Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder

Sharon B Wigal, Ann Childress, Sally A Berry, Heidi Belden, Faith Walters, Phillip Chappell, Nancy Sherman, John Orazem, Donna Palumbo, Sharon B Wigal, Ann Childress, Sally A Berry, Heidi Belden, Faith Walters, Phillip Chappell, Nancy Sherman, John Orazem, Donna Palumbo

Abstract

Objective: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD).

Methods: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS).

Results: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment.

Conclusions: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Keywords: attention-deficit/hyperactivity disorder; children; drug formulation; methylphenidate; safety; treatment efficacy.

Conflict of interest statement

Sharon Wigal receives or has received research support, acted as a consultant, been an advisory board member, and/or served on a speakers bureau for Addrenex Pharmaceuticals, Eli Lilly and Company, Forest Pharmaceuticals, McNeil Consumer & Specialty Pharmaceuticals, NextWave Pharmaceuticals, NIMH, Noven, NuTec Pharma, Otsuka, Pfizer, Purdue, Quintiles, Rho, Rhodes Pharmaceuticals, Shionogi, Shire US, Sunovion, Taisho Pharmaceutical, and Tris Pharma. Ann Childress receives or has received research support, acted as a consultant, been an advisory board member, and/or served as a speaker for Shire Pharmaceuticals, Pearson, Pfizer, Noven, NextWave Pharmaceuticals, Lilly USA, Forest Research Institute, Otsuka, Sunovion, Ironshore, Rhodes, Theravance, Neurovance, Neos, Arbor, Tris Pharma, Purdue, Lundbeck, and Alcobra. Sally A. Berry is an employee of Tris Pharma and has served as a paid consultant for Pfizer in connection with the development of the manuscript. Heidi Belden was a paid consultant for Pfizer in connection with the development of this manuscript. Faith Walters, Phillip Chappell, Nancy A. Sherman, John Orazem, and Donna Palumbo are employees of Pfizer.

Figures

FIG. 1.
FIG. 1.
SKAMP-Combined scores at visit 9, average over all postdose time points; intent-to-treat population. *p < 0.001. SKAMP, Swanson, Kotkin, Agler, M-Flynn, and Pelham.
FIG. 2.
FIG. 2.
Least squares mean (standard error) SKAMP-Combined scores at visit 9, intent-to-treat population. *p < 0.001.

References

    1. Abbas R, Palumbo D, Walters F, Belden H, Berry SA: Single-dose pharmacokinetics and relative bioavailability of a novel methylphenidate extended-release chewable tablet compared with immediate-release methylphenidate chewable tablet. Clin Ther 38:1151–1157, 2016
    1. Adjei A, Teuscher NS, Kupper RJ, Chang WW, Greenhill L, Newcorn JH, Connor DF, Wigal S: Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin((R))) in healthy adult volunteers. J Child Adolesc Psychopharmacol 24:570–578, 2014
    1. American Academy of Pediatrics: ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics 128:1007–1022, 2011
    1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association; 2013
    1. Aptensio XR. [package insert]: Coventry (Rhode Island), Rhodes Pharmaceuticals, 2017
    1. Barkley RA: Major life activity and health outcomes associated with attention-deficit/hyperactivity disorder. J Clin Psychiatry 63(Suppl 12):10–15, 2002
    1. Birnbaum HG, Kessler RC, Lowe SW, Secnik K, Greenberg PE, Leong SA, Swensen AR: Costs of attention deficit-hyperactivity disorder (ADHD) in the US: Excess costs of persons with ADHD and their family members in 2000. Curr Med Res Opin 21:195–206, 2005
    1. Childress A, Sallee FR: The use of methylphenidate hydrochloride extended-release oral suspension for the treatment of ADHD. Expert Rev Neurother 13:979–988, 2013
    1. Childress AC, Brams M, Cutler AJ, Kollins SH, Northcutt J, Padilla A, Turnbow JM: The efficacy and safety of evekeo, racemic amphetamine sulfate, for treatment of attention-deficit/hyperactivity disorder symptoms: A multicenter, dose-optimized, double-blind, randomized, placebo-controlled crossover laboratory classroom study. J Child Adolesc Psychopharmacol 25:402–414, 2015
    1. Concerta [package insert]: Titusville (New Jersey), Janssen Pharmaceuticals, Inc., 2015
    1. Conners CK, Sitarenios G, Parker JD, Epstein JN: The revised Conners' Parent Rating Scale (CPRS-R): Factor structure, reliability, and criterion validity. J Abnorm Child Psychol 26:257–268, 1998
    1. Das D, Cherbuin N, Butterworth P, Anstey KJ, Easteal S: A population-based study of attention deficit/hyperactivity disorder symptoms and associated impairment in middle-aged adults. PLoS One 7:e31500, 2012
    1. Daytrana [package insert]: Miami (Florida), Noven Therapeutics, LLC, 2015
    1. Feldman HM, Reiff MI: Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med 370:838–846, 2014
    1. Fischer R, Schutz H, Grossmann M, Leis HJ, Ammer R: Bioequivalence of a methylphenidate hydrochloride extended-release preparation: Comparison of an intact capsule and an opened capsule sprinkled on applesauce. Int J Clin Pharmacol Ther 44:135–141, 2006
    1. Focalin XR. [package insert]: East Hanover (New Jersey), Novartis Pharmaceuticals Corporation, 2015
    1. Gajria K, Lu M, Sikirica V, Greven P, Zhong Y, Qin P, Xie J: Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder—A systematic literature review. Neuropsychiatr Dis Treat 10:1543–1569, 2014
    1. Guy W: CGI Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology Revised, 1976. US Department Health Education and Welfare. National Institute of Mental Health, 1976, pp. 217–222
    1. Hammerness P, Wilens T, Mick E, Spencer T, Doyle R, Mccreary M, Becker J, Biederman J: Cardiovascular effects of longer-term, high-dose OROS methylphenidate in adolescents with attention deficit hyperactivity disorder. J Pediatr 155:84–89, 89, 2009
    1. International Council for Harmonisation: ICH harmonised tripartite guideline: Statistical principles for clinical trials E9. International Conference on Harmonisation, 1998. Available at (last accessed March30, 2017)
    1. Jerome L, Segal A, Habinski L: What we know about ADHD and driving risk: A literature review, meta-analysis and critique. J Can Acad Child Adolesc Psychiatry 15:105–125, 2006
    1. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N: Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988, 1997
    1. Kimko H, Gibiansky E, Gibiansky L, Starr HL, Berwaerts J, Massarella J, Wiegand F: Population pharmacodynamic modeling of various extended-release formulations of methylphenidate in children with attention deficit hyperactivity disorder via meta-analysis. J Pharmacokinet Pharmacodyn 39:161–176, 2012
    1. Klassen AF, Miller A, Fine S: Health-related quality of life in children and adolescents who have a diagnosis of attention-deficit/hyperactivity disorder. Pediatrics 114:e541–e547, 2004
    1. Lee L, Kepple J, Wang Y, Freestone S, Bakhtiar R, Wang Y, Hossain M: Bioavailability of modified-release methylphenidate: Influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce. Biopharm Drug Dispos 24:233–243, 2003
    1. Lee SS, Humphreys KL, Flory K, Liu R, Glass K: Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: A meta-analytic review. Clin Psychol Rev 31:328–341, 2011
    1. Matza LS, Paramore C, Prasad M: A review of the economic burden of ADHD. Cost Eff Resour Alloc 3:5, 2005
    1. Mcgough JJ, Wigal SB, Abikoff H, Turnbow JM, Posner K, Moon E: A randomized, double-blind, placebo-controlled, laboratory classroom assessment of methylphenidate transdermal system in children with ADHD. J Atten Disord 9:476–485, 2006
    1. Meltzer EO, Welch MJ, Ostrom NK: Pill swallowing ability and training in children 6 to 11 years of age. Clin Pediatr (Phila) 45:725–733, 2006
    1. Metadate CD. [package insert]: Smyrna (Georgia), UCB, Inc., 2015
    1. Michele TM, Knorr B, Vadas EB, Reiss TF: Safety of chewable tablets for children. J Asthma 39:391–403, 2002
    1. Pelham WE, Gnagy EM, Burrows-Maclean L, Williams A, Fabiano GA, Morrisey SM, Chronis AM, Forehand GL, Nguyen CA, Hoffman MT, Lock TM, Fielbelkorn K, Coles EK, Panahon CJ, Steiner RL, Meichenbaum DL, Onyango AN, Morse GD: Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Pediatrics 107:E105, 2001
    1. Pentikis HS, Simmons RD, Benedict MF, Hatch SJ: Methylphenidate bioavailability in adults when an extended-release multiparticulate formulation is administered sprinkled on food or as an intact capsule. J Am Acad Child Adolesc Psychiatry 41:443–449, 2002
    1. Pliszka S: Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 46:894–921, 2007
    1. Polaha J, Dalton WT, III, Lancaster BM: Parental report of medication acceptance among youth: Implications for everyday practice. South Med J 101:1106–1112, 2008
    1. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ: The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168:1266–1277, 2011
    1. Posner K, Oquendo MA, Gould M, Stanley B, Davies M: Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 164:1035–1043, 2007
    1. Quillivant XR. [package insert]: New York, NextWave Pharmaceuticals, Inc.; a subsidiary of Pfizer, Inc., 2016
    1. Ritalin LA. [package insert]: East Hanover (New Jersey), Novartis Pharmaceuticals Corporation, 2015
    1. Robb AS, Findling RL, Childress AC, Berry SA, Belden HW, Wigal SB: Efficacy, safety, and tolerability of a novel methylphenidate extended-release oral suspension (MEROS) in ADHD. J Atten Disord 2014. [Epub ahead of print]; DOI: 10.1177/1087054714533191
    1. Sharma A, Couture J: A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother 48:209–225, 2014
    1. Sugrue D, Bogner R, Ehret MJ: Methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder. Am J Health Syst Pharm 71:1163–1170, 2014
    1. Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E, Greenhill LL, Biederman J, Kollins S, Nguyen AS, Decory HH, Hirshe Dirksen SJ, Hatch SJ: A comparison of once-daily extended-release methylphenidate formulations in children with attention-deficit/hyperactivity disorder in the laboratory school (the COMACS Study). Pediatrics 113(3 Pt 1):e206–e216, 2004
    1. Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, Perou R, Blumberg SJ: Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003–2011. J Am Acad Child Adolesc Psychiatry 53:34–46, 2014
    1. Wigal SB, Childress AC, Belden HW, Berry SA: NWP06, an extended-release oral suspension of methylphenidate, improved attention-deficit/hyperactivity disorder symptoms compared with placebo in a laboratory classroom study. J Child Adolesc Psychopharmacol 23:3–10, 2013
    1. Wigal SB, Greenhill LL, Nordbrock E, Connor DF, Kollins SH, Adjei A, Childress A, Stehli A, Kupper RJ: A randomized placebo-controlled double-blind study evaluating the time course of response to methylphenidate hydrochloride extended-release capsules in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 24:562–569, 2014
    1. Wigal SB, Gupta S, Guinta D, Swanson JM: Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacol Bull 34:47–53, 1998
    1. Wigal SB, Kollins SH, Childress AC, Squires L: A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder. Child Adolesc Psychiatry Ment Health 3:17, 2009
    1. Wigal SB, Wigal TL: The laboratory school protocol: Its origin, use, and new applications. J Atten Disord 10:92–111, 2006
    1. Wolraich ML, Mcguinn L, Doffing M: Treatment of attention deficit hyperactivity disorder in children and adolescents: Safety considerations. Drug Saf 30:17–26, 2007

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する