Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-26T23:34:05.360Z Has data issue: false hasContentIssue false
  • English
  • Français

Post hoc analysis of a randomised, placebo-controlled, active-reference 6-week study of brexpiprazole in acute schizophrenia

Published online by Cambridge University Press:  14 February 2020

Stephen R. Marder Open the ORCID record for Stephen R. Marder [Opens in a new window] ,
Hans Eriksson ,
Yudong Zhao  and
Mary Hobart
Stephen R. Marder*
Affiliation:
Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA, USA
Hans Eriksson
Affiliation:
H. Lundbeck A/S, Valby, Denmark
Yudong Zhao
Affiliation:
H. Lundbeck A/S, Valby, Denmark
Mary Hobart
Affiliation:
Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA
*
Author for correspondence: Stephen R. Marder, Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint – change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.

Methods:

Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.

Results:

Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: −4.3 [95% CI (−8.0, −0.5), p = 0.0254]. OC, ANCOVA: −3.9 [95% CI (−7.3, −0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of −29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of −13.5 [95% CI (−23.1, −4.0), p = 0.0057], and those who did not had an LS mean change of −18.9 and a difference between brexpiprazole and placebo of −2.9 [95% CI (−7.2, 1.4), p = 0.1809].

Conclusion:

Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.

Keywords

antipsychoticschizophreniaclinical trials
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 3 , June 2020 , pp. 153 - 158
Copyright
© Scandinavian College of Neuropsychopharmacology 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

ClinicalTrials.gov identifier: NCT01810380

EudraCT number: 2012-002252-17

References

Federal Drug Administration (2013) SEROQUEL XR®(quetiapine fumarate) extended-release tablets, for oral use. Initial U.S. Approval: 1997. Wilmington, DE, USA: AstraZeneca.Google Scholar
American Psychiatric Association. and American Psychiatric Association. Task Force on DSM-IV (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association.Google Scholar
Barnes, TR (1989) A rating scale for drug-induced akathisia. British Journal of Psychiatry 154, 672–676.CrossRefGoogle ScholarPubMed
Correll, CU, Skuban, A, Ouyang, J, Hobart, M, Pfister, S, Mcquade, RD, Nyilas, M, Carson, WH, Sanchez, R and Eriksson, H (2015) Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. American Journal of Psychiatry 172, 870–880.CrossRefGoogle ScholarPubMed
European Medicines Agency (2018) Rxulti: EPAR - Product Information [Online]. Available at https://www.ema.europa.eu/en/documents/overview/rxulti-epar-medicine-overview_en.pdf (accessed 6 January 2020).Google Scholar
Fleischhacker, WW, Hobart, M, Ouyang, J, Forbes, A, Pfister, S, Mcquade, RD, Carson, WH, Sanchez, R, Nyilas, M and Weiller, E (2017) Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia: a randomized, double-blind, placebo-controlled study. International Journal of Neuropsychopharmacology 20, 11–21.Google ScholarPubMed
Guy, W (1976) Abnormal involuntary movement scale (AIMS) In Guy, W (ed), ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: National Institute of Mental Health, 534–536.Google Scholar
Kane, JM and Leucht, S (2008) Unanswered questions in schizophrenia clinical trials. Schizophrenia Bulletin 34, 302–309.CrossRefGoogle ScholarPubMed
Kane, JM, Skuban, A, Ouyang, J, Hobart, M, Pfister, S, Mcquade, RD, Nyilas, M, Carson, WH, Sanchez, R and Eriksson, H (2015) A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophrenia Research 164, 127–135.CrossRefGoogle ScholarPubMed
Laferton, JAC, Vijapura, S, Baer, L, Clain, AJ, Cooper, A, Papakostas, G, Price, LH, Carpenter, LL, Tyrka, AR, Fava, M and Mischoulon, D (2018) Mechanisms of perceived treatment assignment and subsequent expectancy effects in a double blind placebo controlled RCT of major depression. Front Psychiatry 9, 424.CrossRefGoogle Scholar
Maeda, K, Sugino, H, Akazawa, H, Amada, N, Shimada, J, Futamura, T, Yamashita, H, Ito, N, Mcquade, RD, Mork, A, Pehrson, AL, Hentzer, M, Nielsen, V, Bundgaard, C, Arnt, J, Stensbol, TB and Kikuchi, T (2014) Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. Journal of Pharmacology and Experimental Therapeutics 350, 589–604.CrossRefGoogle ScholarPubMed
Marder, SR, Hakala, MJ, Josiassen, MK, Zhang, P, Ouyang, J, Weiller, E, Weiss, C and Hobart, M (2017) Brexpiprazole in patients with schizophrenia: overview of short- and long-term phase 3 controlled studies. Acta Neuropsychiatrica. Officieel Wetenschappelijk Orgaan van Het IGBP (Interdisciplinair Genootschap voor Biologische Psychiatrie) 29, 278–290.Google Scholar
Posner, K, Brown, GK, Stanley, B, Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, Melvin, GA, Greenhill, L, Shen, S and Mann, JJ (2011) The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. American Journal of Psychiatry 168, 1266–1277.CrossRefGoogle ScholarPubMed
Schatzberg, AF (2015) Development of new psychopharmacological agents for depression and anxiety. Psychiatric Clinics of North America 38, 379–393.CrossRefGoogle ScholarPubMed
Simpson, GM and Angus, JW (1970) A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica. Supplementum 212, 11–19.CrossRefGoogle ScholarPubMed