined as those who have greater than 50% improvement in ADHD symptoms compared with Baseline-2, as measured by the ADHD-RS-IV

  5. Change from Baseline-2 on the inattentiveness and hyperactivity/impulsivity subscales of ADHD-RS-IV [ Time Frame: Baseline-2, Weeks 1, 2, 3, and 4 ]
    Change in the ADHD-RS-IV total score from Baseline-2. The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. Total scores range 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

  6. Change from Baseline-2 outcome, as measured by the Clinical Global Impression of Severity (CGI-S [ADHD version]) and the Clinical Global Impression of Improvement (CGI-I [ADHD version]) [ Time Frame: Baseline-2, Weeks 1, 2, 3, 4 and 6 (Follow-up) ]
    CGI-S assesses the severity of the participants condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill). Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.

  7. Percentage of Responders to the CGI-I (ADHD version) [ Time Frame: Weeks 4 and 6 (Follow-up) ]
    Responders to the CGI-I (ADHD version) are defined as those with scores of much or very much improved

  8. Change from Baseline-2 on the Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline-2, Weeks 1, 4, and 6 (Follow-up) ]
    C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The assessment is done by the nature of the responses, not by a numbered scale.

  9. Change from Baseline-2 on the Profile of Mood States, 2nd Edition, Short Version 2-A (POMS 2-A Short) [ Time Frame: Baseline-2 and Week 4 ]
    POMS 2-A Short version consists of subset of 35 items from the full-length version of 72 mood adjectives assessing 6 mood domains: (i) Compose/Anxious (ii) Agreeable/Hostile (iii) Elated/Depressed (iv) Confident/Unsure (v) Energetic/Tired and (vi) Clearheaded/Confused. Participants rate each of the 35 items using a 4-point Likert-type scale (0=much unlike this; 3=much like this). Items from each domain are summed such that total scores are in the negative- mood direction (i.e., higher scores indicate greater experience of negative moods).

  10. Change from Baseline-2 on the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) [ Time Frame: Baseline-2 and Week 4 ]
    This structured interview consists of 28 items in 7 psychopathologic domains, which are rated by a clinical expert on a 0- to 2-point Likert scale. The psychopathologic domains are inattention, hyperactivity, affective lability, hot temper, stress intolerance, disorganization, and impulsivity. The WRAADDS is used to measure the severity of symptoms in adults with ADHD.

  11. Change from Baseline-2 on the Weiss Functional Impairment Rating Scale - Self Report (WFIRS-S) [ Time Frame: Baseline-2 and Week 4 ]
    The WFIRS-S is a validated rating scale that is used to capture functional difficulties in the lives of individuals with ADHD. It investigates emotional or behavioral problems over the last month in the domains of family, work, school, life skills, self-concept, social problems, and risk-taking. 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 is considered in the clinically impaired range. A total score is derived by summing all scores from every domain.

  12. Change from Week 4 to end of Discontinuation Phase (Follow-up visit) on the ADHD-RS-IV [ Time Frame: Week 4 and End of Discontinuation Phase (Week 6) ]
    Assessment for relapse of symptoms after end of investigational product administration as measured by ADHD-RS-IV



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Signed Written Informed Consent

1. Patients must be able to give informed consent, as required by the Institutional Review Board (IRB), prior to the initiation of any procedures required per protocol.

Target Population

  1. Patients must 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. Patients must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for ADHD (Combined, Predominantly Inattentive or Predominantly Hyperactive-Impulsive Types) on the Mini International Neuropsychiatric Interview Plus, Version 6.0 (M.I.N.I.-Plus)
  3. Patients must have an ADHD-RS-IV score of greater than or equal to 28 at Baseline-1 and Baseline-2.
  4. Patients must have a CGI-S (ADHD version) score of greater than or equal to 4.
  5. Patients must be male.
  6. Patients must be 18 to 55 years old, inclusive.
  7. Patients must be able to read well enough to understand the informed consent form and other patient materials.
  8. Patients must be able to be reliably rated on the psychiatric scales required by the protocol based on investigator's judgment.
  9. Patients must be able to read and understand English.
  10. Patients must have a body mass index (BMI) of approximately 18 to 35 kg/m2. The BMI is to be calculated using the following formula: mass (lb) x 703/(height (in))2. Guidelines for this calculation will be provided to the investigational centers.

Sex and Contraceptive Criteria

  1. Sexually active, fertile males must use effective birth control if their partners are women of childbearing potential. Adequate birth control methods for both males and females (as appropriate) are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectable or patch hormonal contraception, oral contraceptives, an IUD, double-barrier contraception, or true sexual abstinence. The form of birth control for the male and/or partner, where relevant, must be documented at screening and baseline.
  2. Women of childbearing potential (if a partner of a male participant) include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea greater than or equal to 12 consecutive months); or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level greater than 35 mIU/mL. Even women who are 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 are practicing abstinence or where the partner is sterile (e.g., vasectomy), should be considered to be of childbearing potential.

Exclusion Criteria:

  1. Patient has a DSM-IV-TR diagnosis of ADHD not otherwise specified (NOS).
  2. Patients 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 lead-in). Such patients will be withdrawn from the study prior to receiving any active drug.
  3. Patient has a current or lifetime history of bipolar disorder or any psychotic disorder as established by M.I.N.I.-Plus.
  4. Patient has 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 (ECT) or lifetime history of vagal nerve stimulation or deep brain stimulation for the treatment of depression.
  6. Patients 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. Patient has a history of epilepsy, seizures, syncope, unexplained blackout spell(s), head trauma with clinically significant loss of consciousness or noninfantile febrile seizures.
  8. Patient has a currently active medical condition (other than ADHD) that, in the opinion of the investigator, could interfere with the ability of the patient to participate in the study safely.
  9. Patient has a history of clinically significant, diagnosed cardiovascular disease of any kind, including uncontrolled hypertension. Patient has newly diagnosed cardiovascular disease of any kind in the investigator's judgment.
  10. The patient has an IQ less than 80.
  11. In the opinion of the investigator, the patient has not derived significant therapeutic benefit from 2 or more ADHD therapies given with an adequate dose and duration in adulthood (age 18 or older); i.e., 1 failed course of treatment is acceptable, but 2 failed courses of treatment are not acceptable.
  12. Patient taking medication specifically for treatment of ADHD symptoms (e.g., stimulants, atomoxetine, tricyclic antidepressants, bupropion, modafinil, etc) must be off stimulants for 2 weeks and off nonstimulant ADHD therapies for 3 weeks prior to the Baseline-1 Visit and must have returned to the baseline level of ADHD symptoms in the opinion of the investigator. Patients must not have evidence of a discontinuation or withdrawal reaction.
  13. Patient is currently taking any antidepressant medication for any condition.
  14. Patient is currently taking antipsychotic medication, or an anticonvulsant medication (e.g., phenytoin, carbamazepine, lamotrigine, or valproic acid) at anticonvulsant doses.
  15. Patient has a known history of allergy to EB-1020.
  16. Patient is unwilling to refrain from taking medications that may interfere with the assessment of cognitive function and the assessment of sleep. Examples include benzodiazepines, sedating antihistamines, zolpidem, eszopiclone, and zaleplon. Herbal preparations with effects on the central nervous system also are prohibited throughout the study, (e.g., St. John's Wort or melatonin).
  17. Patient has a history of sleep problems in the last 3 months.
  18. Patient is unwilling to refrain from taking more than one unit of alcohol within 24 hours of the investigational center visits.
  19. Patient is unwilling to restrict caffeine to no more than 500 mg/day (5 cups of coffee).
  20. Patient is actively using any drugs with potential for abuse (e.g., marijuana, cocaine, amphetamines)
  21. Patient reports passive or active suicidal ideation or intent.
  22. Patient is concurrently participating in another clinical research study or investigational drug study or has participated in such a study within the past 1 month.
  23. Patient is at high risk of nonadherence to investigational product and the protocol regimen in the investigator's opinion.
  24. Patient may not begin psychotherapy during the study, but may continue therapy at the same intensity and frequency, if begun at least 3 months prior to Baseline-1 Visit. 2.

Exclusion Criteria, Physical and Laboratory Test Findings

  1. Patients who have a positive urine drug screen, which cannot be explained by prescribed medications. The urine drug screen may be repeated based on investigator judgment.
  2. Patients with clinically significantly abnormal thyroid-stimulating hormone (TSH) or a positive result on a standard hepatitis screening panel or human immunodeficiency virus (HIV) screen. NOTE: Adequate thyroid replacement for a previously diagnosed thyroid deficiency, which has been stable for 3 months or more, is acceptable.
  3. Patients with clinically significant laboratory abnormalities or with clinical laboratory values of potential clinical concern.
  4. Diastolic blood pressure greater than 85 mm Hg at Baseline-1.
  5. Systolic blood pressure greater than 135 mg Hg at Baseline-1.
  6. Patient has a QT interval of greater than 450 ms on 2 or more ECG tracings taken within 15 minutes, assessed with the patient in a supine position for 3 minutes.

Other Exclusion Criteria

  1. Prisoners or patients who are involuntarily incarcerated.
  2. Patients who have a compulsory detainment for treatment of either a psychiatric or physical illness.
  3. Patients who plan to have elective surgeries during the course of the study.
  4. Patients with a history of antidepressant-induced hypomania or dysphoria.

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): NCT01939353


Locations
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United States, Florida
Florida Clinical Research Center, LLC.
Bradenton, Florida, United States
Florida Clinical Research Center, LLC.
Maitland, Florida, United States
United States, Nevada
Center for Psychiatry and Behavioral Medicine, Inc.
Las Vegas, Nevada, United States
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
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Principal Investigator: Andrew J Cutler, MD Florida Clinical Research Center, LLC

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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01939353     History of Changes
Other Study ID Numbers: EB-1020-SR-ADHD-201
First Posted: September 11, 2013    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Adult ADHD

Additional relevant MeSH terms:
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Attention Deficit Disorder with Hyperactivity
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders