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Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study

  • W. Wolfgang Fleischhacker (a1), Raymond Sanchez (a2), Pamela P. Perry (a2), Na Jin (a3), Timothy Peters-Strickland (a2), Brian R. Johnson (a2), Ross A. Baker (a2), Anna Eramo (a4), Robert D. McQuade (a2), William H. Carson (a2), David Walling (a5) and John M. Kane (a6)...
Abstract
Background

Long-acting injectable formulations of antipsychotics are treatment alternatives to oral agents.

Aims

To assess the efficacy of aripiprazole once-monthly compared with oral aripiprazole for maintenance treatment of schizophrenia.

Method

A 38-week, double-blind, active-controlled, non-inferiority study; randomisation (2:2:1) to aripiprazole once-monthly 400 mg, oral aripiprazole (10–30 mg/day) or aripiprazole once-monthly 50mg (a dose below the therapeutic threshold for assay sensitivity). (Trial registration: clinicaltrials.gov, NCT00706654.)

Results

A total of 1118 patients were screened, and 662 responders to oral aripiprazole were randomised. Kaplan–Meier estimated impending relapse rates at week 26 were 7.12% for aripiprazole once-monthly 400mg and 7.76% for oral aripiprazole. This difference (−0.64%, 95% CI −5.26 to 3.99) excluded the predefined non-inferiority margin of 11.5%. Treatments were superior to aripiprazole once-monthly 50mg (21.80%, P⩽0.001).

Conclusions

Aripiprazole once-monthly 400mg was non-inferior to oral aripiprazole, and the reduction in Kaplan–Meier estimated impending relapse rate at week 26 was statistically significant v. aripiprazole once-monthly 50 mg.

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Copyright
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial licence (http://creativecommons.org/licenses/by-nc/4.0/), which permits noncommercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Corresponding author
W. Wolfgang Fleischhacker, MD, Division of Biological Psychiatry, Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Email: wolfgang.fleischhacker@i-med.ac.at
Footnotes
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Previously presented at the following conferences: 51st Annual Meeting of the American College of Neuropsychopharmacology (ACNP), 2–6 December 2012, Hollywood, Florida, USA; 14th International Congress on Schizophrenia Research (ICOSR), 21–25 April 2013, Orlando, Florida, USA; 166th Annual Meeting of the American Psychiatric Association (APA), 18–22 May 2013, San Francisco, California, USA; US Psychiatric and Mental Health Congress (USPMHC), 30 September–3 October 2013, Las Vegas, Nevada, USA; and Neuroscience Education Institute Psychopharmacology Congress (NEI), 14–17 November 2013, Colorado Springs, Colorado, USA.

Declaration of interest

W.W.F. has received research grants from Otsuka, Pfizer, Janssen and Reckitt-Benckiser as well as consulting honoraria from Lundbeck, Roche, Bristol-Myers Squibb, Otsuka, Janssen, Pfizer, MedAvante, Takeda, Endo and Vanda. He has received speaker honoraria from Lundbeck, Janssen, Otsuka and Takeda as well as holds stock from MedAvante. R.S., P.P., N.J., T.P.-S., B.R.J., R.A.B., R.D.M. and W.H.C. are employees of Otsuka Pharmaceutical Commercialization, Inc. (Tokyo, Japan). A.E. is an employee of Lundbeck LLC. D.W. has received research grants from Otsuka, Pfizer, Eli Lilly, Janssen, Targacept, Lundbeck, Sunovion, Merck, Alkermes, Bristol-Myers Squibb, Reckitt, Elan, Abbott and Amgen. J.M.K. has received honoraria for lectures and/or consulting from Alkermes, Amgen, Bristol-Myers Squibb, Cephalon, Eisai, Boehringer Ingelheim, Eli Lilly, Forrest, Genentech, Intracellular Therapeutics, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Pierre Fabre, Proteus, Reviva, Roche, Sunovion and Targacept. He is a shareholder of MedAvante.

Footnotes
References
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Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study

  • W. Wolfgang Fleischhacker (a1), Raymond Sanchez (a2), Pamela P. Perry (a2), Na Jin (a3), Timothy Peters-Strickland (a2), Brian R. Johnson (a2), Ross A. Baker (a2), Anna Eramo (a4), Robert D. McQuade (a2), William H. Carson (a2), David Walling (a5) and John M. Kane (a6)...
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eLetters

Ethics of suboptimal dose

Roger D Walters, Child and Adolescent Psychiatrist
10 October 2014

Given the stated intent of including a suboptimal dose "A suboptimal dose was included to confirm assay sensitivity (i.e. to demonstrate that the study was able to differentiate an effective treatment from a less effective or ineffective intervention by demonstrating superior efficacy" I would be interested in hearing an ethical debate about exposing patientsto the risks involved when departing from research studies based on therapeutic equipoise, in this case from the information given I have concerns with regard to the ethics of this part of the research study but appreciate that a published paper may not contain full details of all aspects of the thinking behind a particular research design.

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Conflict of interest: None declared

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The 'unknown' safety concern for Aripiprazole once-monthly

Sumit K Gupta, Assistant Professor of Psychiatry
09 September 2014

This article by Fleischhacker et al. reports that the treatment emergent adverse effects are comparable for Aripirazole 400mg once monthlyand suboptimal dose of Aripirazole (50 mg) once-monthly. Also, the 'clinical relevance' of statistically significant difference in Barnes Akathisia Rating Scale Score with for Aripirazole 400mg once monthly against oral Aripirazole is stated to be 'unknown'. Akathisia is known to be the most clinically relevant adverse effect with oral Aripirazole because of the subjective distress caused to the patient and the increasedrisk of agitation and suicide associated with it. Hence, a higher rate of akathisia with Aripirazole 400mg once monthly cannot be discounted as being of 'unknown clinical relevance'. Further, a deeper look at apparently similar rate of 'any treatment-emergent adverse effects' for Aripirazole 400mg once monthly and suboptimal dose of Aripirazole (50 mg) once-monthly reveals that the ratesmay not be similar if 'Psychotic disorder' and 'schizophrenia' (which are efficacy outcomes and in no way can be considered as adverse affect for the purposes of this study) are removed from the list.The article minimizes the possible safety concerns associated with Aripirazole 400mg once monthly. A precise assessment of safety concerns (besides efficacy) is of utmost importance for a potential prescriber and there is potential of a prescriber being misguided by superficially reading this article. Further, efficacy outcomes of the study could have been contaminated by noticeably high and differential discontinuation rates in the two active arms. LOCF used for analysis of missing data tends to underestimate the worsening in ITT analysis. A comparison of results generated by ITT and Per Protocol analysis could have been more informative in assessing the efficacy outcomes.

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Conflict of interest: This article has been discussed in the Academic Journal Club of Department of Psychiatry, Institute of Human Behaviour and Allied Sciences. The response may include the observations of other members of Department of Psychiatry. However, the response may not necessarily reflect an official position of IHBAS.

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