Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Adult Laboratory Classroom Study of the Efficacy and Safety of PRC-063 (Extended-Release Methylphenidate) for the Treatment of ADHD

Ann Childress, Andrew J Cutler, Andrea H Marraffino, Sailaja Bhaskar, Graeme Donnelly, Ann Childress, Andrew J Cutler, Andrea H Marraffino, Sailaja Bhaskar, Graeme Donnelly

Abstract

Objective: To evaluate the efficacy, safety, and duration of action of the once-daily extended-release methylphenidate formulation PRC-063 for the treatment of ADHD in an adult laboratory classroom (ALC).

Method: After dose optimization with PRC-063 over 7 weeks, adults with ADHD were randomized to 1 week of double-blind treatment with PRC-063 or placebo that ended with an ALC evaluation. The primary outcome measure was Permanent Product Measure of Performance-Total (PERMP-T) score.

Results: Of 288 subjects enrolled, 221 completed the ALC visit. PERMP-T score was significantly higher for PRC-063 versus placebo at every assessment from 1 to 16 hours post-dose at the ALC visit and when averaged over 16 hours post-dose (least-squares mean difference 16.3, 95% confidence interval 7.6-24.9). The most frequent adverse events during dose optimization were headache, decreased appetite, and insomnia.

Conclusion: PRC-063 provided rapid and sustained symptom relief in adults with ADHD and was well tolerated. NCT03618030.

Keywords: ALC environment; adult ADHD; efficacy; methylphenidate; safety; sustained and long-lasting stimulant.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AC: Consultant—Arbor, Ironshore, Neos Therapeutics, Neurovance, Purdue, Rhodes, Sunovion, Tris, KemPharm, Supernus, Jazz, Corium, Lumos; Speakers Bureau—Takeda (Shire), Arbor, Ironshore, Neos Therapeutics, Tris, Supernus; Research Support—Allergan, Takeda (Shire), Emalex, Pearson, Akili, Arbor, Ironshore, Aevi Genomic Medicine, Neos Therapeutics, Neurovance, Otsuka, Purdue, Adlon, Rhodes, Sunovion, Tris, KemPharm, Supernus, U.S. Food and Drug Administration, Servier; Writing Support—Takeda (Shire), Arbor, Ironshore, Neos Therapeutics, Purdue, Rhodes, Sunovion, Tris; Advisory Board—Takeda (Shire), Akili, Arbor, Cingulate, Ironshore, Neos Therapeutics, Neurovance, Otsuka, Purdue, Adlon, Rhodes, Sunovion, Tris, Supernus, NLS Pharma, Corium. AJC: Consultant—Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Attentive, Ironshore, Otsuka, Purdue Canada, Shire, Supernus, Takeda, Tris; Speakers Bureau—Arbor Pharmaceuticals, Ironshore, Otsuka, Shire, Supernus, Takeda, Tris; Research Support—Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, KemPharm, Ironshore, Otsuka, Purdue Canada, Rhodes, Shire, Supernus, Takeda. AHM: Consultant—Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Supernus Pharmaceuticals, Inc.; Speakers Bureau—Ironshore Pharmaceuticals Inc.; Research Support—Acadia Pharmaceuticals, Akili Interactive Labs, Allergan, Arbor Pharmaceuticals, LLC, Avanir, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai, Inc., Ironshore Pharmaceuticals & Development, Inc., KemPharm, Inc., Neos Therapeutics, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., Purdue Pharma, Roche, Sage Therapeutics, Shire, Sunovion Pharmaceuticals, Inc., Supernus Pharmaceuticals, Inc., Takeda Pharmaceutical Company Ltd., and Tonix Pharmaceuticals, Tris Pharma.

Figures

Figure 1.
Figure 1.
Overall study design. Note. ALC = adult laboratory classroom.
Figure 2.
Figure 2.
Subject disposition. Note. ALC = adult laboratory classroom.
Figure 3.
Figure 3.
PERMP-T score during the full-day ALC visit (full analysis population): (A) LS mean PERMP-T score and (B) LS mean change in PERMP-T score from pre-dose score. Note. ALC = adult laboratory classroom; LS = least-squares; PERMP-T = Permanent Product Measure of Performance-Total; SE = standard error. *p < .05 for PRC-063 versus placebo.
Figure 4.
Figure 4.
Mean ADHD-RS-IV total score and mean PRC-063 dose by study visit (full analysis population). Note. ADHD-RS-IV = ADHD Rating Scale IV; ALC = adult laboratory classroom; SD = standard deviation.
Figure 5.
Figure 5.
SKAMP-C score during the full-day ALC visit (full analysis population). Note. ALC = adult laboratory classroom; LS = least-squares; SKAMP-C = Swanson, Kotkin, Agler, M-Flynn, and Pelham-Combined; SE = standard error. *p < .05 for PRC-063 versus placebo.

References

    1. Adler L., Cohen J. (2004). Diagnosis and evaluation of adults with attention-deficit/hyperactivity disorder. The Psychiatric Clinics of North America, 27(2), 187–201.
    1. Bain S. K., Jaspers K. E. (2010). Test review: Review of Kaufman Brief Intelligence Test, Second Edition:
    1. Kaufman A. S., Kaufman N. L. (2004). Kaufman Brief Intelligence Test, Second Edition. Bloomington, MN: Pearson, Inc. Journal of Psychoeducational Assessment, 28(2), 167–174.
    1. Buitelaar J., Asherson P., Soutullo C., Colla M., Adams D. H., Tanaka Y., Haynes V. S., Escobar R., Upadhyaya H. (2015). Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder. European Neuropsychopharmacology, 25(10), 1611–1621.
    1. Busner J., Targum S. D. (2007). The clinical global impressions scale: Applying a research tool in clinical practice. Psychiatry (Edgmont), 4(7), 28–37.
    1. Childress A. C., Brams M. N., Cutler A. J., Donnelly G. A. E., Bhaskar S. (2020). Efficacy and safety of multilayer, extended-release methylphenidate (PRC-063) in children 6-12 years of age with attention-deficit/hyperactivity disorder: A laboratory classroom study. Journal of Child Adolescent Psychopharmacology, 30(10), 580–589.
    1. Childress A., Mehrotra S., Gobburu J., McLean A., DeSousa N. J., Incledon B. (2018). Single-dose pharmacokinetics of HLD200, a delayed-release and extended-release methylphenidate formulation, in healthy adults and in adolescents and children with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 28(1), 10–18.
    1. Childress A. C., Newcorn J. H., Cutler A. J. (2019). Gender effects in the efficacy of racemic amphetamine sulfate in children with attention-deficit/hyperactivity disorder. Advances in Therapy, 36(6), 1370–1387.
    1. Cortese S., Adamo N., Del Giovane C., Mohr-Jensen C., Hayes A. J., Carucci S., Atkinson L. Z., Tessari L., Banaschewski T., Coghill D., Hollis C., Simonoff E., Zuddas A., Barbui C., Purgato M., Steinhausen H.-C., Shokraneh F., Xia J., Cipriani A. (2018). Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis. Lancet Psychiatry, 5(9), 727–738.
    1. DuPaul G. J., Power T. J., Anastopoulos A. D., Reid R. (2006). ADHD rating scale-IV: Checklists, norms, and clinical interpretation. Journal of Psychoeducational Assessment, 24(2), 172–178.
    1. Erensen J. G., Beusterien K., Cambron-Mellott M. J., Hallissey B., Matos J., Mikl J. (2020). Unlocking patient preferences for long-acting treatments for ADHD: Results of a discrete choice experiment [Poster]. 2020 American Professional Society of ADHD and Related Disorders (APSARD) Annual Meeting. Washington, D.C., United States.
    1. Fallu A., Dabouz F., Furtado M., Anand L., Katzman M. A. (2016). A randomized, double-blind, cross-over, phase IV trial of oros-methylphenidate (CONCERTA((®))) and generic novo-methylphenidate ER-C (NOVO-generic). Therapeutic Advances in Psychopharmacology, 6(4), 237–251.
    1. Fayyad J., Sampson N. A., Hwang I., Adamowski T., Aguilar-Gaxiola S., Al-Hamzawi A., Andrade L. H. S. G., Borges G., de Girolamo G., Florescu S., Gureje O., Haro J. M., Hu C., Karam E. G., Lee S., Navarro-Mateu F., O’Neill S., Pennell B.-E., Piazza M., . . . Kessler R. C. (2017). The descriptive epidemiology of DSM-IV Adult ADHD in the World Health Organization World Mental Health Surveys. Attention Deficit and Hyperactivity Disorders, 9(1), 47–65.
    1. Gajria K., Lu M., Sikirica V., Greven P., Zhong Y., Qin P., Xie J. (2014). Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder – A systematic literature review. Neuropsychiatric Disease and Treatment, 10, 1543–1569.
    1. Ginsberg Y., Quintero J., Anand E., Casillas M., Upadhyaya H. P. (2014). Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: A review of the literature. The Primary Care Companion for CNS Disorders, 16(3), PCC.13r01600.
    1. Goodman D. W. (2007). The consequences of attention-deficit/hyperactivity disorder in adults. Journal of Psychiatric Practice, 13(5), 318–327.
    1. Gormez V., Avery B., Mann H. (2013). Switching from immediate release to sustained release methylphenidate in the treatment of children and adolescents with attention deficit/hyperactivity disorder. European Review for Medical and Pharmacological Sciences, 17(17), 2345–2349.
    1. Guy W. (1976). Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology—Revised (pp. 217–222). U.S. Department of Health, Education, and Welfare; Public Health Service; Alcohol, Drug Abuse, and Mental Health Administration; National Institute of Mental Health; Psychopharmacology Research Branch; Division of Extramural Research Programs.
    1. Huss M., Duhan P., Gandhi P., Chen C. W., Spannhuth C., Kumar V. (2017). Methylphenidate dose optimization for ADHD treatment: Review of safety, efficacy, and clinical necessity. Neuropsychiatric Disease and Treatment, 13, 1741–1751.
    1. Huss M., Ginsberg Y., Tvedten T., Arngrim T., Philipsen A., Carter K., Chen C.-W., Kumar V. (2014). Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: A randomized double-blind placebo-controlled trial. Advances in Therapy, 31(1), 44–65.
    1. Katzman M., Mattingly G., Klassen L. J., Cataldo M. J., Donnelly G. A. E. (2020). Randomized controlled crossover trials of the pharmacokinetics of PRC-063, a novel multilayer extended-release formulation of methylphenidate, in healthy adults. Journal of Clinical Psychopharmacology, 40(6), 579–587.
    1. Katzman M. A., Armata R. S., Fotinos K., Fine A., Furtado M., Canzonieri A., Lokuge S., Sherifi E., Sternat T. (2019). Attention deficit hyperactivity disorder and its effects in the Canadian workplace. EC Psychology and Psychiatry, 8.4, 278–288.
    1. Kollins S., Cutler A., Khattak S., Weiss M., Donnelly G., Reiz J. (2016). A randomized, double-blind, placebo-controlled, multicenter study measuring the efficacy and safety of a novel, extended-release formulation of methylphenidate (PRC-063) in adolescents with attention-deficit/hyperactivity disorder [Poster presentation]. Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), New York, NY, United States.
    1. Lachaine J., Beauchemin C., Sasane R., Hodgkins P. S. (2012). Treatment patterns, adherence, and persistence in ADHD: A Canadian perspective. Postgraduate Medicine, 124(3), 139–148.
    1. McCrimmon A. W., Smith A. D. (2012). Review of the Wechsler abbreviated scale of intelligence, second edition (WASI-II). Journal of Psychoeducational Assessment, 31(3), 337–341.
    1. NICE. (2018). Attention deficit hyperactivity disorder: Diagnosis and management. National Institute for Health and Care Excellence. Retrieved February 11, 2021, from
    1. Pineiro-Dieguez B., Balanza-Martinez V., Garcia-Garcia P., Soler-Lopez B., Group C. A. T. S. (2016). Psychiatric comorbidity at the time of diagnosis in adults with ADHD: The CAT study. Journal of Attention Disorders, 20(12), 1066–1075.
    1. Swanson J. M. (2005). Long-acting stimulants: Development and dosing. The Canadian Child and Adolescent Psychiatry Review, 14(suppl 1), 4–9.
    1. Swanson J. M., Agler D., Fineberg E., Wigal S., Flynn D., Fineberg K., Quintana Y., Talebi H. (2000). University of California, Irvine, laboratory school protocol for pharmacokinetic and pharmacodynamic studies. In Greenhill L., Osman B. (Eds.), Ritalin: Theory and practice (2nd ed., pp. 405–430). Mary Ann Liebert.
    1. Weiss M. D., Childress A. C., Donnelly G. A. E. (2020). Efficacy and safety of PRC-063, extended-release multilayer methylphenidate in adults with ADHD including 6-month open-label extension. Journal of Attention Disorders. Advance online publication. 10.1177/1087054719896853
    1. Wigal S. B. (2019). Laboratory school protocol mini-review: Use of direct observational and objective measures to assess ADHD treatment response across the lifespan. Frontiers in Psychology, 10, 1796.
    1. Wigal S. B., Childress A., Berry S. A., Belden H. W., Chappell P., Wajsbrot D. B., Nagraj P., Abbas R., Palumbo D. (2018). Optimization of methylphenidate extended-release chewable tablet dose in children with ADHD: Open-label dose optimization in a laboratory classroom study. Journal of Child and Adolescent Psychopharmacology, 28(5), 314–321.
    1. Wigal S. B., Gupta S., Guinta D., Swanson J. M. (1998). Reliability and validity of the SKAMP rating scale in a laboratory school setting. Psychopharmacology Bulletin, 34(1), 47–53.
    1. Wigal S. B., Wigal T., Childress A., Donnelly G. A. E., Reiz J. L. (2020). The time course of effect of multilayer-release methylphenidate hydrochloride capsules: A randomized, double-blind study of adults with ADHD in a simulated adult workplace environment. Journal of Attention Disorders, 24(3), 373–383.
    1. Wigal T., Brams M., Frick G., Yan B., Madhoo M. (2018). A randomized, double-blind study of SHP465 mixed amphetamine salts extended-release in adults with ADHD using a simulated adult workplace design. Postgraduate Medicine, 130(5), 481–493.
    1. Wigal T., Childress A., Frick G., Yan B., Wigal S., Madhoo M. (2018). Effects of SHP465 mixed amphetamine salts in adults with ADHD in a simulated adult workplace environment. Postgraduate Medicine, 130(1), 111–121.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner