Nocebo effect of nintedanib on gastrointestinal events in interstitial lung diseases

Background Nintedanib is known to be associated with gastrointestinal adverse events including diarrhoea, nausea and vomiting. We investigated whether a nocebo effect (an unfavourable effect that may be attributed to expectation) may have contributed to the gastrointestinal adverse events reported in clinical trials of nintedanib in patients with interstitial lung diseases (ILDs). Methods Using data from the placebo groups of trials of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) (TOMORROW, INPULSIS), systemic sclerosis-associated ILD (SENSCIS) and progressive fibrosing ILDs other than IPF (INBUILD), we analysed rates of gastrointestinal adverse events in the on-treatment period and the post-discontinuation period. Results In TOMORROW, rates per 100 patient-years of diarrhoea, nausea and vomiting, respectively, were 19.8, 11.4 and 5.5 in the on-treatment period, and 0, 0 and 0 in the post-discontinuation period. In INPULSIS, rates per 100 patient-years of diarrhoea, nausea and vomiting, respectively, were 23.1, 7.6 and 2.9 in the on-treatment period and 2.4, 2.4 and 0 in the post-discontinuation period. In SENSCIS, rates per 100 patient-years of diarrhoea, nausea and vomiting, respectively, were 33.1, 11.8 and 9.0 in the on-treatment period and 19.1, 2.4 and 7.4 in the post-discontinuation period. In INBUILD, rates per 100 patient-years of diarrhoea, nausea and vomiting, respectively, were 23.3, 7.7 and 3.6 in the on-treatment period and 2.2, 9.5 and 0 in the post-discontinuation period. Conclusions In trials of nintedanib in patients with ILDs, the rates of gastrointestinal adverse events fell after placebo was discontinued, suggesting the possibility of a nocebo effect. Trial registration The trials were prospectively registered at ClinicalTrials.gov with identifier numbers NCT00514683 (TOMORROW), NCT01335464 and NCT01335477 (INPULSIS), NCT02597933 (SENSCIS) and NCT02999178 (INBUILD).