Non-inferiority designs comparing placebo to a proven therapy for childhood pneumonia in low-resource settings

Abstract

Background/aims:

After a new treatment is recommended to be first-line treatment for a specific indication, outcome and population, it may be unethical to use placebo as a comparator in trials for that setting. Nevertheless, in specific circumstances, use of a placebo group might be warranted, for example, when it is believed that an active treatment may not be efficacious or cost-effective for a specific subpopulation. An example is antibiotic treatment for pneumonia, which may not be effective for many patients taking it due to the emergence of antibiotic-resistant strains or the high prevalence of viral and low prevalence of bacterial pneumonia.

Methods:

We explore the applicability of different design options in cases where the benefit of an established treatment is questioned, with particular emphasis on issues that arise in a low-resource setting. Using the example of a clinical trial comparing the effectiveness of placebo versus amoxicillin in treating children 2–59 months of age with fast breathing pneumonia in Lilongwe, Malawi, we discuss the pros and cons of superiority versus non-inferiority designs, an intent-to-treat versus as-treated analysis and the use and interpretation of one- versus two-sided confidence intervals.

Results:

We find that a non-inferiority design using an intent-to-treat analysis is the most appropriate design and analysis option. In addition, the presentation of one- versus two-sided confidence intervals can depend on the results but can maintain type I error.

Conclusion:

In the setting where the benefit of a previously established beneficial treatment is questioned, a non-inferiority design that includes placebo as the tested treatment option can be the most appropriate design option.