298 chapter 4 Material and Methods Study design and participants The Efficacy of [18F]FDG-PET in Evaluation of Cytological indeterminate Thyroid nodules prior to Surgery (EfFECTS) trial was a blinded, randomised controlled multicentre trial performed in all eight academic and seven large community hospitals in the Netherlands. At all study sites, local investigators and physicians were highly experienced in the multidisciplinary diagnosis and treatment of thyroid nodules and thyroid carcinoma, and worked in accordance with national and international guidelines [17, 467]. Adult euthyroid patients in whom diagnostic surgery was scheduled for an indeterminate thyroid nodule, defined as Bethesda III (confirmed on two subsequent FNAC procedures) or Bethesda IV cytology, were eligible for study participation [18]. Bethesda III or IV diagnosis was established by blinded central review by two dedicated thyroid pathologists (AE and BK). Prior to inclusion in the trial, clinical and ultrasound characteristics of the index nodule were considered in a multidisciplinary setting by the local physicians to establish the indication for diagnostic surgery, in accordance with current guidelines [17]. Patients were excluded from study participation if they had contra-indications for [18F]FDG-PET/CT or a higher a priori risk of thyroid malignancy based on their presentation or history (i.e., unexplained stridor, vocal cord paralysis, or radiation exposure to the thyroid), if they already underwent any non-routine pre-operative diagnostic stratification (i.e., [18F]FDG-PET/CT or molecular diagnostics) or were unable to undergo randomisation (e.g., patient preference for surgery) [468]. Full eligibility criteria are listed in the study protocol. Written informed consent was obtained from all participants prior to any study activity. The study protocol was approved by the Medical Research Ethics Committee on Research Involving Human Subjects region Arnhem-Nijmegen, Nijmegen, the Netherlands. The trial was overseen by a trial steering committee and an independent study safety committee. The funder of the study had no role in its design, data collection and analysis, or writing of this report. Randomisation Patients were individually randomly assigned to the [18F]FDG-PET/CT-driven group or diagnostic surgery group in a 2:1 ratio. To pursue an even distribution of risk factors for differentiated thyroid carcinoma across both arms, stratification was applied by patient sex, age (dichotomised at 45 years), ultrasonographic thyroid nodule size (0-10, 11-20, 21-40 or >40 mm), Bethesda classification (III or IV), and study site. Randomisation was performed in the trial management system, Castor Electronic Data Capture (Castor EDC, Amsterdam, the Netherlands), which uses a validated variable block randomisation model.
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