Methodological advantages and disadvantages of parallel and crossover randomised clinical trials on methylphenidate for attention deficit hyperactivity disorder: a systematic review and meta-analyses

Abstract

ObjectiveTo assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).DesignSecondary analyses of a Cochrane systematic review.Setting and participantsWe searched relevant databases up to March 2015 and included data from parallel and crossover randomised trials assessing children and adolescents up to 18 years with ADHD.InterventionsMethylphenidate compared with placebo or no-treatment interventions.Primary and secondary outcomesThe primary outcomes were teacher-rated ADHD symptoms and serious adverse events. The secondary outcomes were non-serious adverse events.ResultsWe included 38 parallel trials (n=5111) and 147 crossover trials (n=7134). When comparing methylphenidate with placebo or no-treatment on ADHD symptoms, we found no differences between the end of parallel trials and the first-period from crossover trials (Χ²=1.06, df=1, p=0.30, I²=5.5%). We also found no differences when combining the end of first-period crossover trials with the end of parallel trials and comparing them to the end of last-period crossover trials (Χ²=3.25, df=1, p=0.07, I²=69.2%). We found no differences in serious and non-serious adverse events, and no risk of period and carryover effects. However, only two trials contributed data to the latter analyses.ConclusionsBoth parallel and crossover trials seem suitable for investigating methylphenidate in children and adolescents with ADHD, with comparable estimates on ADHD symptom severity and adverse events. However, parallel trials might still offer ethical and statistical advantages over crossover trials.

Sleep Promotion among Critically Ill Patients: Earplugs/Eye Mask versus Ocean Sound—A Randomized Controlled Trial Study

“…In this study, despite the small sample size, we found the significant effect of the intervention on sleep which might be because of the strong design randomized controlled trial crossover design. A study conducted by Krogh et al emphasized that the advantage of the crossover design is the need for fewer participants and resource consumption [ 42 ]. Similarly, previous studies with less sample size have found a significant effect on sleep quality [ 13 , 15 , 23 , 29 ].…”

A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Clinical Trial of ORADUR-Methylphenidate for Treating Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

“…The above, combined with the predominantly male sample, and the fact that the sample was restricted to patients at only three medical centers in Taiwan, limit the ability to generalize our findings to a wide clinical population suffering from ADHD. Fourth, we used a two-way crossover study design without a washout period rather than a parallel study design (Krogh et al 2019 ). We took advantage of the fewer samples that such a two-way crossover study needs, as well as the ability to obtain more precise estimates of treatment effects by removing any biological and methodological variation that are present within the crossover study design (Mills et al 2009 ; Li et al 2015 ; Krogh et al 2019 ).…”

“…Fourth, we used a two-way crossover study design without a washout period rather than a parallel study design (Krogh et al 2019 ). We took advantage of the fewer samples that such a two-way crossover study needs, as well as the ability to obtain more precise estimates of treatment effects by removing any biological and methodological variation that are present within the crossover study design (Mills et al 2009 ; Li et al 2015 ; Krogh et al 2019 ). Importantly, MPH has a short half-life, short-lived effectiveness, and a very limited carryover effect, and in this context, a meta-analysis has reported that four fifths of MPH clinical trials have used a crossover design (Krogh et al 2019 ).…”

Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia: A meta-analysis of randomised, placebo-controlled trials

“…Several methods exist for including information from crossover studies in quantitative analysis (Elbourne et al, 2002); however, incorporating the result only from the first or last period of crossover studies revealed similar results in the final analysis (Krogh et al, 2019). Hence, we included the last-period result of the crossover studies in our quantitative analysis to obtain relatively unbiased data (Ding et al, 2015).…”