Effects of discontinuation of levothyroxine treatment in older adults: a self-controlled study.

Many older persons in the Netherlands use levothyroxine (2015: >215.000 aged
65+), and often have been using levothyroxine for a very long time. Initial
indications for treatment are often not well registered, inaccurate or even
inappropriate due to changing guidelines. Currently, levothyroxine treatment is
indicated for patients with overt hypothyroidism (high Thyroid Stimulating
Hormone [TSH], low free Thyroxin [fT4]). For subclinical hypothyroidism (high
TSH, normal fT4), the most common thyroid disorder in older people (3-18% aged
65+), guidelines vary. Recently, in the TRUST trial, it was shown that
levothyroxine treatment was not clinically beneficial in people aged 65 years
and older with subclinical hypothyroidism. Given the high prevalence of
levothyroxine use, the ambiguous treatment indications, the lack of evidence
for beneficial effects of treatment and the health risks associated with
(over)treatment, we hypothesize that discontinuation of levothyroxine is
feasible in many older persons without negative consequences.

Primary aim
1) To investigate what proportion of levothyroxine users aged 60 years and
older can withdraw from levothyroxine treatment successfully, defined as having
normal fT4 levels and TSH levels <10 mU/L at 52 weeks after start of the
discontinuation.

Secondary aims
1) To study the effect of discontinuing levothyroxine on a) thyroid specific
quality of life, b) general health and c) treatment satisfaction for
medication, by comparing scores on validated questionnaires before and after
stopping in a self-controlled design.
2) To study what proportion of levothyroxine users aged 60 years and older can
achieve a substantial dose lowering of their levothyroxine dose after one year.
a. Substantial dose lowering will be defined as >=50% dose reduction
b. Substantial dose lowering will be defined by the participant themselves.
3) To study the demographic, clinical characteristics and attitudes towards
discontinuation of those levothyroxine users aged 60 years and older willing to
discontinue levothyroxine treatment and those successfully reducing their
dosage.
4) To study the characteristics of persons aged 60 years and older that
physicians consider safe to withdraw thyroid medication from, and medical
reasons not to discontinue treatment.

Through add-on observational studies in Routine Medical Care data including the
ELAN data warehouse, we will get insights in how often general practitioners
stop levothyroxine treatment (or lower dose) in usual care.

Through add-on qualitative studies, we will get insights in physicians*
experience on the recruitment of patients and the consultations, but also
participants* experience of discontinuation of medication.

A self-controlled study.

Stepwise levothyroxine treatment discontinuation. Levothyroxine at a dose of <=
150 microgram per day will be tapered by the treating physician according to a
predetermined schedule while thyroid function is monitored after every step
down. Treatment with levothyroxine is ended when a levothyroxine dose of < 25
microgram per day is reached and thyroid function still falls within the
standard.

In the run-in period participants enter the study with pre-baseline
measurements in which treatment with levothyroxine is continued per usual care
with unadjusted daily routine. The pre-baseline measurements are a set of
questionnaires and a standard thyroid function laboratory test in a venous
blood sample. During the discontinuation phase the participant will start
lowering the dose of levothyroxine guided by their own physician according to
the study-protocol. Laboratory tests for thyroid function will be assessed
accordingly. During final assessment at 12 months, questionnaires and a thyroid
function measurement will be collected.

The added burden for the participant consists of completing questionnaires and
a few extra thyroid function laboratory tests to control the effects of
discontinuation on thyroid function. These laboratory tests are routinely done
in patients using levothyroxine at least once a year.

In summary the extent of the burden of participation consist of:
- visits to the laboratory for venous blood sampling to determine thyroid
function (up to 9 visits)
- filling out various questionnaires (3 - 8) at 5 or 6 time points
- consultation with the treating physician (up to 9 times)
- collecting a new dosage of levothyroxine from the pharmacist (up to 5 times)

Abnormal thyroid function might arise during discontinuation of levothyroxine
due to a deficiency of thyroid hormone. Symptoms related to hypothyroidim may
occur, including fatigue, cold intolerance, dry skin, constipation, weight
gain, muscle ache, change in cognitive functioning and change of mood.
Participants will be required to stop lowering the dose of their levothyroxine
treatment when a TSH level >= 10 mU/L or low fT4 levels (below normal range) is
identified during any of the laboratory control visits and is confirmed in a
re-visit. The treating physician will treat the patient according to the
standard guideline.

Safety of the participants will be monitored by an independent Data Safety and
Monitoring Board and judged according to pre-defined termination rules.
Participants* own physician is responsible for monitoring the clinical safety
of the participant (usual care).

This study will not interfere with standard care, diagnostics and treatment.