Two-to-one randomization is associated with increased control-arm patient withdrawal.

Patient withdrawal from a randomized clinical trial before starting the study treatment complicates the interpretation of the trial results, especially if a larger proportion patients withdraw from the control-treatment arm than the experimental-treatment arm. This may happen in an open-label trial if the patients are disappointed with their treatment assignment. It has been hypothesized that two-to-one randomization may lead to more disappointment withdrawals. To investigate this, we examined a cohort of 396 published oncology trials from four journals (2022-2025) to assess the differential pre-treatment withdrawal rates. We found that in 35 open-label trials with two-to-one randomization patients were, on average, 3.72 times more likely to withdraw on the control-treatment arm (95% CI = 2.66 to 5.22). This is a larger relative risk than was seen in the 181 open-label trials with one-to-one randomization, 1.99 (95% CI = 1.67 to 2.37). To avoid differential withdrawal, trials should be blinded when possible.