Elsevier

Clinical Therapeutics

Volume 34, Issue 4, April 2012, Pages 980-992
Clinical Therapeutics

Pediatric, adolescent, & maternal therapeutics
Original research
Effect of Aripiprazole 2 to 15 mg/d on Health-Related Quality of Life in the Treatment of Irritability Associated with Autistic Disorder in Children: A Post Hoc Analysis of Two Controlled Trials

https://doi.org/10.1016/j.clinthera.2012.02.023Get rights and content

Abstract

Background

There are limited published data on the impact of treatment on the health-related quality of life (HRQOL) in individuals with autistic disorder.

Objective

The aim of this study was to evaluate the impact of aripiprazole on HRQOL in the treatment of irritability in pediatric patients (aged 6–17 years) with autistic disorder.

Methods

This post hoc analysis assessed data from two 8-week, double-blind, randomized, placebo-controlled studies that compared the efficacy of aripiprazole (fixed-dose study, 5, 10, and 15 mg/d; flexible-dose study, 2−15 mg/d) with placebo in the treatment of irritability associated with autistic disorder. HRQOL was assessed at baseline and week 8 using 3 Pediatric Quality of Life Inventory (PedsQL™) scales. Clinically relevant improvement in HRQOL was determined using an accepted distribution-based criterion—1 standard error of measurement.

Results

In total, 316 patients were randomly assigned to receive treatment with aripiprazole (fixed-dose study, 166; flexible-dose study, 47) or placebo (fixed-dose study, 52; flexible-dose study, 51). Aripiprazole was associated with significantly greater improvement than placebo in PedsQL combined-scales total score (difference, 7.8; 95% CI, 3.8–11.8; P < 0.001) and in 3 PedsQL scale scores (differences [95% CI]: Emotional Functioning, 7.8 [3.4–12.2]; Social Functioning, 6.2 [0.7–11.8]; Cognitive Functioning, 9.3 [3.8–14.9]; all, P < 0.05). Patients who received aripiprazole were significantly more likely than those who received placebo to have a clinically meaningful improvement on the combined-scales total score (odds ratio [OR] = 1.9; 95% CI, 1.0–3.3; P < 0.05), Emotional Functioning scale (OR = 2.2; 95% CI, 1.2–4.0; P < 0.05) and Social Functioning scale (OR = 2.2; 95% CI, 1.2–4.1; P < 0.05), and were significantly less likely to experience deterioration (OR: 0.3, 95% CI: 0.1–0.8; P < 0.05) when “Stable” was used as the reference group.

Conclusions

The findings from the present post hoc analysis suggest that aripiprazole was associated with improved HRQOL, as assessed using 3 PedsQL scales, in pediatric patients with irritability associated with autistic disorder.

Introduction

Health-related quality of life (HRQOL), as defined by the World Health Organization (WHO) and the US Food and Drug Administration (FDA), represents a multidimensional construct of physical, psychological (including emotional and cognitive), and social dimensions.1, 2 Measurement of HRQOL is increasingly used as an outcome measure in health care decision-making. HRQOL can be used to evaluate the effects of health care interventions, including pharmaceuticals, on health status, and it is recommended that HRQOL assessment be conducted regularly during clinical trials.3

A number of pediatric-specific HRQOL instruments have been developed to address the unique challenges of measuring HRQOL in pediatric patients. One of the most widely utilized instruments is the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales. The PedsQL 4.0 Generic Core Scales were developed as a generic pediatric HRQOL instrument for use across a wide range of pediatric populations, including patients with both acute and chronic conditions.4 The PedsQL instrument is ideally suited for use in a pediatric population because it is quick to administer, taking ∼5 minutes to complete, and has been validated for use across a wide range of ages (2–<18 years). Additionally, the 6-item PedsQL Cognitive Functioning scale, originally developed as a subscale of the PedsQL Multidimensional Fatigue scale,5 can be used as a standardized means of assessing cognitive functioning. The Cognitive Functioning scale has been reported to have significant correlations with the Behavior Rating Inventory of Executive Function scale in a pediatric population with head trauma6 and in pediatric liver transplant recipients,7 suggesting that this scale measures important aspects of executive functioning. The Cognitive Functioning scale was also recently utilized to assess cognitive functioning in pediatric patients with Asperger syndrome.8

Autistic disorder is a neurodevelopmental disorder characterized by impairments in social interaction and communication, as well as restricted, repetitive, and stereotyped patterns of behavior, activities, or interests.9 Secondary behaviors sometimes associated with autistic disorder include irritability, which may manifest as tantrums, aggressiveness, self-injurious behavior, and sudden mood changes. These associated behaviors may have a substantial impact on individuals and their families, and they may have a significant negative effect on education and social development.10 Minimizing the impact of these associated behavioral symptoms on an individual's functional independence and HRQOL is recognized as a primary goal of a total treatment program that includes a combination of behavioral and pharmacologic approaches.11 Recent research examining the HRQOL of children with autistic disorder using the PedsQL reported that these individuals have worse HRQOL for total, psychosocial, emotional, and social functioning than do other children with chronic health conditions.12 That research also reported that HRQOL was associated with a variety of behavioral challenges associated with autistic disorder, suggesting that treatments aimed at improving these behaviors may improve HRQOL as measured using the PedsQL scales.12 Despite this, there are limited published data on the impact of treatment on HRQOL in this population.

Aripiprazole was recently approved by the FDA for the treatment of pediatric patients (aged 6−17 years) with irritability associated with autistic disorder, including symptoms of aggression toward others, deliberate self-injury, temper tantrums, and quickly changing moods.13 Two 8-week, multicenter, randomized, double-blind, placebo-controlled studies reported that aripiprazole was efficacious and generally well tolerated in the treatment of pediatric patients with irritability associated with autistic disorder.14, 15 These trials were not designed or intended to evaluate the effects of aripiprazole on the core symptoms of autistic disorder. These 2 studies were similar in design, with the exception of aripiprazole dosing. One study used a fixed-dose study design in which patients were randomly assigned to receive aripiprazole 5, 10, or 15 mg/d or placebo,14 whereas the other used a flexible-dose design in which patients were randomly assigned to receive flexibly dosed aripiprazole (2–15 mg/d, titrated to clinical effect, with a target dose of 5, 10, or 15 mg/d) or placebo.15 In both studies, aripiprazole was associated with significantly greater improvements in irritability compared with placebo, based on mean changes from baseline in scores on the Aberrant Behavior Checklist–Irritability (ABC-I) subscales at week 8 (the primary efficacy end point). Both studies also included assessments of HRQOL, measured using the PedsQL Emotional Functioning, Social Functioning, and Cognitive Functioning scales. The present analysis reports the findings from these assessments and from a post hoc analysis of these data to further evaluate the impact of aripiprazole on HRQOL in children.

Section snippets

Study Designs and Treatments

This post hoc analysis assessed data from 2 randomized, double-blind, placebo-controlled studies conducted at multiple sites in the United States (ClinicalTrial.gov identifiers: NCT00337571 and NCT00332241).14, 15 Patients were enrolled from June 2006 through June 2008 in the fixed-dose study and through February 2008 in the flexible-dose study. Full details of the study design have been reported previously.14, 15 Both studies had a screening phase followed by an 8-week treatment phase.

In the

Disposition and Baseline Characteristics of the Study Population

In total, 316 patients were randomly assigned to receive treatment with aripiprazole (fixed-dose study, 166 patients; flexible-dose study, 47 patients) or placebo (fixed-dose study, 52 patients; flexible-dose study, 51 patients). The demographic characteristics of the individuals included in each of these 2 studies have been presented previously.14, 15 In both studies, the majority of patients were white boys. The rates of study completion were similar between the 2 studies; overall, 82% of the

Discussion

The findings from this post hoc analysis of PedsQL data from 2 placebo-controlled studies suggest that aripiprazole has the potential to improve HRQOL when used to treat pediatric patients with irritability associated with autistic disorder. When data from the 2 studies were pooled, patients receiving aripiprazole had greater improvement than patients receiving placebo on the PedsQL combined-scales total score, as well as on the PedsQL Emotional Functioning, Social Functioning, and Cognitive

Conclusions

The findings from the present post hoc analysis suggest that aripiprazole had the potential to improve HRQOL when used to treat pediatric patients with irritability associated with autistic disorder. Specifically, clinically meaningful improvements in aspects of emotional and social functioning, as measured using the PedsQL, were experienced by significantly more patients receiving aripiprazole than placebo, and cognitive functioning was preserved.

Conflicts of Interest

This research and its publication were supported by Bristol-Myers Squibb Co. and Otsuka Pharmaceutical Co., Ltd. Editorial support for the preparation of the manuscript was funded by Bristol-Myers Squibb Co.

Dr. Varni holds the copyright and the trademark for the PedsQL™ and receives financial compensation from the MAPI Research Trust, a nonprofit research institute that charges distribution fees to for-profit companies that use the PedsQL. Dr. Handen has served as a consultant to Bristol-Myers

Acknowledgments

Editorial support for the preparation of the manuscript was provided by Ogilvy Healthworld Medical Education. The authors acknowledge and thank the children and their families for participation in these trials. Drs. Handen, Corey-Lisle, Marcus, Owen, McQuade, Carson and Mankoski were involved in the design, analysis, and conduct of the original trials and the post-hoc analyses. Dr. Varni, Ammerman, and Ms. Mathew were involved in the post-hoc analysis plan and provided additional interpretation

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