SHP465 mixed amphetamine salts effective, safe for ADHD in adults

In adults with attention-deficit/hyperactivity disorder (ADHD), SHP465 mixed amphetamine salts (MAS; 25 mg) brought about significantly greater improvements in sustained attention compared with placebo, according to study results published in Postgraduate Medicine.

SHP465 MAS is an extended-release, once-daily product approved by the FDA for the treatment of ADHD in patients aged 13 years and older. It contains equal amounts of dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, and amphetamine aspartate monohydrate.

Researchers sought to assess the efficacy, duration of effect, and safety of 25 mg SHP465 MAS compared with placebo using the Permanent Product Measure of Performance (PERMP) total scores in adults with ADHD in the Adult Workplace Environment (AWE).

The PERMP is a 10-minute math test that can be used to measure sustained attention, including the ability to initiate and perform effortful work, and stay on task. The test is not a measure of math abilities but is considered a useful way to assess drug response. The AWE is a structured environment complete with activities designed to simulate those occurring during a typical work day.

For this phase 2, double-blind, randomized, two-period, two-treatment crossover study, researchers treated 73 adults aged 18 to 55 years (mean age: 29.1 years; 55.1% male; 85.9% white) with placebo or SHP465 MAS.

To be included, patients had to meet the Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria for a diagnosis of ADHD and have a baseline ADHD-RS-IV total score of ≥ 24. Subjects also had an IQ of ≥ 80 and no medical abnormalities. Most were aged 18 to 25 years (48.7%), and had the combined ADHD subtype. All underwent screening, baseline, and orientation visits, followed by a double-blind crossover phase during which they made two visits separated by 7 days.

Patients were randomized to treatment with SHP465 MAS (n=35) followed by placebo, or placebo followed by SHP465 MAS (n=38). They completed 6 additional PERMP practice tests for a total of 12 tests before the double-blind crossover phase.

On day 7 of each 7-day treatment period, researchers assessed the efficacy of treatment over 16.5 hours after dosing with PERMP testing. The primary endpoint was the change in PERMP total score from baseline.

In the placebo group, predose mean PERMP total scores were 226.9, and in the SHP465 MAS group, 217.5.

At 2 to 16 hours after dosing, PERMP total scores for the average of classes 1 to 6 were 248.8 and 267.9, respectively. In the intent-to-treat population (ITT), total score treatment differences with SHP465 MAS were significantly favored by least squares (LS) mean over placebo at all time points after dosing (P < 0.0001). The LS mean treatment differences also favored the SHP465 MAS from 4 to 16 hours after dosing.

In the per protocol (PP) population, similar findings were seen for the average of all and each postdose time point.

In the placebo group, the mean number of problems answered correctly was 111.8, compared with 106.4 in the SHP465 MAS ITT population. Mean problems attempted by both groups were 115.1 and 111.0, respectively.

The LS mean treatment difference for the average of all postdose time points for problems attempted and problems answered correctly slightly favored the SHP465 MAS group over placebo, as did the LS mean treatment differences for problems attempted/answered correctly at 4 hours through 16 hours after dosing. Findings in the PP group were similar, with the exception of questions answered correctly, which only became slightly better in the 25-mg SHP465 MAS group 8 hours after dosing.

Further testing for secondary endpoints with the ADHD self-rating scale (ADHD-SRS) showed nominally improved scores in patients treated with SHP465 MAS, including total ADHD-SRS scores, hyperactivity/impulsivity, and inattentiveness subscale score, for an average across all cycles of P < 0.0001 and at each cycle after dosing of P < 0.01. Researchers saw no significant difference in improvements after testing with the clinician-rated Time Segment Rating System (Co-ADHD-RS TSRS scale).

Treatment-emergent adverse events were higher in the SHP465 MAS group, with only insomnia rated as severe (reported by three subjects compared with none in the placebo group). One patient in the SHP465 MAS group discontinued the study due to insomnia and another because of moderate nasopharyngitis. The most frequent adverse events, reported by 5% or more of subjects treated with SHP465 MAS, included insomnia, decreased appetite, dry mouth, headache, and anorexia.

In the SHP465 MAS group, researchers observed higher mean SBP, DBP, and pulse, although most of these increases were small.

Limitations of the study included the use of only a single dose without a dose-optimization phase, and the short duration of treatment (1 week).

“SHP465 MAS (25 mg) produced statistically significantly greater increases in PERMP total score in a simulated AWE compared with placebo, with efficacy observed 4 hours postdose through the last postdose assessment time of 16 hours. In addition, treatment differences nominally favored 25 mg SHP465 MAS over placebo on the self-reported ADHD-SRS but not on the counselor-administered and clinician-rated Co-ADHD-RS TSRS, potentially due to a lack of discriminating output on the Co-ADHD-RS TSRS,” wrote the authors.

“Overall, these findings point to the importance of utilizing both objectively rated measures, such as the PERMP, and subjective rating measures (eg, self-reported scales and clinician-rated scales) when assessing the efficacy of an ADHD medication. These findings also point to the importance of appropriate titration and dose optimization for achieving clinically relevant effects of medication on ADHD symptomatology,” they concluded.

Clinical research was funded by Shire Development LLC, Lexington, MA.