Adult Attention Deficit Hyperactivity Disorder (ADHD) Study With Amphetamine Sulfate

A Multicenter, Fixed-Dose, Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of AR19 (Amphetamine Sulfate) in Adult Subjects (Ages 18-55) With Attention Deficit Hyperactivity Disorder (ADHD)

The purpose of the AR19.004 study is to assess the efficacy of AR19 compared to placebo using the Adult ADHD Investigator Symptom Rating Scale (AISRS)

This is a randomized, fixed-dose, double-blind, multicenter trial to investigate the safety and efficacy of AR19 in the treatment of ADHD in adults from 18 through 55 years of age. Safety parameters and therapeutic effect will be evaluated throughout the trial. A target of 312 subjects is set for enrollment. Once subjects are determined to meet all inclusion criteria and were screened, they will be randomized to 20 or 40 mg AR19 daily or placebo.

Inclusion Criteria:

1. Is male or female between 18 and 55 years of age, inclusive, at the time of Screening.

2. Meets criteria for diagnosis of ADHD using Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) adapted for DSM-5™ (CAADID), including onset of ADHD symptoms before the age of 12.

3. Has an AISRS total score of ≥26 at Visit 2.

4. Has a clinician-administered Clinical Global Impression-Severity (CGI-S) score of 4 or greater at Visit 2.

5. In the clinical judgment of the Investigator, the subject needs pharmacological treatment for ADHD.

6. Must read and write English at a level sufficient to provide written informed consent and to complete study-related materials.

7. For subjects currently on a stable dose of allowed non-ADHD medication, there will be no expected changes in subject's medications during the study with the exception of medications listed in Section 5.9.2.

8. Males and females who are fertile and sexually active with a partner of the opposite sex must adhere to contraception requirements for the duration of the study as follows:

   • Females of childbearing potential must agree to be abstinent or to use highly effective forms of contraception.
   • Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
   • Males , with female partners of childbearing potential must agree to be abstinent or use a medically acceptable form of contraception from screening through the end of study.

Exclusion Criteria:

1. Has a primary psychiatric diagnosis other than ADHD.

2. Has any other current secondary or co-morbid medical, psychiatric, or social condition which, in the opinion of the investigator, might compromise subject safety, or is likely to interfere with protocol compliance or to confound the assessment of safety or efficacy.

3. Has a history or current symptoms of bipolar disorder, schizophrenia, or psychotic disorder.

4. Has clinically significant cognitive impairment in the clinical judgment of the Investigator.

5. Has a Body Mass Index (BMI) of <17 or ≥39 kg/m2.

6. Has a Screening or Baseline triplicate-average blood pressure of ≥139 millimeter of mercury (mmHg) systolic or ≥89 mmHg diastolic. Blood pressure will be taken in triplicate, and the average will be used for evaluating entry criteria.

7. Is pregnant or breastfeeding, or is planning to become pregnant during the study.

8. Has a history of any of the following disorders:

   • Seizure disorder (excluding a history of isolated febrile seizures <6 years old),

   • Inadequately or not treated hypertension is defined as a subject who has blood pressure indicative of Stage 2 hypertension (systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg). Subjects who are adequately treated must be on a stable dose of antihypertensive medications for 3 months prior to screening and their antihypertensive medications are not anticipated to change.

   • Untreated thyroid disease. Subjects with a history of thyroid disease who have been on a stable dose of thyroid hormone for at least three months are eligible to participate if their thyroid-stimulating hormone (TSH) does not fall in the excluded range, shown below in 14.

   • Glaucoma

   • Tourette's disorder, or chronic tics.

   • Subjects who have had gastrointestinal surgery or a procedure that involves:

     • Excision or partial excision of the esophagus, stomach, small and large intestine, liver, pancreas or biliary tree. Appendectomy, cholecystectomy and/or removal of gallstones in the bile ducts (as long as the ducts remain intact) are exceptions.
     • Reduction of the stomach volume without excision or partial excision of the stomach (e.g. restrictive surgery/procedure)
     • Obesity treatments that can affect gastrointestinal (GI) capacity or function, such as electrical stimulation systems, gastric balloon systems, and gastric external drainage systems

9. Has Electrocardiogram (ECG) or clinical evidence of the following:

   • Fridericia's corrected QT wave interval (QTcF) > 470 milliseconds (msec) for females, and > 450 msec for males
   • Atrial or ventricular hypertrophy
   • Intraventricular conduction defects other than incomplete right bundle branch block in the absence of other heart disease
   • Myocardial infarct, ischemia, or symptomatic coronary artery disease within 1 year prior to the Screening Visit
   • Clinically significant atrial or ventricular dysrhythmia; the heart must be in predominantly normal sinus rhythm
   • Second or third degree atrioventricular block
   • Heart failure
   • Functionally significant cardiac structural abnormality or valvular disease
   • Cardiomyopathy
   • Any other cardiovascular condition that the Investigator feels may predispose the subject to cardiovascular events (e.g. myocardial infarction, stroke) or arrhythmia

10. Known family history of sudden cardiac death in the absence of pre-existing heart disease.

11. Use of any psychotropic medication within 28 days of the Baseline visit except for ADHD medication. (Sedative hypnotics prescribed as a sleep aid at a stable dose for at least 28 days prior to Baseline, at bedtime only, are allowed during the study.)

12. Has used prohibited drugs or agents within 28 days of the Baseline visit through Study Visit 7. (Stimulant medications are allowed until 7 days before the Baseline visit.) Non-stimulant ADHD medications (guanfacine, bupropion, clonidine, and/or atomoxetine) are not allowed within 28 days of Visit 2 or at any time during the study. Note: Medications that are being taken for psychiatric or medical disorders other than ADHD should not be discontinued for the purpose of qualifying for study participation unless the medication is deemed medically unnecessary by the prescribing physician.

13. Has received an investigational drug within 60 days of the Screening visit.

14. Has an abnormal laboratory test value, vital sign, or other exam finding at Screening or Baseline that, in the opinion of the Investigator, warrants exclusion from the study. In addition, subjects with laboratory values listed below are considered exclusionary:

    • Serum aspartate transaminase (AST) or alanine transaminase (ALT) >1.5 × upper limit of normal (ULN)
    • Serum total bilirubin >1.5 × ULN unless due to Gilbert's Syndrome
    • Serum creatinine >1.3 × ULN
    • Glycosylated hemoglobin (HbA1c) ≥7.0%.
    • TSH <0.9 × lower limit of normal (LLN) or TSH >1.2 × ULN

15. Reports a history of hypersensitivity or intolerance to any formulation of amphetamine.

16. Reports a history of poor therapeutic response to any formulation of amphetamine or methylphenidate despite a clearly adequate trial (including dose and duration).

17. Is unable to swallow medication in capsule form.

18. Is unable or unwilling to follow directions of study staff or comply with all the testing and requirements of the protocol.

19. Has a positive urine drug result at Screening (with the exception of current ADHD stimulant therapy, if any). Note: subjects should be informed that they should not participate in the trial or submit to urine drug testing if they are using any controlled or recreational drug (other than a prescribed stimulant for ADHD), and non-use should be confirmed prior to testing.

20. Has a positive blood alcohol level at Screening. Note: subjects should be informed that alcohol consumed within 12 hours of screening may result in a positive test.

21. Has current or known history of drug or alcohol abuse within the past 12 months.

22. Has a history of human immunodeficiency virus (HIV), hepatitis B, or untreated hepatitis C infection. Note: subjects with a history of hepatitis C infection who have been treated and whose hepatitis C virus ribonucleic acid (HCV RNA) is currently undetectable are not excluded.

23. In the past 12 months, has had an intensity of suicidal ideation of greater than 1or any self-injurious behavior using the Columbia Suicide Severity Rating Scale at the Screening or Baseline visits.