Introduction Sample size (SS) calculation with sufficient power to detect significant and clinically meaningful differences vs placebo is necessary to ensure the validity of confirmatory Phase 3 pivotal trials in irritable bowel syndrome with constipation (IBS-C).
Method Using data from a pilot Phase 2b study of linaclotide (Constella®; LIN) in IBS-C (Study 202) and the pivotal Phase 3 LIN trials (Trial 302; Trial 31), we compared 2 statistical assumptions for the Phase 3 SS calculation for the European Medicines Agency (EMA) co-primary endpoints: 1) minimally important clinical differences (MICD) and 2) replication of Phase 2b 290 µg/day results. Protocol design, patient population and endpoints of the trials were also compared.
Results There were no relevant differences in protocol design or patient population in the Phase 2b/3 trials. For endpoint assessments, only the range of the pain/discomfort scale differed (Phase 2b: range 1–5; Phase 3: range 0–10). For both EMA endpoints, Phase 2b data showed a higher placebo effect and greater improvement vs placebo compared with Phase 3 data (both not statistically significant; Table 1). The SS for the Phase 3 trials was estimated to have ≥95% global power to detect an MICD of 15% in both endpoints. Based on replication of Phase 2b results, an SS of 134 patients per treatment arm would have been sufficient to achieve ≥95% global power to detect an effect size comparable to Phase 2b. However, this sample size would have only 46% and 67% overall power to detect the actual observed results of Trials 31 and 302, respectively, and even less overall power (13% and 47%, respectively) when the MICD is reduced to 10%.
Conclusion In the LIN IBS-C clinical programme, Phase 2b results were not a good predictor of Phase 3 outcome, even without major differences in study design. Caution is needed when calculating SS for Phase 3 IBS-C trials to ensure sufficient power to detect clinically relevant differences vs placebo.
Disclosure of interest M. Falques Employee of: Almirall S. A., C. Díaz Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.
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