04. Efficacy and Safety of Lisdexamfetamine in Preschool Children with ADHD

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Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will look at the effectiveness and safety of lisdexamfetamine in preschool children with ADHD 4–5 years of age. The authors conducted a double-blind, fixed-dose study in 199 preschool children with ADHD treated with fixed-dose lisdexamfetamine—5 mg, 10 mg, 20 mg, or 30 mg—or placebo for 6 weeks. Whereas most psychotropic medications for ADHD are not FDA approved in preschool children, pharmacotherapy is increasingly being used to treat preschool children with ADHD, particularly preschool children 4–5 years of age.

Nonetheless, far too few studies have examined the safety and effectiveness of psychotropic medication in preschool children with ADHD. Moreover, as stimulant medications are typically the first-line pharmacotherapy for school-age children, adolescents, and adult patients with ADHD, this is a logical place to start. So, what did they find? First, lisdexamfetamine was well tolerated in preschool children 4–5 years old, with no new safety signals. Also, in preschool children 4–5 years old with ADHD, lisdexamfetamine was significantly more effective than placebo in reducing ADHD symptoms.

It is important to note, though, that although lisdexamfetamine pooled doses—10 mg, 20 mg, and 30 mg—were superior to placebo in treating ADHD symptoms, lisdexamfetamine was not as effective in preschool children 4–5 years old with ADHD as compared to school-age children and adolescents with ADHD. Interestingly, in the primary outcome measure in the study, the Clinical Global Impression Improvement score (CGI-I), even though more participants in the pooled lisdexamfetamine group were rated as improved, these improved scores did not reach statistical significance. However, the mean or average CGI-Improvement score was significantly lower than in the pooled lisdexamfetamine group.

So, confusing, right? What does all this mean, and how does it come together? The bottom line is that this raises far more questions than it answers. Moreover, this is a very tough population to study. If you do enough statistical tests, there can be a significant chance of finding that may not be clinically significant. However, due to the multiple comparisons, the law of averages, and the more tests you do, the more likely you are to find something. The authors controlled for this, but it still raises many questions. There are some significant limitations in this being a fixed-dose rather than a flexible-dose study, which is more commonly done in clinical practice; that is, we titrate a medication up or down, monitoring for side effects and trying to hit the sweet spot of maximal efficacy and minimal toxicity. In this study, lisdexamfetamine was titrated to a fixed dose.

The children could have been on suboptimal doses—either too low or too high or possibly not long enough on the best particular dose for a particular child. This was also a 6-week study, so it may have needed more time to monitor for efficacy and side effects. Notice that this is an industry-funded study by the sponsor, with the research being funded by Shire Development and coauthors on the study being with Shire and the Takeda Group of Companies.

Takeda Pharmaceutical Company has also provided funding for writing assistance for this manuscript, and the statistical expert on the study was also with Takeda Developmental Center Americas, Incorporated. The bottom line is that this is a potentially promising new lead but not yet ready for prime time. More study is needed, especially in this vulnerable young population where behavioral and parent/caregiver management interventions are recommended as first line before pharmacotherapy is considered.

Abstract

Efficacy and Safety of Lisdexamfetamine in Preschool Children With Attention-Deficit/Hyperactivity Disorder

Ann C Childress, Eric Lloyd, Leslie Jacobsen, Lhanoo Gunawardhana, Steven A Johnson Jr, Robert L Findling

Objective: To evaluate the acute efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) vs placebo (PBO) in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD).

Method: This phase 3, double-blind, fixed-dose study randomly assigned children (aged 4-5 years) with ADHD to 6 weeks of LDX (5, 10, 20, 30 mg) or PBO. The prespecified primary (change from baseline at week 6 in ADHD Rating Scale IV, Preschool version, total score [ADHD-RS-IV-PS-TS]) and key secondary (Clinical Global Impression-Improvement [CGI-I] score at week 6) efficacy endpoints were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and changes in pulse and blood pressure (BP).

Results: The study comprised 199 participants randomly asigned 5:5:5:5:6 to receive 5, 10, 20, 30 mg LDX or PBO, respectively. Least squares (LS) mean (95% CI) treatment difference at week 6 between pooled LDX (10, 20, 30 mg) and PBO was statistically significant for ADHD-RS-IV-PS-TS change (-5.9 [-11.01, -0.78], p = .0242; effect size [ES], -0.43). CGI-I scores improved (ie, 1-2 on CGI-I) in 41.7% for pooled LDX and 24.3% for PBO (p = .0857). The LS mean (95% CI) treatment difference between pooled LDX and PBO for CGI-I score at week 6 was -0.6 (-1.03, -0.16; p = .0074; ES, -0.52). Frequency of TEAEs was 46.6% across all 4 LDX doses vs 42.2% with PBO; the most frequent TEAEs were decreased appetite (13.7% vs 8.9%, respectively) and irritability (9.6% vs 0%). Discontinuations because of TEAEs were 5.5% for all LDX doses and 4.4% for PBO. Mean ± SD pulse/BP changes from baseline at week 6/early termination were numerically greater with LDX vs PBO (pulse beats/min: 2.7 ± 10.79 vs 1.2 ± 9.90; systolic BP, mm Hg: 1.0 ± 7.51 vs 0.3 ± 6.06; diastolic BP, mm Hg: 1.7 ± 5.90 vs 0.0 ± 6.88).

Conclusion: In children aged 4 to 5 years with ADHD, LDX was more efficacious than PBO in reducing symptoms. The observed ES for change in ADHD-RS-IV-PS-TS appears to be smaller in magnitude than has been reported for studies of LDX conducted in older children and adolescents. LDX was generally well tolerated, and no new safety signals were identified.

Reference

Childress, A. C., Lloyd, E., Jacobsen, L., Gunawardhana, L., Johnson, S. A., & Findling, R. L. (2022). Efficacy and safety of Lisdexamfetamine in preschool children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 61(12), 1423-1434.