Blinding in clozapine trials: a problem and a potential solution.

Background: A methodological problem arises when efficacy of clozapine is compared with other antipsychotic medication in double blind randomized studies. Due to the risk of leucopenia and agranulocytosis, patients in the clozapine condition need to have regular blood testing. The problem is that in order to maintain blinding, patients in the comparison conditions need to undergo blood testing as well and this can lead to underestimation of treatment acceptability and efficacy of the comparators.

Methods: A thought experiment considering all possible solutions for the methodological problem.

Results: We propose a special study design that preserves randomization and blinding while at the same time prevents underestimation of the effect in the comparator treatments. In addition, the necessity for blood testing is limited to only a small number of patients who receive comparative treatments. The design involves initial randomization to a sub-study including clozapine and a small comparator arm or to a sub-study that includes only comparator arms. Blood testing is only necessary in the first sub-study.

Discussion: Limitations of the proposed design are discussed. It is noted that this study design may offer a solution to similar situations where blood testing or other types of monitoring (e.g. as with lithium) is required in one but not in all of the treatment arms of a double blind randomized study.