Aernoud Fiolet

38 Chapter 1 the drug on surrogate outcomes. We will use state-of-the-art statistical analyses to reduce the risk of Type I statistical errors due to multiplicity. We will apply strictly defined, universal, and unambiguous cardiovascular end points. The complete methodology is accessible and peer-reviewed by both the international scientific community as well as by national authorities prior to the analyses. (Chapter 4). Second, with an approved trial design, we will conduct a multinational clinical trial. Since colchicine does not have a patent holder in most countries, the trial is investigator-initiated, with funding from generic pharmaceutical companies, government grants, and in-kind contributions from clinical investigators. The trial design will be pragmatic, risk based, and designed to provide evidence on effect sizes that are clinically meaningful. Findings from the trial should be able to serve as pivotal evidence for therapy guidelines. (Chapter 5) We will use the public domain to confer with the international scientific community regarding interpretations and limitations of our findings. (Chapter 6) Furthermore, we will assemble an international consortium to pool our own findings with those of other major cardiovascular trials. Using a tabular meta-analysis, we can add the most accurate estimates of the efficacy and safety of the drug. We will evaluate the effect of the drug on individual efficacy and safety outcomes. (Chapter 7) Finally, we will conduct an in-depth analysis of the presence of a treatment effect of the drug in relation to the occurrence of prior acute coronary syndromes, to provide insights into the clinically relevant question of when to commence treatment. (Chapter 8) PART III: INSIGHTS IN MECHANISM AND TOLERANCE The third part of this thesis will translate clinical findings into insights of mechanism, outlining the scientific route backwards from bedside to bench. First, we will provide an overviewof the biochemical effects of the drug by describing the short-term effect of colchicine exposure on inflammatory biomarkers, hematologic parameters, and renal clearance. (Chapter 9) To provide an in-depth examination of the level of inflammatory proteins, we will conduct a proteomic analysis that will include a broad array of proteins. (Chapter 10) Again, going one step deeper in understanding its mechanism of action, we will describe the magnitude of change of inflammatory biomarkers and the nucleotide-binding oligomerisation domain–, leucine-rich repeat–, and pyrin domain–containing protein 3 (NLRP3) inflammasome. (Chapter 11) Lastly, translating these findings back to clinical care, we will investigate the occurrence of early perceived side effects of the drug and try to identify demographic and pharmacologic parameters that are associated with intolerance to the drug. (Chapter 12)