Efficacy of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules in the treatment of ADHD was established in the following trials: 

  * Three short-term trials in adults (18 to 55 years, Studies 1, 2, and 3) 
  * Two short-term trials in pediatric patients (13 to 17 years, Studies 4 and 5) 



Adult Patients (18 to 55 years) with ADHD 

The approved adult doses, 12.5 mg, 25 mg, and 37.5 mg are based on Studies 1 and 3 and the 50 mg dose efficacy is based on Study 2. Doses up to 75 mg per day (1.5 times the maximum recommended adult dosage) were evaluated, but demonstrated no additional clinical benefit. 

A 4 week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration, safety and efficacy study (Study 1) was conducted in adults aged 18 to 55 years (N=275) who met DSM-5 criteria for ADHD. Patients were randomized in a 1:1:1 ratio, to two dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment groups and a placebo group. Group 1 received a dose of 12.5 mg/day throughout the study. Group 2 were titrated on a weekly basis from the initial dose 12.5 mg until target dose of 37.5 mg/day was reached by Week 3 and were maintained at 37.5 mg throughout the study. Group 3 received placebo. 

The primary efficacy endpoint was defined as the change from baseline of the adult ADHD-Rating Scale (RS) with prompts total score at Week 4. Baseline adult ADHD-RS with prompts total score was defined as the last valid adult ADHD-RS with prompts total score assessment prior to taking the first dose of double-blind investigational product, usually at Visit 2. The primary comparison of interest was at Week 4 for each dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules dose compared with placebo. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules demonstrated a statistically significant treatment effect compared with placebo on change of ADHD-RS total score from baseline at visit 6 (Week 4), for both 12.5 mg and 37.5 mg doses respectively (Study 1 in Table 4). Patients on dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules also showed statistically significantly greater improvement on the Clinical Global Impression of Improvement (CGI-I) score compared with placebo treatment. 

Two multicenter, randomized, double-blind, placebo-controlled, crossover studies of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules 25 mg/day (Study 3) and 50 mg/day (Study 2) were conducted in adult patients who met DSM-IV TR criteria for ADHD. The efficacy was determined using the Permanent Product Measure of Performance (PERMP), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Efficacy assessments were conducted at 2, 4, 8, 12, 14, and 16 hours post-dose using the PERMP. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment, compared to placebo, reached statistical significance at either 2 hours (Study 2) or 4 hours (Study 3) post-dose to 16 hours post-dose in both studies. In a prespecified supplementary analysis for Study 2, the maximum approved dose of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules (50 mg) demonstrated a statistically significant treatment effect compared with placebo beginning at 2 to 16 hours post-dose (Study 2 and Study 3 in Table 4). 

Pediatric Patients (13 to 17 years) with ADHD

A 4 week, randomized, double-blind, multicenter, placebo-controlled, dose-optimization, safety and efficacy study (Study 4) was conducted. In Study 4, the 157 pediatric patients 13 to 17 years old who met DSM-IV TR criteria for ADHD, were randomized in a 1:1 ratio to dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules or placebo group. Subjects were titrated from a dose of 12.5 mg/day until an optimal dose was reached (up to a maximum dose of 25 mg); this dose was maintained during the dose-maintenance period (Study 4 in Table 4). 

The primary efficacy endpoint was defined as the change from baseline of the ADHD-RS-IV Total Score at Week 4. The baseline ADHD-RS-IV Total Score was defined as the last valid ADHD-RS-IV Total Score assessment prior to taking the first dose of double-blind investigational product, usually at Visit 2. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules demonstrated a statistically significant treatment effect compared with placebo on the change of ADHD RS-IV total scores from baseline at Visit 6 (Week 4). Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules also showed statistically significantly greater improvement on the Clinical Global Impression of Improvement (CGI-I) score at Visit 6 (Week 4). 

A multicenter, randomized, double-blind, placebo-controlled, crossover study of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules 25 mg/day (Study 5) was conducted in adolescent patients who met DSM-IV TR criteria for ADHD. The efficacy was determined using the Permanent Product Measure of Performance (PERMP), a skill-adjusted math test that measures attention in ADHD. PERMP total score results from the sum of the number of math problems attempted plus the number of math problems answered correctly. Efficacy assessments were conducted at 2, 4, 8, 12, 14, and 16 hours post-dose using the PERMP. Dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate extended-release capsules treatment, compared to placebo, reached statistical significance at 2 to 16 hours post-dose (Study 5 in Table 4, Figure 2).

Figure 2: LS Mean (SE) PERMP Total Score by Treatment and Time-Point for Adolescents Ages 13 to 17 with ADHD After 1 Week of Double Blind Treatment (Study 5)

In both adults and pediatric patients, examination of a population subset based on gender or race did not reveal any differences.