Journal of Thyroid Research / 2018 / Article / Tab 1

Research Article

Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives?

Table 1

Suggestions for improvement in trial design for randomised controlled T3/T4 combination studies.

CriteriumIssue of Previous Trials Improvement

QoL instrumentlack of sensitivity and specificity of older methodsuse of validated thyroid-specific methods

Detectable effect on QoLsmall effect sizemoderate effect size

Statistical powervery lowlow

Sample size requirementvery largelarge

Patient selectionselection bias due to inclusion of heterogenous patient groups by etiology and prognosisinclusion of homogeneous diagnostic categories, use of stratified randomisation

Proportion of symptomatic patientsdilution of the true effectrandomized controlled designs for subgroups with persistent symptoms

Treatment-related improvementhealthy control group lackinginclusion of a healthy control group

Dose adequacyTSH targets may be misguided.Treatment-related altered equilibria have to be considered.

Response heterogeneitywide variation in the treatment responsephysiologically based categorisation

Specific confoundersT4 to T3 conversion efficiencyidentify conversion issues and apply strata

Statistical analysispresence of unknown hierarchies and latent groupslatent class analysis

Statistical methodamalgamation bias (Simpson’s paradox), disaggregation of within-group and between group effects over timemultilevel models,
cross-over design

Patient expectanciesexpectancy bias from treatment uncertainty in RCTs vs treatment certainty under actual conditions of intended drug userandomization to randomization probabilities (R2R) adjusting for differences in patient expectancies

Tissue effectsnot addressed by RCTs due to lack of differential markers for organ-specific effectslimited usefulness of surrogate markers, requirement for novel markers

Actions of non-classical thyroid hormonesnot addressedimprovement of assay technology, evaluation as possible additional treatment targets

Safety profilenot addressed by RCTsprospective acquisition and analysis of big data, especially from T3 users

Drug-related issues of LT4generally reduced and variable T4 to T3 conversion ratesmeasuring conversion efficiency and targeted T3 addition

Drug-related issues of LT3pharmacological properties, among others short half-life, high peak levelsslow-release preparations

Drug-related issues of natural desiccated thyroid extractspopular choice among patients, but few studieseffective large-scale trials

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