Study 329 Lessons: published conclusions about drugs efficacy and safety should not be read as authoritative

Study 329 reanalysis illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base

study-329 poster
Unpublished and misreported studies make it difficult to determine the true value of a treatment. RIAT stands for “restoring invisible and abandoned trials.

2015 (2nd) Study Abstract

The RIAT re-analysis marks a new chapter in the story of Study 329, showing the remarkable power of open data. But it also shows how much our current systems are failing patients and the public. It should not have taken 14 years to get to this point. It shows that we need regulation, and perhaps legislation, to ensure that the results of all clinical trials are made publicly available and that individual patient data are available for legitimate independent third party scrutiny.

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.

More on Study 329 from The BMJ
  • Study 329, doi.org/10.1136/bmj.h4973, 17 September 2015.
  • Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence, doi.org/10.1136/bmj.h4320, 16 September 2015.
  • No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility, doi.org/10.1136/bmj.h4629, 16 September 2015.
  • Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence, doi.org/10.1136/bmj.h4320, 16 September 2015.
  • Restoring invisible and abandoned trials: a call for people to publish the findings, doi.org/10.1136/bmj.f2865, June 28, 2013.
More on Study 329 from Dr David Healy’s blog
More on Study 329
  • Initial – 1st – Study 329, jaacap, July 2001.
  • Restoring Study 329, website.
  • About : Documenting Seroxat : An Epic Medical Scandal, truthman30/.

Author: DES Daughter

Activist, blogger and social media addict committed to shedding light on a global health scandal and dedicated to raise DES awareness.

4 thoughts on “Study 329 Lessons: published conclusions about drugs efficacy and safety should not be read as authoritative”

      1. thanks! well, it kinda build up after 9 years!.. none of it was intentional, was just reacting to being prescribed the horrid Seroxat, never intended to put so much into it.. but glad I have 🙂

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