To evaluate the efficacy of Vyvanse for maintenance treatment in children and adolescents with ADHD, Shire elected to conduct a double-blind, placebo-controlled, randomized withdrawal clinical trial. In this design, patients who respond to a treatment are randomized to continue receiving that treatment or placebo. Using the proportion of patients experiencing symptom relapse as a primary outcome, this type of study in patients with ADHD can be used to demonstrate long-term efficacy in lieu of conducting a long-term, placebo-controlled, parallel-group study. The utility of this design is that the period of placebo exposure, with the potential for worsening of ADHD symptoms, is relatively short.
The double-blind, placebo-controlled, randomized withdrawal study was conducted in 276 children and adolescents aged 6 to 17 with ADHD. Of these patients, 236 participated in a preceding study and 40 directly enrolled. The study consisted of 4 phases:
- 4-week, open-label, dose-optimization phase in which patients received Vyvanse 30 mg/day, 50 mg/day, or 70 mg/day. Eligible subjects started on Vyvanse 30 mg/day and could be titrated in weekly increments of 20 mg until an optimal dose was reached (up to a maximum of 70 mg/day)
- 20-week, open-label, maintenance phase
- 2-week, open-label, fixed-dose phase in which patients were discontinued if they required further dose adjustments, experienced unacceptable tolerability, or had an Attention-Deficit/Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score >22 or Clinical Global Impression Severity (CGI-S) score ≥3. Patients who maintained treatment response entered the randomized withdrawal phase.
- 6-week, double-blind, randomized withdrawal phase in which patients either received ongoing treatment with the same dose of Vyvanse (N=78) or were switched to placebo (N=79).
The primary outcome measure was the proportion of patients who met criteria for relapse of ADHD symptoms (treatment failure) at end point during the double-blind, randomized withdrawal phase. The end point measurement was defined as the last post-randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were observed. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind, randomized withdrawal phase. On the primary end point, significantly fewer patients met criteria for symptom relapse with Vyvanse (15.8%) versus placebo (67.5%) ( P<.001).
During the 26-week open-label phase, 12 patients (4.3%) reported serious adverse events (SAEs), and 45 patients (16.3%) reported treatment-emergent adverse events (TEAEs) that resulted in Vyvanse discontinuation. During the randomized withdrawal phase, no SAEs were reported in the Vyvanse group, no patients in the Vyvanse group discontinued due to a TEAE, and 1 patient in the placebo group discontinued due to a TEAE. In addition, 39.7% (31/78) of patients receiving Vyvanse and 25.3% (20/79) on placebo reported TEAEs. The most common TEAEs (≥2%) reported in the Vyvanse treatment group during the randomized withdrawal phase included nasopharyngitis, headache, abdominal pain upper, oropharyngeal pain, decreased appetite, vomiting, weight decrease, abdominal pain, accidental overdose, aggression, cough, nausea and rhinitis.