Data over doubt: Clarifications on calcium butyrate efficacy in pediatric irritable bowel syndrome

We thank the colleagues for their comments1 on our study.2 We agree that the treatment effect magnitude was notable and derives from rigorous methodological choices. Placebo success rates in Disorders of gut–brain interactions result heterogeneous (2.8%–62.5%), with lower responses associated with stringent designs and objective endpoints.3, 4 Our methodology aligns with these conditions. The run-in period, requiring persistent symptoms for randomization, ensured a stable symptomatic cohort: nine children improved during run-in and were excluded. Spontaneously remitting patients, a key contributor to inflated placebo responses, were thus reduced. Microbiota and metabolome shifts supported the clinical efficacy plausibility. All participants received identical standardized clinical care: positive diagnosis, functional nature explanation, and reassurance.4 No additional therapies were introduced, and families were instructed to avoid dietary changes and other probiotic/prebiotic use. Regarding baseline imbalance, although an analysis of covariance (ANCOVA) was not performed, we analyzed change-from-baseline scores, which inherently control for initial values. Combined with highly significant p values, this provides evidence that the observed improvement reflected a treatment effect rather than baseline differences. Randomization was computer-generated; active and placebo tablets were indistinguishable and pre-packaged. Investigators, participants, and outcome assessors remained blinded until database lock. Placebo contained maltodextrins as excipients for the active formulation. Adherence was monitored by tablet counts and diary review; all but one participant (difficulty in swallowing the tablets) met criteria, and diary completion was high with no missing data. Treatment success was determined using 7-day averages Visual Analog Scale (VAS) scores, as recommended.5 The manufacturer's involvement was limited to providing active and placebo products free of charge; they had no role in design, data handling, analysis, interpretation, or manuscript preparation. Study registered on: https://clinicaltrials.gov. Number of registration: NCT04566679. Date of registration: September 28, 2020. Date of first enrollment of patients: May 1, 2021. The authors declare no conflict of interest.