Related Experiment Video
Updated: Aug 14, 2025
A Clinical Trial Assessing the Safety, Efficacy, and Delivery of Olive-Oil-Based Three-Chamber Bags for Parenteral Nutrition
Published on: September 20, 2019
Usefulness of the placebo lead-in design for clinical trials with binary outcomes
Gosuke Homma1, Takashi Daimon2
1Biostatistics & Data Science, Boehringer-Ingelheim Co., Ltd, Tokyo, Japan.
Background:
In placebo-controlled clinical trials to develop new drugs for the treatment of psychiatric or neurological disorders, a high and sometimes greater-than-expected placebo response makes it difficult to show the superiority of an investigational drug over a corresponding placebo. To avoid such difficulty, a placebo lead-in design has been presented, but its usefulness has been open to discussion. Although the statistical properties of the placebo lead-in design are investigated in the context of continuous outcomes, whether these properties can be generalized for binary or ordinal cases remains unclear.
Methods:
We investigate whether the placebo lead-in design is useful in clinical trials with binary outcomes through mathematical formulae and a numerical investigation. Specifically, we compare the proportion of placebo responders, the drug-placebo difference, and the effect size between two populations: one enriched for placebo nonresponders and the other comprising the all-comers.
Results:
Under positive correlation of the data between the lead-in stage and the randomized stage for both treatment groups, we mathematically show that the proportion of responders in the population enriched for placebo nonresponders is less than that in the all-comers population, and whether the placebo lead-in design increases the drug-placebo difference depends on the variances of outcomes in both treatment groups as well as the correlations of the outcomes between two stages. Further, through a numerical investigation, we show that whether the placebo lead-in design increases the effect size strongly depends on the magnitude of the correlations and their difference.
Conclusion:
If the correlation of the placebo-placebo group is much higher than that of the placebo-drug group, the placebo lead-in design is advantageous in most cases but has an impact on an estimand in placebo nonresponders. Therefore, we do not recommend using the placebo lead-in design for clinical trials with binary outcomes.
More Related Videos
08:50How to Study Placebo Responses in Motion Sickness with a Rotation Chair Paradigm in Healthy Participants
Published on: December 14, 2014
06:55Inverse Probability of Treatment Weighting Propensity Score using the Military Health System Data Repository and National Death Index
Published on: January 8, 2020
Related Concept Videos
01:11Blinding
02:07Blind Procedures
01:54The Placebo Effect
01:16Crossover Experiments
Crossover designs are performed even with smaller sample sizes since the samples can act as their controls. These are better than simple randomized trials since patients are exposed to all the treatments.
01:23Types of Biopharmaceutical Studies: Controlled and Non-Controlled Approaches
Non-controlled studies, commonly employed for initial exploration, lack a control group, rendering them susceptible to biases and external influences. In contrast,...
01:16Clinical Trials
There are four phases in a clinical trial. A phase one...