Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05821881 |
| Other study ID # |
NL69753.058.19 |
| Secondary ID |
NL7978839110026 |
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 13, 2020 |
| Est. completion date |
January 1, 2024 |
Study information
| Verified date |
April 2023 |
| Source |
Leiden University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Many older persons use the thyroid hormone levothyroxine which is often continued for life.
Scientifically, there is much uncertainty whether simple continuation is the optimal
approach. The goal of this self-controlled observational study is to investigate how many
participants of 60 years and older who are currently using levothyroxine, can be successfully
withdrawn from levothyroxine treatment, either fully or partially, while maintaining a normal
thyroid function (defined as a free T4 level within the reference range and a thyroid
stimulating hormone [TSH] level <10 mU/L), 52 weeks after the start of the discontinuation.
Levothyroxine treatment is discontinued gradually guided by the participant's general
practitioner, using a step-wise approach with regular monitoring of thyroid function. In
addition, the effects of discontinuation of levothyroxine on thyroid-specific quality of life
and general health will be studied using questionnaires.
Description:
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.
