Abstract and Introduction
Abstract
Objectives To reanalyse SmithKline Beecham's Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression. The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Design Double blind randomised placebo controlled trial.
Setting 12 North American academic psychiatry centres, from 20 April 1994 to 15 February 1998.
Participants 275 adolescents with major depression of at least eight weeks in duration. Exclusion criteria included a range of comorbid psychiatric and medical disorders and suicidality.
Interventions Participants were randomised to eight weeks double blind treatment with paroxetine (20–40 mg), imipramine (200–300 mg), or placebo.
Main outcome measures The prespecified primary efficacy variables were change from baseline to the end of the eight week acute treatment phase in total Hamilton depression scale (HAM-D) score and the proportion of responders (HAM-D score ≤8 or ≥50% reduction in baseline HAM-D) at acute endpoint. Prespecified secondary outcomes were changes from baseline to endpoint in depression items in K-SADS-L, clinical global impression, autonomous functioning checklist, self-perception profile, and sickness impact scale; predictors of response; and number of patients who relapse during the maintenance phase. Adverse experiences were to be compared primarily by using descriptive statistics. No coding dictionary was prespecified.
Results The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine and placebo groups (P=0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.
Conclusions Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
Introduction
In 2013, in the face of the selective reporting of outcomes of randomised controlled trials, an international group of researchers called on funders and investigators of abandoned (unpublished) or misreported trials to publish undisclosed outcomes or correct misleading publications. This initiative was called "restoring invisible and abandoned trials" (RIAT). The researchers identified many trials requiring restoration and emailed the funders, asking them to signal their intention to publish the unpublished trials or publish corrected versions of misreported trials. If funders and investigators failed to undertake to correct a trial that had been identified as unpublished or misreported, independent groups were encouraged to publish an accurate representation of the clinical trial based on the relevant regulatory information.
The current article represents a RIAT publication of Study 329. The original study was funded by SmithKline Beecham (SKB; subsequently GlaxoSmithKline, GSK). We acknowledge the work of the original investigators. This double blinded randomised controlled trial to evaluate the efficacy and safety of paroxetine and imipramine compared with placebo for adolescents diagnosed with major depression was reported in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001, with Martin Keller as the primary author. The RIAT researchers identified Study 329 as an example of a misreported trial in need of restoration. The article by Keller and colleagues, which was largely ghostwritten, claimed efficacy and safety for paroxetine that was at odds with the data. This is problematic because the article has been influential in the literature supporting the use of antidepressants in adolescents.
On 14 June 2013, the RIAT researchers asked GSK whether it had any intention to restore any of the trials it sponsored, including Study 329. GSK did not signal any intent to publish a corrected version of any of its trials. In later correspondence, GSK stated that the study by Keller and colleagues "accurately reflects the honestly-held views of the clinical investigator authors" and that GSK did "not agree that the article is false, fraudulent or misleading."
Study 329 was a multicentre eight week double blind randomised controlled trial (acute phase), followed by a six month continuation phase. SKB's stated primary objective was to examine the efficacy and safety of imipramine and paroxetine compared with placebo in the treatment of adolescents with unipolar major depression. Secondary objectives were to identify predictors of treatment outcomes across clinical subtypes; to provide information on the safety profile of paroxetine and imipramine when these drugs were given for "an extended period of time"; and to estimate the rate of relapse among patients who responded to imipramine, paroxetine, and placebo and were maintained on treatment. Study enrolment took place between April 1994 and March 1997.
The first RIAT trial publication was a surgery trial that had been only partly published before. Few previously published randomised controlled trials have ever been subsequently reported in published papers by different teams of authors.