The Pharmaceutical Journal
Vol 275 No 7371 p475
15 October 2005

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Pioglitazone trial claims' are questioned

Researchers should not have used a secondary outcome to support claims that pioglitazone (Actos) reduces macrovascular events when the primary outcome was not significant, an article in last week's BMJ argues (2005;331:836).

At the European Association for the Study of Diabetes conference in Athens last month, researchers presented results of the PROactive trial (pioglitazone clinical trial in macrovascular events), and reported that pioglitazone could prevent macrovascular events (PJ, 17 September, p330).

However, Nick Freemantle, professor of clinical epidemiology and biostatistics at the University of Birmingham, warns that the researchers’ use of the principal secondary outcome, when the study’s principal primary outcome was not significant, was unsound. “When the primary outcome is not significant … the secondary outcome is only nominally significant and should in all but exceptional circumstances be considered explanatory and hypothesis generating rather than hypothesis testing,” he says. He argues that if the effects of treatment had been real and substantial, consistent results across all important cardiovascular outcomes would have been expected.

The results of the trial were published in The Lancet last week (2005;366:1279). In an accompanying editorial, Hannele Yki-Järvinen, of the University of Helsinki, explains that a number of unfortunate elements of the study’s design, such as using procedure endpoints, which are less specific and less sensitive than disease endpoints, reduced the likelihood of its primary outcome reaching a positive result.

“PROactive is an important study that leaves us with some good news, some bad news and some unknowns,” he concludes (ibid, p1241).

Professor Freemantle’s article was written before The Lancet article was published. “Publication should enable a more informed and detailed debate on the safety and efficacy of pioglitazone in poorly controlled type 2 diabetes, and, hopefully, a shift from sound bite to science,” he says.