RESEARCH OPEN ACCESS Restoring Study 329: efficacy and harms of paroxetine and BMJ: first published as 10.1136/bmj.h4320 on 16 September 2015. Downloaded from imipramine in treatment of major depression in adolescence Joanna Le Noury,1 John M Nardo,2 David Healy,1 Jon Jureidini,3 Melissa Raven,3 Catalin Tufanaru,4 Elia Abi-Jaoude5 1School of Medical Sciences, ABSTRACT (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) Bangor University, Bangor, OBJECTIVES at acute endpoint. Prespecified secondary outcomes Wales, UK To reanalyse SmithKline Beecham’s Study 329 were changes from baseline to endpoint in depression 2 Emory University, Atlanta, (published by Keller and colleagues in 2001), the items in K-SADS-L, clinical global impression, Georgia, USA primary objective of which was to compare the efficacy autonomous functioning checklist, self-perception 3Critical and Ethical Mental Health Research Group, and safety of paroxetine and imipramine with placebo profile, and sickness impact scale; predictors of Robinson Research Institute, in the treatment of adolescents with unipolar major response; and number of patients who relapse during University of Adelaide, depression. The reanalysis under the restoring invisible the maintenance phase. Adverse experiences were to Adelaide, South Australia, Australia and abandoned trials (RIAT) initiative was done to see be compared primarily by using descriptive statistics. 4Joanna Briggs Institute, Faculty whether access to and reanalysis of a full dataset from No coding dictionary was prespecified. of Health Sciences, University of a randomised controlled trial would have clinically RESULTS Adelaide, Adelaide, South relevant implications for evidence based medicine. Australia, Australia The efficacy of paroxetine and imipramine was not 5Department of Psychiatry, The DESIGN statistically or clinically significantly different from Hospital for Sick Children, Double blind randomised placebo controlled trial. placebo for any prespecified primary or secondary University of Toronto, Toronto, SETTING efficacy outcome. HAM-D scores decreased by 10.7 Ontario, Canada 12 North American academic psychiatry centres, from (least squares mean) (95% confidence interval 9.1 to Correspondence to: J Jureidini 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, [email protected] 20 April 1994 to 15 February 1998. respectively, for the paroxetine, imipramine and Additional material is published PARTICIPANTS placebo groups (P=0.20). There were clinically online only. To view please visit 275 adolescents with major depression of at least the journal online (http://dx.doi. significant increases in harms, including suicidal eight weeks in duration. Exclusion criteria included a org/10.1136/bmj.h4320) ideation and behaviour and other serious adverse range of comorbid psychiatric and medical disorders Cite this as: BMJ 2015;351:h4320 events in the paroxetine group and cardiovascular doi: 10.1136/bmj.h4320 and suicidality. problems in the imipramine group. Accepted: 03 August 2015 INTERVENTIONS http://www.bmj.com/ CONCLUSIONS Participants were randomised to eight weeks double Neither paroxetine nor high dose imipramine showed blind treatment with paroxetine (20-40 mg), efficacy for major depression in adolescents, and there imipramine (200-300 mg), or placebo. was an increase in harms with both drugs. Access to MAIN OUTCOME MEASURES primary data from trials has important implications for The prespecified primary efficacy variables were both clinical practice and research, including that change from baseline to the end of the eight week published conclusions about efficacy and safety acute treatment phase in total Hamilton depression should not be read as authoritative. The reanalysis of on 2 October 2021 by guest. Protected copyright. scale (HAM-D) score and the proportion of responders Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base. WHat IS ALREADY KNOWN ON THIS TOPIC There is a lack of access to data from most clinical randomised controlled trials, Introduction making it difficult to detect biased reporting In 2013, in the face of the selective reporting of outcomes In the absence of access to primary data, misleading conclusions in publications of of randomised controlled trials, an international group of those trials can seem definitive researchers called on funders and investigators of aban- SmithKline Beecham’s Study 329, an influential trial that reported that paroxetine doned (unpublished) or misreported trials to publish was safe and effective for adolescents, is one such study undisclosed outcomes or correct misleading publica- tions.1 This initiative was called “restoring invisible and WHat THIS stUDY ADDS abandoned trials” (RIAT). The researchers identified On the basis of access to the original data from Study 329, we report a reanalysis many trials requiring restoration and emailed the funders, that concludes that paroxetine was ineffective and unsafe in this study asking them to signal their intention to publish the unpub- Access to primary data makes clear the many ways in which data can be analysed lished trials or publish corrected versions of misreported and represented, showing the importance of access to data and the value of trials. If funders and investigators failed to undertake to reanalysis of trials correct a trial that had been identified as unpublished or misreported, independent groups were encouraged to There are important implications for clinical practice, research, regulation of trials, publish an accurate representation of the clinical trial licensing of drugs, and the sociology and philosophy of science based on the relevant regulatory information. Our reanalysis required development of methods that could be adapted for future The current article represents a RIAT publication reanalyses of randomised controlled trials of Study 329. The original study was funded by the bmj | BMJ 2015;101hh432 | doi1 10.00;6/bmj.h4320 1 RESEARCH SmithKline Beecham (SKB; subsequently GlaxoSmith- information on the safety profile of paroxetine and imip- BMJ: first published as 10.1136/bmj.h4320 on 16 September 2015. Downloaded from Kline, GSK). We acknowledge the work of the original ramine when these drugs were given for “an extended investigators. This double blinded randomised con- period of time”; and to estimate the rate of relapse among trolled trial to evaluate the efficacy and safety of parox- patients who responded to imipramine, paroxetine, and etine and imipramine compared with placebo for placebo and were maintained on treatment. Study enrol- adolescents diagnosed with major depression was ment took place between April 1994 and March 1997. reported in the Journal of the American Academy of The first RIAT trial publication was a surgery trial that Child and Adolescent Psychiatry (JAACAP) in 2001, with had been only partly published before.7 Few previously Martin Keller as the primary author.2 The RIAT published randomised controlled trials have ever been researchers identified Study 329 as an example of a subsequently reported in published papers by different misreported trial in need of restoration. The article by teams of authors.8 Keller and colleagues, which was largely ghostwritten,3 claimed efficacy and safety for paroxetine that was at Methods odds with the data.4 This is problematic because the We reanalysed the data from Study 329 according to the article has been influential in the literature supporting RIAT recommendations. To this end, we used the clini- the use of antidepressants in adolescents.5 cal study report (SKB’s “final clinical report”), including On 14 June 2013, the RIAT researchers asked GSK appendices A-G, which are publically available on the whether it had any intention to restore any of the trials GSK website,9 other publically available documents,10 it sponsored, including Study 329. GSK did not signal and the individual participant data accessed through any intent to publish a corrected version of any of its SAS Solutions OnDemand website,11 on which GSK sub- trials. In later correspondence, GSK stated that the sequently also posted some Study 329 documents (avail- study by Keller and colleagues “accurately reflects the able only to users approved by GSK). After negotiation,12 honestly-held views of the clinical investigator authors” GSK posted about 77 000 pages of de-identified individual and that GSK did “not agree that the article is false, case report forms (appendix H) on that website. We used fraudulent or misleading.”6 a tool for documenting the transformation from regula- Study 329 was a multicentre eight week double blind tory documents to journal publication, based on the CON- randomised controlled trial (acute phase), followed by a SORT 2010 checklist of information to include when six month continuation phase. SKB’s stated primary reporting a randomised trial. The audit record, includ- objective was to examine the efficacy and safety of imip- ing a table of sources of data consulted in preparing ramine and paroxetine compared with placebo in the each part of this paper, is available in appendix 1. treatment of adolescents with unipolar major depres- Except where indicated, in accordance with RIAT http://www.bmj.com/ sion. Secondary objectives were to identify predictors of recommendations, our methods are those set out in the treatment outcomes across clinical subtypes; to provide 1994-96 protocol for Study 329.13 In cases when the meth- ods