Crossover Study to Evaluate the Efficacy of AR11 in Pediatric Patients With ADHD in a Laboratory Classroom Setting

This is a dose-optimized, randomized, double-blind, placebo-controlled crossover study in approximately 100 pediatric patients (aged 6 to 12 years) with ADHD. Eligible patients will enroll in the study to take open-label AR11 twice daily and undergo dose optimization activities for 8 weeks. Patients who achieve a stable dose during the dose optimization period will continue participation and will be randomized to take double-blind medication (AR11 or placebo) orally twice daily for 1 week. At the end of the first double-blind treatment period, patients will be evaluated for ADHD symptoms in a laboratory classroom setting utilizing SKAMP and PERMP assessments. At the end of the second double blind treatment period, patients will be evaluated for ADHD symptoms in a second laboratory classroom setting utilizing SKAMP and PERMP assessments.

• AR11 (Drug), also known as amphetamine sulfate
• Placebo (Drug), also known as matching Placebo

Primary outcomes

• SKAMP-Combined Scores [2 hours post-dose]: Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale \[SKAMP\]-combined scores measured during Laboratory Classroom Days. The SKAMP scale is a validated subjective measure of ADHD symptoms in a laboratory classroom, comprised of 13 items on which subjects are rated according to a 7 point scale (0=normal to 6=maximal impairment); maximum score 78. The SKAMP-combined score is obtained by summing the rating values for each of the 13 items, whereby the higher the SKAMP score, the greater the impairment.

Secondary outcomes

• SKAMP-Combined Scores [0.75, 4, 6, 8, 10 hours post-dose]: Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale \[SKAMP\]-combined scores measured during Laboratory Classroom Days. The SKAMP scale is a validated subjective measure of ADHD symptoms in a laboratory classroom, comprised of 13 items on which subjects are rated according to a 7 point scale (0=normal to 6=maximal impairment); maximum score 78. The SKAMP-combined score is obtained by summing the rating values for each of the 13 items, whereby the higher the SKAMP score, the greater the impairment.
• SKAMP Subscale - Attention Scores [0.75, 2, 4, 6, 8, and 10 hours post-dose]: The SKAMP scale is a validated subjective measure of ADHD symptoms. It is comprised of 13 items (grouped under the subcategories of attention, deportment, quality of work, and compliance) on which subjects are rated according to a 7-point scale (0 = normal to 6 = maximal impairment). The SKAMP-Attention subscale score is comprised of four of the 13 items with a maximum score of 24.
• SKAMP Subscale - Deportment Scores [0.75, 2, 4, 6, 8, and 10 hours post-dose]: The SKAMP scale is a validated subjective measure of ADHD symptoms. It is comprised of 13 items (grouped under the subcategories of attention, deportment, quality of work, and compliance) on which subjects are rated according to a 7-point scale (0 = normal to 6 = maximal impairment). The SKAMP-Deportment subscale score is comprised of four of the 13 items with a maximum score of 24.
• PERM-P Scores - Number of Problems Attempted [0.75, 2, 4, 6, 8, and 10 hours post-dose]: Permanent Product Measure of Performance (PERMP) assessments measured during Laboratory Classroom Days. The PERMP is an individualized, five-page math exam consisting of 400 problems. Subjects are instructed to complete as many math problems as possible in 10 minutes. Performance is evaluated using the number of problems attempted (maximum score = 400) and the number of problems correct (maximum score = 400).
• PERM-P Scores - Number of Problems Correct [0.75, 2, 4, 6, 8, and 10 hours post-dose]: Permanent Product Measure of Performance (PERMP) assessments measured during Laboratory Classroom Days. The PERMP is an individualized, five-page math exam consisting of 400 problems. Subjects are instructed to complete as many math problems as possible in 10 minutes. Performance is evaluated using the number of problems attempted (maximum score = 400) and the number of problems correct (maximum score = 400).

Sex: All, ages: 6 Years to 12 Years

Inclusion Criteria:

1. Male or female between 6 and 12 years of age, inclusive, at the time of Screening.
2. Diagnosed as meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria for ADHD.
3. A clinician-administered Clinical Global Impression of Severity (CGI-S) score of 3 or greater.
4. An ADHD Rating Scale (ADHD-RS) score at Screening and Baseline greater than or equal to the 90th percentile normative values for gender and age in at least one of the following categories: hyperactive-impulsive subscale, inattentive subscale, or total score.

Exclusion Criteria:

1. Secondary or co-morbid diagnoses other than ADHD, with the exception of simple phobias, oppositional defiant disorder, elimination disorders, motor skills disorders, communication disorders, learning disorders, adjustment disorders, and sleep disorders if, in the opinion of the investigator, the associated symptoms do not confound assessment of safety or efficacy.
2. Clinically significant cognitive impairment as assessed in the clinical judgment of the Investigator.
3. History of any of the following medical disorders: seizure disorder (excluding a history of febrile seizures), structural cardiac disorders, serious cardiac conditions, hypertension, untreated thyroid disease, glaucoma, Tourette's disorder, or chronic tics.
4. Clinically significant abnormal ECG finding or abnormal cardiac finding on physical exam (including presence of a pathologic murmur) at Screening.
5. Use of any psychotropic medication (sedative hypnotics prescribed as a sleep aid at a stable dose for at least 30 days prior to Baseline, at bedtime only, are allowed during the study).
6. A history of hypersensitivity or intolerance to any formulation of amphetamine or lisdexamfetamine.

Participant flow

Outcome results

• SKAMP-Combined Scores (Primary), Mean, units on a scale: AR11 (Amphetamine Sulfate) 10.0 +/- 8.24; Placebo 17.8 +/- 1.94 (p <0.0001)
• SKAMP-Combined Scores (Secondary), Mean, units on a scale: AR11 (Amphetamine Sulfate) 11.8 +/- 10.56; Placebo 17.3 +/- 11.38 (p <0.0001)
• SKAMP Subscale - Attention Scores (Secondary), Mean, units on a scale: AR11 (Amphetamine Sulfate) 2.2 +/- 2.64; Placebo 3.4 +/- 3.06 (p <0.0001)
• SKAMP Subscale - Deportment Scores (Secondary), Mean, units on a scale: AR11 (Amphetamine Sulfate) 2.1 +/- 3.53; Placebo 3.9 +/- 4.82 (p <0.0001)
• PERM-P Scores - Number of Problems Attempted (Secondary), Mean, number of problems attempted: AR11 (Amphetamine Sulfate) 111.6 +/- 53.53; Placebo 91.2 +/- 47.35 (p <0.0001)
• PERM-P Scores - Number of Problems Correct (Secondary), Mean, number of problems correct: AR11 (Amphetamine Sulfate) 104.5 +/- 54.49; Placebo 83.9 +/- 46.96 (p <0.0001)

Adverse events

Time frame: AE reporting occurred during the 8-week open label treatment phase (i.e. AR11 dose optimization) and the 2-week double blind phase (i.e. crossover period)

Other adverse events by term

• Childress AC, Brams M, Cutler AJ, Kollins SH, Northcutt J, Padilla A, Turnbow JM. The Efficacy and Safety of Evekeo, Racemic Amphetamine Sulfate, for Treatment of Attention-Deficit/Hyperactivity Disorder Symptoms: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled Crossover Laboratory Classroom Study. J Child Adolesc Psychopharmacol. 2015 Jun;25(5):402-14. doi: 10.1089/cap.2014.0176. Epub 2015 Feb 18. PMID 25692608
• Results publication: Childress AC, Newcorn JH, Cutler AJ. Gender Effects in the Efficacy of Racemic Amphetamine Sulfate in Children with Attention-Deficit/Hyperactivity Disorder. Adv Ther. 2019 Jun;36(6):1370-1387. doi: 10.1007/s12325-019-00942-5. Epub 2019 Apr 10. PMID 30972657

• Laurence Downey, MD, Study director, Arbor Pharmaceuticals, LLC.