The fragility of randomized placebo-controlled trials for irritable bowel syndrome.

Background: The fragility index (FI) represents the number of participants whose status in a trial would have to change from a non-event (not experiencing the primary endpoint) to an event (experiencing the primary endpoint) in order to turn a statistically significant result into a non-significant result. We sought to evaluate the fragility indices of irritable bowel syndrome [IBS-mixed (IBS-M), IBS-constipation (IBS-C), & IBS-diarrhea (IBS-D)] trials.

Methods: Irritable bowel syndrome trials published in high-impact journals were identified from Medline. Trials had to be in adults, randomized, parallel-armed, with at least one statistically significant binary outcome, and an achieved primary endpoint of therapeutic efficacy. FI and correlation coefficients were calculated, and regression modeling used to identify predictors of a high FI.

Key Results: Twelve trials were analyzed with a median FI of 6 (range: 0-38). Median sample size in all trials was 366 (range: 44-856). Trial publication year (p = 0.71), journal impact factor (p = 0.52), duration of study (p = 0.12), and number need to treat [NNT] (p = 0.29) were not predictive of a high FI. While a lower p-value correlated with a higher FI (p = 0.039), no correlation was noted between FI and impact factor (R = -0.20, p = 0.52), trial publication year (R = 0.12, p = 0.71), duration of trial (R = -0.46, p = 0.13), NNT (R = -0.34, p = 0.29), and sample size (R = 0.23, p = 0.5). The highest FI was in a Ramosetron trial (FI = 30) for IBS-D.

Conclusion & Inferences: A median of six participants is needed to nullify results in the included IBS trials suggesting how easily statistical significance based on a threshold p-value may be overturned.