DOC News April 1, 2006
Volume 3 Number 4 p. 3
© 2006 American Diabetes Association
Clarifying the PROactive Plan
John A. Dormandy, DSc the PROactive Study Executive Committee and the Data and Safety
Monitoring Committee
Jay S. Skyler, MD, in his editorial "PROactive Results Over-stated
and Misleading" (DOC News, December 2005) reported that the
principal secondary end point in PROactive1 was not prespecified
and that the finding was obtained through a post hoc analysis. This belief is
based, in part, on an earlier publication of the PROactive Study
design,2 which listed the primary and secondary end points but did
not mention this specific composite.
During the latter part of 2004 and in early 2005, a working party
representing members of the PROactive Study Executive Committee and the
sponsor prepared a formal Statistical Analysis Plan for the study. At this
time, it was recognized that the clinically important composite of death,
myocardial infarction, and stroke was not currently part of the intended
analysis. This was added to the plan in a draft circulated in March 2005, and
the final version of the plan clearly identifies this end point as the
intended principal secondary end point. The final version was signed and
released on May 13, 2005. (A copy of the plan was registered as received by
the Food and Drug Administration on May 17.) The study database was formally
locked on May 25, and statistical analysis of unblinded data was only
commenced following that date.
Although it is relatively uncommon, it is legitimate for the end points of
a study to be amended at any time as the study progresses, providing this is
agreed to and documented prior to any knowledge of unblinded data by the
trialists. Indeed, this is more likely when the study is of long duration and
results of contemporary studies become available. We accept that, in this
instance, the prior publication of a design paper has created some confusion,
and so we are pleased to be able to clarify the issue.
The PROactive Study Executive Committee was not aware of any results of the
study before the official unblinding of the study on May 25, 2005. The Data
and Safety Monitoring Committee was not part of the discussions regarding
determination of the principal secondary end point.
THE AUTHOR REPLIES
Jay S. Skyler, MD
I appreciate the PROactive investigators' precisely clarifying the time
sequence for their derivation of the "principal secondary end
point" and that this was done before the database was locked. I noted in
my commentary that at the Athens presentation—but not in the Lancet
paper1—the
authors indicated they had inserted this measure into the statistical plan
prior to breaking the code and analyzing the data. The authors' letter again
states this. Because I recognized this assertion in my original commentary, I
stand by my conclusions in that commentary.
References
1. Dormandy JA, Charbonnel B, Eckland DJ, et al., for the PROactive
investigators: Secondary prevention of macrovascular events in patients with
type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical
Trial In macroVascular Events): A randomised controlled trial.
Lancet 366:1279–1289, 2005.[Medline]2. Charbonnel B, Dormandy J, Erdmann E, et al., for the PROactive
Study Group: The Prospective Pioglitazone Clinical Trial in Macrovascular
Events (PROactive): Can pioglitazone reduce cardiovascular events in diabetes?
Study design and baseline characteristics of 5,238 patients.
Diabetes Care 27:1647–1653, 2004.[Abstract/Free Full Text]
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