REduction of LEvothyroxine in Adults; a SElf Controlled Study

Study design - This is a self-controlled trial investigating the stepwise discontinuation of levothyroxine treatment in adults aged 60 years and older with a follow-up of 1 year. Outcomes will be measured 12 weeks before the start of discontinuation, at the start of discontinuation, at 6 weeks, at the end of discontinuation, and after 52 weeks. The outcomes will be compared within participants.

Study phases

• This study consists of 3 phases: a control phase of 12 weeks (T-12 to T0), the discontinuation phase (minimum of 6 weeks, maximum of 36 weeks; T0 to Tx), and a follow-up phase (from the end of discontinuation till 52 weeks after the start of discontinuation; Tx to T52).
• Control phase: participants enter the study during a control period with pre-baseline measurements of thyroid function and secondary outcome parameters to determine natural variation after which treatment with levothyroxine is continued per usual care for at least 12 weeks. Participants with a pre-baseline TSH level ≥10 mU/L do not proceed to the discontinuation phase.
• Discontinuation phase: this phase starts with baseline measurements of thyroid function and secondary outcome parameters, followed by a consultation of the participant with their GP during which discontinuation of levothyroxine is initiated, except when TSH level ≥10 mU/L. Levothyroxine is discontinued stepwise, and at intervals of ≥ 6 weeks to ascertain a steady-state concentration has been reached before the following control visit. During each '6-week' visit, the GP evaluates thyroid function and symptoms with the participant. Upon agreement, the daily dose of levothyroxine can then be lowered provided thyroid function is within the predefined limits, i.e. a normal fT4 and TSH \< 10 mU/L. With each step, the dose of levothyroxine is reduced by approximately 25 mcg. The discontinuation phase ends after the evaluation of complete withdrawal of the levothyroxine treatment (i.e. 6 weeks after the final discontinuation step). Secondary outcome parameters are collected at the first '6-week' visit and the end of discontinuation.
• Follow-up phase: this phase ends with a final visit 52 weeks after the start of the discontinuation phase and includes the assessment of thyroid function, current dose of levothyroxine, and secondary outcome parameters.

Sample size

• The sample size calculation is based on the primary outcome, the proportion of participants successfully stopping levothyroxine treatment between baseline and final follow-up at 52 weeks. The investigators estimated a proportion of 50% of the participants would successfully discontinue levothyroxine treatment. A sample size of 385 participants was chosen because this allows to estimate the expected proportion of 50% with a 95% confidence interval of which the lower and upper limit is expected to deviate by 5 percentage points from the found percentage (i.e. 45% to 55% when the found percentage is indeed 50%). Taking a maximum of 25% loss to follow up into account over the duration of 15 months (exclusion at T-12 when TSH level ≥ 10 mU/L and/or fT4 below reference range, withdrawal, moving away, or death between T-12 and T52) a maximum of 513 participants will be recruited.

Data analysis

• GPs transfer participants' data after each visit using a validated electronic data capture (EDC) system (Castor EDC). Questionnaires are completed on paper or electronically (Castor EDC). All participant data are coded. Only the principal investigators and the research team have access to the key to these codes. The handling of personal data complies with the European General Data Protection Regulation. Database validation checks are run routinely and are tracked and escalated as appropriate.
• To determine the proportion of the population that can be withdrawn from levothyroxine treatment, categorical data involving measurements at baseline and final follow-up will be analyzed. Univariable and multivariable logistic regression analyses will be performed to assess factors that are associated with successful discontinuation of levothyroxine treatment. To estimate the effect of discontinuation on secondary outcome parameters measured at baseline and/or final follow-up, descriptive, univariable and multivariable analyses will be performed for the overall group and for the group of participants who successfully discontinued levothyroxine. Measurements pre and post discontinuation will be compared. Variations in thyroid function, thyroid-related quality of life, treatment satisfaction for levothyroxine, general health, and participant's attitude toward deprescribing will be determined using pre-baseline and baseline measurements. All analyses will be carried out with the population of participants who enrolled at baseline (T0). Participants that experience intercurrent events not related to the study procedure resulting in missing data at final follow-up will be excluded. Primary and secondary analyses will be repeated with all participants who enrolled at baseline who have data for the outcome variable of interest and have had their final follow-up visit. Statistical significance for the primary outcome requires P ≤ 0.05.

Safety and monitoring

• Withdrawal. Participants can withdraw their consent for involvement in the study at any time, without an obligation to justify the decision, and without consequences for their usual care. The research team can advise withdrawing participants from the intervention if it is deemed to be in the best interest of the participant. Participants who withdraw from the study are not replaced. The Data Safety and Monitoring Board (DSMB) can advise to stop the study.
• (Serious) adverse events. All adverse events reported spontaneously by the participant or their general practitioner (GP) are recorded and followed up. If complaints are reported during the discontinuation phase, these will be assessed by the research nurse. It is at the discretion of the GP to decide to either continue the withdrawal of levothyroxine or to maintain or increase the dosage. Serious adverse events are sought out actively and reported to the sponsor, the accredited Medical Ethics Committee (MEC), and competent authority using electronic case report forms.
• Monitoring. At regular intervals, the DSMB advises the study project group and sponsor (Leiden University Medical Center [LUMC]) whether it is safe and appropriate to continue the study. Periodic routine reports on the progress of the study are sent to the DSMB for review. Serious adverse events are reported immediately. No interim analyses for efficacy or futility will be performed. The DSMB meets at least 5 times and is composed of medical experts and a biostatistician without any involvement in the study as investigators or as study participant care physicians. Annual study monitoring visits are conducted by an independent clinical research associate (LUMC) according to a study-specific monitoring plan. A summary of the study progress is submitted to the MEC yearly, including the date of inclusion of the first participant, the number of participants included, the number of participants that have completed the trial, serious adverse events, and amendments.