Aernoud Fiolet

31 General introduction and thesis outline stroke, or cardiovascular death by 15% and reduced the risk of the composite end point of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death or urgent hospitalisation for angina leading to urgent revascularisation by 17%. 111 Although these results were ground breaking, canakinumab is a costly drug, and the findings from the trial have not led to registration of the drug for secondary prevention in cardiovascular disease. Colchicine is a well-known anti-inflammatory drug used to treat one of the most distinct types of crystalloid diseases: gout. It has a strong inhibitory effect on the NLPR3 inflammasome and reduces expression of interleukin – 1 and interleukin – 6. 112,113 However, the drug has a plethora of cell interactions, which all could contribute to an atheroprotective effect. 114,115 Neutrophil mobilisation and recruitment are diminished as colchicine inhibits endothelial adhesiveness. 116 Furthermore, leukocyte-platelet aggregation seems to be supressed during colchicine use. 117,118 Thus, the strong effects of colchicine on the crystal-induced inflammatory pathway is most likely complemented by additional inflammation modulatory effects. THE METHODOLOGICAL PERSPECTIVE: HOW TO FACILITATE DRUG REPURPOSING AND IMPROVE PRAGMATIC TRIAL CONDUCT Although colchicine may have potential to modulate the broad inflammatory pathway driving atherosclerosis and its thrombotic complications, it can be seen as an unusual drug from the perspective of the conventional routes of clinical research. To understand this, the structure of conventional drug research and development needs an explanation. Conventional routes of drug research Themajority of clinical research is conducted in a structurewhere a pharmaceutical company sponsors a commercial or academic research organisation. These institutions execute the clinical experiment to the highest standards of scientific integrityinanideallycompletelyautonomousmanner—aconceptguardedby,among others, blind treatment allocation, data monitoring boards, and independence of the academics to the sponsor when conducting pre-specified analyses. The conditions and requirements for such research that – in case of positive results – could lead to clinical implementation, are set by legislation and national