A trial can show that two doses beat placebo without demonstrating that one dose beats the other. That distinction is explicit in a 2017 SHP465 mixed amphetamine salts trial.
What was randomized?
The four-week double-blind trial assigned 275 adults with ADHD to oral placebo, 12.5 mg/day SHP465 or 37.5 mg/day SHP465: 91, 92 and 92 participants, respectively. This was a forced-dose design rather than individualized optimization throughout the trial.
The safety population contained 271 participants, and the full analysis set 263: 86 placebo, 89 lower-dose and 88 higher-dose participants. Two hundred thirty-six completed the study. Recruitment and analytic denominators therefore differ.
Both doses showed a placebo-adjusted benefit
For change in the adult-prompt ADHD rating scale at week four, the least-squares mean difference versus placebo was −8.1 points for 12.5 mg/day, with a 95% confidence interval of −11.7 to −4.4. For 37.5 mg/day, it was −13.4 points, with an interval of −17.1 to −9.7.
Both placebo comparisons were significant. The corresponding standardized effect sizes were 0.67 and 1.11. Clinician global-improvement outcomes also favored each active dose over placebo.
Why this is not a tested dose comparison
The larger numerical effect at 37.5 mg/day is compatible with a dose-related difference. However, the investigators did not statistically compare the active doses with each other and expressly cautioned against claiming an established dose-dependent effect.
Subtracting two reported effects in commentary does not supply the prespecified comparison, its uncertainty or a complete benefit-risk analysis. Nor does a larger group mean guarantee greater benefit for every participant.
Who was excluded?
The trial excluded people with a history of inadequate response to an adequate amphetamine course, as well as several psychiatric, substance-use and medical risks. This enriches the sample relative to an unselected clinical population.
The formulation used mixed salts with a specific release system. Its milligram doses should not be generalized to immediate-release amphetamine, lisdexamfetamine or methamphetamine.
Safety and applicability
Appetite reduction, dry mouth and insomnia were among reported adverse events. Four weeks is insufficient to settle uncommon harms or long-term outcomes. A symptom-score improvement is also not a direct measurement of occupational functioning or driving.
The defensible historical conclusion is that each tested dose improved the measured symptoms relative to placebo in the selected adult ADHD sample. A claim that the higher dose was proved superior, or that increasing dose is appropriate for an individual, goes beyond the reported comparison.
Scientific source
Weisler RH, Greenbaum M, Arnold V, et al. Efficacy and Safety of SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled, Forced-Dose Clinical Study. CNS Drugs. 2017;31:685–697. doi:10.1007/s40263-017-0455-7. Original commentary on the supplied paper.
Leave a Reply