Adult Attention Deficit Hyperactivity Disorder

Study Overview
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Brief Summary
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A Phase 2 study of SEP-225289 in adults with attention deficit hyperactivity disorder (ADHD).

Detailed Description
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This is a Phase 2, randomized, double-blind, parallel-group, multicenter, outpatient study evaluating the efficacy and safety of SEP 225289 in adults with ADHD using 2 oral dosages (4 or 8 mg SEP 225289 once daily [QD]) versus placebo over a 4 week treatment period.

Official Title
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A Randomized, Double Blind, Parallel Group, Multicenter Efficacy and Safety Study of SEP-225289 Versus Placebo in Adults With Attention Deficit Hyperactivity Disorder (ADHD)

Conditions
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Adult Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: SEP-225289
* Drug: SEP-225289
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject meets Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD (inattentive, hyperactive, or combined subtype) established by a comprehensive psychiatric evaluation that reviews DSM-IV-TR criteria. Diagnosis is confirmed by Conners' Adult ADHD Diagnostic Interview (CAADID) Part 2. Subject currently taking medication (stimulant or nonstimulant) for the control of ADHD symptoms has an ADHD RS-IV score of ≥ 22 at screening. Subject currently not taking any medication for the purpose of controlling ADHD symptoms has an ADHD RS-IV score of ≥ 26 at screening. Subject has a CGI-S score of ≥ 4 at screening. Subject has a lifetime history of treatment with at least one medication for ADHD (stimulant or nonstimulant). Subjects may be either medicated or unmedicated for ADHD at the time of screening (all ADHD medications must be washed out during screening). Subject has a negative breath alcohol test and a negative urine drug screen (UDS) for any illicit drug at screening, unless a false positive is suspected, in which case the UDS will be repeated. If the subject has a positive drug screen for ADHD medications (ie, methylphenidate or amphetamine) at screening; the subject must have a negative UDS after a washout period at least 3 days prior to baseline. Subject is male or a non-pregnant, non-lactating female. Female subjects must have a negative serum pregnancy test at screening; women who are post-menopausal (defined as at least 12 months of spontaneous amenorrhea) and those who have undergone hysterectomy or bilateral oophorectomy will be exempted from the pregnancy test. Female subjects of childbearing potential and male subjects with female partners of child-bearing potential must agree to use an effective and medically acceptable form of birth control throughout the study period and for one month (30 days) after study completion. Medically acceptable and effective contraceptives include abstinence, prescription hormonal contraceptives (oral, patch, vaginal ring, implant, or injection), diaphragm with spermicide, intrauterine device (IUD), condom with spermicide, surgical sterilization, or vasectomy. For male subjects adequate contraception is defined as abstinence or continuous use of 2 barrier methods of contraception (eg, spermicidal condom). Subject is 18 to 55 years old, inclusive, at the time of informed consent. 11. Subject can read well enough to understand the informed consent form and other subject materials. Exclusion Criteria: Subject has a DSM-IV-TR diagnosis of ADHD not otherwise specified. Subject is receiving adequate benefit from current ADHD medication in the opinion of the investigator. Subject has an Axis I disorder other than ADHD that has been the primary focus of treatment at any time during the 12 months prior to screening. Subject has a past history of, or current presentation consistent with, bipolar disorder (including bipolar I, bipolar II, and bipolar not otherwise specified [NOS]), schizophrenia, schizoaffective disorder, or any other psychotic disorder. Subject has a history of drug dependence or substance abuse (excluding nicotine and caffeine) within the 12 months prior to screening, as defined by the DSM-IV-TR criteria. Subject has a current Axis II disorder per DSM-IV-TR criteria. Subject has a history of epilepsy, seizures (except childhood febrile seizures), unexplained syncope or other unexplained blackouts (except single incident), or head trauma with loss of consciousness lasting more than 5 minutes. Subject has a currently active medical condition (other than ADHD) that, in the opinion of the investigator, could interfere with the ability of the subject to participate in the study. Subject is currently taking an antidepressant medication (eg, bupropion, selective serotonin reuptake inhibitor [SSRI]/ serotonin norepinephrine reuptake inhibitor [SNRI], monoamine oxidase [MAO] blocker, tricyclic, etc) or St. John's Wort. Subject is currently taking or has taken within the previous 6 months an anticonvulsant medication (eg, phenytoin, carbamazepine, lamotrigine, valproic acid, etc); antipsychotic medication; or lithium (any lithium preparation or formulation). Subject is currently taking an alpha-2 adrenergic receptor agonist (including clonidine and guanfacine). Subject has a Body Mass Index (BMI) less than 18 or greater than 35 kg/m2 (refer to Appendix V) Subject answers yes to Suicidal Ideation item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS assessment at screening (in the past month). Subjects who answer yes to this question must be referred to the Investigator for follow-up evaluation. Subject has attempted suicide within 2 years prior to the screening period. Subject has history of positive test for Hepatitis B surface antigen or Hepatitis C antibody. Note: Subjects with a history of a positive test for Hepatitis B surface antigen or Hepatitis C antibody may be enrolled in the study if they have liver function test results at screening within the normal range. Subject is known to have tested positive for human immunodeficiency virus (HIV). Subject has a clinically significant abnormality on screening evaluation including physical examination, vital signs, ECG, or laboratory tests that the investigator in consultation with the medical monitor considers to be inappropriate to allow participation in the study. The subject's screening ECG shows a corrected QT interval using Fridericia's formula (QTcF) of ≥ 450 msec for male subjects or ≥ 470 msec for female subjects. The subject's screening hematology results show an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value ≥ 2 times the upper limit of normal (ULN), or a blood urea nitrogen (BUN) value ≥ 1.5 times the ULN for the reference lab. Subject who is currently participating or has participated in a clinical trial within the last 180 days or who participated in more than 2 clinical trials within the past year. This includes studies using marketed compounds or devices. Subject is at high risk of non-compliance in the investigator's opinion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SEP-225289 4mg<br>SEP-225289 4mg once daily taken as a combination of SEP-225289 2mg and placebo capsules to achieve 4mg QD doses | Drug: SEP-225289<br>* SEP-225289 4mg once daily<br>* Other names: Dasotraline;|
| Experimental: SEP-225289 8mg<br>SEP-225289 8mg once daily taken as a combination of SEP-225289 2mg and placebo to achieve 8mg QD doses | Drug: SEP-225289<br>* SEP-225289 8mg once daily<br>* Other names: Dasotraline;|
| Placebo Comparator: Placebo<br>4 capsules of placebo | Drug: Placebo<br>* Placebo once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Week 4 in ADHD Symptoms Measured With the ADHD Rating Scale Version IV With Adult Prompts (ADHD RS IV) | The ADHD RS-IV with adult prompts is an 18 item scale based on the DSM IV TR criteria for ADHD that provides a rating of the severity symptoms. Scoring is based on a 4 point Likert-type severity scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Clinicians scored the highest score that was generated for the prompts for each item. The ADHD rating scale total score is defined as sum of all 18 item scale scores. | 4 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in ADHD Symptoms Measured With the ADHD RS IV at Weeks 1, 2, 3. | The ADHD RS-IV with adult prompts is an 18 item scale based on the DSM IV TR criteria for ADHD that provides a rating of the severity symptoms. Scoring is based on a 4 point Likert-type severity scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Clinicians scored the highest score that was generated for the prompts for each item. The ADHD rating scale total score is defined as sum of all 18 item scale scores (range 0 - 54). | Weeks 1, 2, 3 | 
| Change From Baseline in Clinical Global Impression - Severity of Illness Scale (CGI S) at Weeks 1, 2, 3, 4. | The CGI-S modified asked the clinician one question: Considering your total clinical experience with adult ADHD, how mentally ill is the subject at this time?.The clinician's answer was rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = ng the most extremely ill subjects. | Weeks 1, 2, 3, 4 | 
| Change From Baseline in the Inattentiveness and Hyperactivity Subscales of the ADHD RS IV at Weeks 1, 2, 3, 4 | The ADHD RS-IV with adult prompts is an 18 item scale based on the DSM IV TR criteria for ADHD that provides a rating of the severity symptoms. Scoring is based on a 4 point Likert-type severity scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Clinicians scored the highest score that was generated for the prompts for each item. The even number items (2, 4, 6, 8, 10, 12, 14, 16, 18) assess hyperactive impulsive symptoms and the odd number items (1, 3, 5, 7, 9, 11, 13, 15, 17) assess inattentive symptoms. The ADHD inattentiveness subscale score is defined as sum of items (1, 3, 5, 7, 9, 11, 13, 15, 17) scores (range 0 - 27). The ADHD hyperactive impulsive subscale score is defined as sum of items (2, 4, 6, 8, 10, 12, 14, 16, 18) scores (range 0 - 27). | Weeks 1, 2, 3, 4 | 
| The Number of Responders at Weeks 1, 2, 3, 4. A Responder is Defined as a Subject With a ≥ 30% Improvement in ADHD Symptoms Compared With Baseline as Measured by the ADHD RS IV. |  | Weeks 1, 2, 3, 4 | 
| Change From Baseline in the Wender-Reimher Adult Attention Deficit Disorder Scale (WRAADDS) as Measured at Weeks 1, 2, 3, 4. | The WRAADDS measured the severity of the target symptoms of adults with ADHD. It measured symptoms in 7 categories: attention difficulties, hyperactivity/restlessness, temper, affective lability, emotional overreactivity, 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 subscores (range 0 - 56). | Weeks 1, 2, 3, 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD, Attention deficit hyperactivity disorder