Characteristics of placebo responders in pediatric clinical trials of attention-deficit/hyperactivity disorder.
ABSTRACT Understanding placebo response is a prerequisite to improving clinical trial methodology. Data from placebo-controlled trials of atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) were analyzed to identify demographic and clinical characteristics that might predict placebo response in future clinical trials.
Data were pooled across 731 placebo-treated pediatric patients who participated in 10 acute, randomized, placebo-controlled trials. Responder status was based on empirically derived thresholds of change on the total score of the ADHD Rating Scale with minimal and robust response defined as 25% or greater and 40% or greater decrease, respectively. Study design characteristics, including randomization ratio, dose, and titration strategy, and patient demographic and clinical characteristics were examined as potential predictors of placebo response.
Inattentive subtype, lack of previous stimulant treatment, presence of comorbid tics and nonwhite ethnicity were associated with robust placebo response. A subset analysis of patients completing 6 weeks of treatment (to eliminate the effects of early dropout) identified inattentive subtype and lack of previous stimulant experience as significant predictors of robust placebo response.
Placebo response is less likely in subjects with combined-subtype ADHD who are not stimulant-naive. Limiting ADHD clinical trials to this more restricted subject group is likely to maximize treatment differences. However, because this is not always possible or desirable, identifying other methods of mitigating placebo response is essential.
- [show abstract] [hide abstract]
ABSTRACT: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.Neurology 12/2005; 65(12):1941-9. · 8.25 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: This multicenter, randomized, fixed-dose, double-blind, placebo-controlled study evaluated efficacy of extended-release dexmethylphenidate (d-MPH-ER) in adults with attention-deficit/hyperactivity disorder (ADHD). Randomized adults with ADHD (n=221) received once-daily d-MPH-ER 20 mg, 30 mg, or 40 mg or placebo for 5 weeks. The primary efficacy variable was change from baseline to final visit in DSM-IV ADHD Rating Scale (ADHD-RS) total score. Secondary efficacy parameters included the proportion of patients with improvement>or=30% in ADHD-RS total score and final scores on Clinical Global Impressions-Improvement (CGI-I) scale. Of 218 evaluable patients, 184 completed the study. All d-MPH-ER doses were significantly superior to placebo in improving ADHD-RS total scores. Placebo scores improved by 7.9; d-MPH-ER, 20 mg, improved by 13.7 (p=.006); d-MPH-ER, 30 mg, improved by 13.4 (p=.012); and d-MPH-ER, 40 mg, improved by 16.9 (p<.001). Overall distribution of CGI-I ratings at final visit was significantly better with each d-MPH-ER dosage than with placebo. There were no unexpected safety or tolerability concerns, based on experience with racemic methylphenidate (MPH) in adults and dexmethylphenidate (d-MPH) in children. Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.Biological Psychiatry 06/2007; 61(12):1380-7. · 9.25 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Patients receiving placebo do not merely receive an inert substance but also receive support, concern, and reassurance that assists the therapeutic alliance and encourages the positive attitude that forms the basis of cognitive treatment. Response to non-specific factors is seen in all fields of medicine but is particularly potent in psychiatry. The placebo response is variable across settings and across time and is unpredictable. Historical data cannot therefore provide an adequate control for treatment effects in studies of new drugs. The scientific position is clear that a comparison against placebo is required for the unequivocal demonstration of the efficacy of a treatment. Evidence from at least two positive well designed and conducted placebo-controlled studies is generally accepted as appropriate to establish the efficacy of a drug. Attention to diagnosis, severity of illness, and to possible comorbid conditions is needed in the design and conduct of placebo-controlled studies in order to optimise the chance of obtaining valid data. The use of all data obtained, including dropouts due to lack of efficacy, should be maximised. The use of placebo may not be possible in some conditions that represent medical emergencies or may be difficult to justify in serious disorders where an effective treatment has already been established. Alternative designs to placebo-controlled studies can be considered. Consistent superior efficacy compared with a well accepted, effective treatment, given in an easily defended dose, is considered to be good evidence of efficacy provided that the studies are well designed and well conducted. Evidence of superior efficacy to an established effective comparator treatment may be regarded as evidence of efficacy. The demonstration of a dose-response relationship where one dose is found to be significantly better than another, can be taken as evidence for efficacy, particularly where there is already placebo-controlled evidence of the efficacy of the identified dose. Where a new treatment is found, under controlled conditions, to be equivalent to an existing well accepted comparator treatment, given at a clearly effective dose, this may be taken as evidence of efficacy, but only if the comparator is consistently superior to placebo and if equivalence has been defined beforehand. The claims for efficacy based on results from equivalence studies are less easily sustained than the evidence from placebo-controlled studies or studies demonstrating superior efficacy, due to the fact that those studies have no internal validation.European Neuropsychopharmacology 04/1999; 9(3):265-9. · 4.60 Impact Factor