Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder

Frank A López, Stephen V Faraone, Jeffrey H Newcorn, Helen A Doll, Stephanie Rhoten, Hannah B Lewis, Tayyaba F Khan, Norberto J DeSousa, Floyd R Sallee, Bev Incledon, Frank A López, Stephen V Faraone, Jeffrey H Newcorn, Helen A Doll, Stephanie Rhoten, Hannah B Lewis, Tayyaba F Khan, Norberto J DeSousa, Floyd R Sallee, Bev Incledon

Abstract

Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.

Keywords: DR/ER-MPH; HLD200; caregiver strain; methylphenidate; psychometrics; validation.

Conflict of interest statement

F.A.L. has served as a consultant to and received speaker fees and/or research support from Eli Lilly, GSK, Ironshore, Neos, Novartis, Noven, Pfizer, Shire, Sunovion, Supernus, and Tris. S.V.F. received income, potential income, travel expenses, continuing education support, and/or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Ironshore, Rhodes, Akili Interactive Labs, Sunovion, Supernus, and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium/hydrogen exchange inhibitors in the treatment of ADHD. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts, and Elsevier: ADHD: Non-Pharmacologic Interventions. He is Program Director of www.adhdinadults.com. J.H.N. has been an advisor and/or consultant for Akili Interactive, Cingulate Therapeutics, LLC, Enzymotec, NeuroLifeSciences Pharma, Rhodes Pharmaceuticals, Shire, Supernus Pharmaceuticals, Inc., and the U.S. National Football League. He has received research grants from Enzymotec, Otsuka America Pharmaceutical, Inc., Shire, and Supernus Pharmaceuticals, Inc.; he is a DSMB member of Pfizer and Sunovion Pharmaceuticals, Inc., and he has received meeting honoraria from Shire. H.B.L. is an employee of ICON Clinical Research Limited, and S.R. and H.A.D. are former employees of ICON Clinical Research Limited, which was funded by Ironshore Pharmaceuticals & Development to perform the validation studies. S.R is currently an employee of IQVIA, and previous employee of Guidehouse, and H.A.D. is currently an employee of Clinical Outcomes Solutions. T.F.K. is an employee of Highland Therapeutics, Inc., N.J.D. and B.I. are employees of Ironshore Pharmaceuticals & Development, Inc., F.R.S. is an employee of Ironshore Pharmaceuticals, Inc., and is a member of the Board of Directors for P2D Biosciences.

Figures

FIG. 1.
FIG. 1.
CGSQ total scores after 3 weeks of treatment. Error bars denote standard error. CGSQ, Caregiver Strain Questionnaire; DR/ER-MPH, delayed-release and extended-release methylphenidate; LS, least-squares; SD, standard deviation; SE, standard error.

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