# Operating characteristics of unequal allocation ratios in platform trials with the staggered addition of drugs using binary endpoints

## TL;DR

The paper examines how using unequal allocation ratios in platform trials affects study outcomes, finding that while it can preserve statistical power, it may also increase sample size and duration.

## Contribution

The study quantifies the trade-offs of using unequal allocation ratios in platform trials with binary endpoints and concurrent controls.

## Key findings

- Unequal allocation increases total sample size and prolongs study duration under low enrollment.
- Unequal allocation preserves hypothesis testing power better than equal allocation despite incorrect mortality assumptions.
- The benefits of unequal allocation depend on enrollment speed, drug effect, and addition intervals.

## Abstract

One recommendation for the allocation ratio between multiple drugs and a shared placebo control group in platform trials (PTs) is to use a k:1 allocation ratio for the placebo group relative to the drug group, where k is the number of drug groups with ongoing patient enrollment during the trials. However, the practical utility of such unequal allocation ratios in PTs lacks adequate study.

We compared the performances of equal and unequal allocation ratios through simulations to imitate practical PTs using only concurrent controls and binary endpoints for hospitalized patients with infectious diseases. The operating characteristics, including the type I error rate, power of hypothesis testing, and total sample size, were evaluated.

In PTs, using an unequal allocation ratio (i) results in a considerable augmentation of the total sample size and prolongs the study duration when monthly patient enrollment is low, but (ii) the target power of hypothesis testing is often preserved compared to an equal allocation ratio, even when we incorrectly specify the drug and placebo group mortality rates assumed in the sample size calculation. The average power increase using an unequal allocation ratio relative to the equal allocation ratio per 100-patient increase in the placebo group was approximately 1.9 % in the selected scenarios of our simulation studies.

The results of the current study highlight the quantitative advantages and disadvantages of using unequal allocation ratios in PTs using only concurrent controls under the specific conditions assumed in our simulations and analyses.

•Unequal allocation benefits vary by enrollment speed, sample size, number of drugs, drug effect, and addition intervals.•Low enrollment in platform trials with unequal allocation increases sample size and study duration.•Unequal allocation preserved power better than equal allocation in platform trials, despite incorrect mortality assumptions.

Unequal allocation benefits vary by enrollment speed, sample size, number of drugs, drug effect, and addition intervals.

Low enrollment in platform trials with unequal allocation increases sample size and study duration.

Unequal allocation preserved power better than equal allocation in platform trials, despite incorrect mortality assumptions.