Impact of treatment changes on the interpretation of the Concorde trial

BACKGROUND: The Concorde trial compared two policies of therapy with zidovudine (ZVD) in individuals with asymptomatic HIV infection: immediate or deferred ZDV. Participants in both groups could stop their blinded trial therapy for several reasons and/or could start open-label ZDV. The difference in survival and disease progression between the two groups was estimated allowing for treatment changes. METHODS: The relationship between latest CD4 count, treatment changes and time to AIDS-related complex (ARC), AIDS or death was investigated using time-updated proportional hazards models, but these models gave seriously biased estimates of the effect of ZDV. Therefore, a method based on the comparison of the randomized groups was used. A model relating a participant's events times to the treatment actually received was used to estimate what would have been observed if the deferred group had not received ZDV before ARS or AIDS, and to explore alternative policies for starting Pneumocystis carinii pneumonia (PCP) prophylaxis. RESULTS: The major treatment changes during the trial were the termination of blinded therapy because of adverse events or personal reasons (575 out of 1749 participants), starting open-label ZDV (745 participants), and starting PCP prophylaxis (613 participants). Starting open-label ZDV and PCP prophylaxis were strongly related to latest CD4 count. The uncorrected hazard ratios for immediate compared with deferred groups were 0.89 for time to ARC, AIDS or death [95% confidence interval (CI), 0.75-1.05], 1.01 for time to AIDS or death (95% CI, 0.82-1.24), and 1.26 for time to death (95% CI, 0.93-1.70). After correction for treatment changes, these hazard ratios were 0.79 (95% CI, 0.57-1.11), 1.01 (95% CI, 0.81-1.26), and 1.37 (95% CI, 0.91-2.08), respectively. Correction for PCP prophylaxis made little difference to the results. CONCLUSIONS: Open-label ZDV before ARC or AIDS in the deferred group was likely to have diluted any differences between the immediate and deferred groups. After correction for this dilution, both the estimated benefit of immediate treatment in delaying progression to ARC, AIDS or death and the estimated disadvantage of immediate treatment in accelerating death were somewhat increased, but both remained consistent with chance alone. This study demonstrated the large potential bias inherent in non-randomization-based methods of analysis of clinical trials.