Review Article: Surrogate Endpoints to Assess Treatment Efficacy in Disorders of Gut–Brain Interaction of Lower Gastrointestinal Tract

Background

Surrogate endpoints such as laboratory parameters that are not direct measurements of, but predict, clinical benefit are approved by regulatory agencies for initial proof of efficacy. No surrogate endpoints are approved for disorders of gut–brain interaction.

Aim

To assess the correlation of scintigraphic colonic transit (CT) with response rates according to patient-reported symptom-based endpoints (composite/global symptoms, abdominal pain or stool frequency/consistency) in irritable bowel syndrome (IBS) or chronic idiopathic constipation (CIC).

Methods

We reviewed available data from, randomised controlled trials (RCTs) reporting effects on CT at 24 h and 48 h with drug versus placebo and extracted the difference in the proportions responding to drug or placebo, using rates from individual RCTs or from meta-analyses when more than one RCT existed for a drug. We analysed associations between differences (drug vs. placebo) in CT and in response rates using Spearman correlation. Additional analyses of CT at 24 h with composite/global symptom or pain endpoints were performed with exclusion of alosetron (the only drug slowing CT).

Results

CT at 24 h correlated significantly with composite/global symptom endpoints (Rs = −0.755, p = 0.021). CT correlated with stool frequency or consistency (at 24 h, Rs = 0.506, p = 0.074; at 48 h, Rs = 0.631, p = 0.026). CT at 24 h did not correlate with abdominal pain (Rs = −0.054, p = 0.843). With the exclusion of alosetron data, CT at 24 h was non-significantly correlated with the composite/global symptom endpoint (Rs = −0.667, p = 0.073), but not with abdominal pain (Rs = 0.377, p = 0.419).

Conclusion

Scintigraphic CT measurement fulfils the expectation of a surrogate endpoint for symptom-based outcomes, particularly in IBS-D or IBS-C and CIC.