N=1-studies In Statin-intolerance; Objectifying Nocebo Effects (NISONE): a study protocol for a randomised controlled...

Lipid-lowering therapies, particularly statins, are central to the prevention of atherosclerotic cardiovascular disease. However, their effectiveness is often compromised by statin-associated muscle symptoms, leading to non-adherence, discontinuation and/or switching to alternative, more expensive therapies such as Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors or bempedoic acid. Recent studies suggest that N=1-interventions may help distinguish true side effects from nocebo-driven symptoms and support reinitiation of statin therapy.

The 'N=1-studies In Statin-intolerance; Objectifying Nocebo Effects' (NISONE) trial is a study with 249 patients with atherosclerotic cardiovascular disease or familial hypercholesterolaemia who stopped using two or more statins due to perceived symptoms. Participants are randomised (2:1) to an N=1-intervention or usual care. The intervention consists of four double-blind 6-week periods of statin (rosuvastatin 10 mg 1-2 tablets/day or atorvastatin 20 mg 1-2 tablets/day) or placebo treatment during which patients are required to record their symptoms through questionnaires in an application developed for this study. During the subsequent fifth treatment period, feedback on symptoms during the intervention periods is provided in a personalised report, which will be discussed by a healthcare professional. Statin continuation is encouraged if symptoms are similar for statin and placebo periods, but remains voluntary. Statin-intolerant patients in the usual care group will be treated according to the cardiovascular risk management guidelines. The primary outcome, the percentage of patients continuing their statin after 1 year, will be analysed using an odds ratio and its 95% Confidence Interval. Secondary outcomes will be analysed similarly, and cost-effectiveness will be assessed using seemingly unrelated regression equations, adjusted for baseline scores, costs and quality of life.

The study protocol was approved by a Medical Ethical Research Committee in The Netherlands (EU CT-number 2023-507489-20-00). The study results will be disseminated via peer-reviewed medical journals, conference presentations, advisory boards and, if possible, by using various media channels.

This trial is registered in the EU Clinical Trials Information System (CTIS) (https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en): 2023-507489-20-00.