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Being Alive

MUCH ADO ABOUT THE CONCORDE: Study Design and Changes About AZT




 

Being Alive 1993 May 5: 2

Enrollment was open to anyone who had not yet developed AIDS or symptoms and was willing to be randomized to receive, on a blinded placebo-controlled basis, either 1000mg/day of AZT immediately or a placebo which would be switched to the same dose of AZT only after symptoms developed. The two arms were called "Immediate" and "Deferred." The enrollees were stratified into three groups by initial CD4 counts. About 100 started with less than 200 T-cells, about 900 were in the 200-500 range and over 700 started with more than 500. The plan was to follow the participants at least three years unless interim analysis showed one arm of the study to be clearly superior. The two arms of the study were to be compared by percentage surviving, percentage without AIDS, percentage without symptoms, and average CD4 changes at certain specified time periods after enrollment, e.g. one year, 18 months and three years.

A year into the Concorde study, a somewhat similar US study (ACTG 019) was halted earlier than planned for those who started with less than 500 T-cells because interim analysis showed that after one year the AZT group had fewer progressions from asymptomatic to symptoms or AIDS than did the placebo group. The difference was small but statistically significant. On this basis, the US National Institutes of Health (NIH) recommended that anyone with less than 500 T-cells begin AZT.

The Concorde investigators were then in a quandary about whether it was ethical to continue their study, i. e., whether to allow those participants in the Deferred arm who had less than 500 T-cells to continue to take a placebo. Many participants wanted to start taking AZT immediately on the basis of the American results. Many physicians and researchers (in the US as well as Europe), however, felt that the American study had been stopped too soon. They felt that the real question at issue is when to start AZT to maximize long-term survival rather than short-term benefit and that AZT is a rather toxic drug which might have as many negative as positive net effects over a long time.

Concorde decided to continue the study but modify the design to allow anyone who so chose to start AZT on an unblinded ("open label") basis as soon as they had two successive T-cell counts under 500. This seemed to satisfy the ethical concerns, but opened the study to the criticism that comparison of the original Deferred and Immediate groups would be unfair, in that some of the Deferred group would in fact have been taking AZT before symptoms appeared and thus any real differences between the two treatment strategies would be diluted in the study results. The Concorde investigators felt that the large size of the trial as well as a supplementary analysis of the actual AZT taken by each group would still allow a meaningful comparison.

Unlike the American 019 study, interim analyses did not show statistically significant benefit for either arm, so the trial was allowed to continue the full three years. Follow-up is continuing even longer. 



 




Information in this article was accurate in May 5, 1993. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.