Postponing breakfast in patients using levothyroxine: old-fashioned?

Levothyroxine (LT4) must be taken on an empty stomach 30-60 minutes before
breakfast to ensure adequate intestinal absorption. However, for many patients
delaying breakfast is challenging. Taking LT4 with breakfast would be a more
convenient option, but this may result in reduced LT4 absorption. This will
subsequently lead to under-replacement of thyroid hormones and thus a risk of
developing hypothyroidism measured as an increase in serum thyroid stimulating
hormone (TSH) levels. Yet, we hypothesize that this can be avoided by
increasing the LT4 dose, which could enable patients to take LT4 during
breakfast.

Primary Objective:
To investigate whether there is a difference in the number of participants that
will reach optimal LT4 supplementation (i.e. stability of TSH levels and
symptoms) in the breakfast group compared to the fasting group.

Secondary Objectives:
- To investigate whether reached TSH levels and taking LT4 with or without
breakfast are associated with a self-reported well-being of the participant for
both the breakfast and fasting group.
- To investigate whether participants of the breakfast group have been able to
continue LT4 intake with breakfast after a follow-up period of six and twelve
months.
- To investigate the effect of taking LT4 with or without breakfast on
metabolic factors (such as body weight, glucose tolerance and lipid levels) for
future research purposes.

An open-label, randomized controlled pilot study in which patients with
hypothyroidism treated with LT4 visiting the internal medicine outpatient
clinic of our hospital (Zuyderland Medical Center, the Netherlands) on a
scheduled appointment because of thyroid or non-thyroid related pathology will
be invited to participate in this study. Moreover, patients who gave consent to
contact them for future studies during a prior questionnaire study will be
invited as well. Eligible participants who had two consecutive TSH levels (the
most recent available TSH and TSH at t=0 weeks) in the reference range before
study enrolment will enter the study and will be randomized either to the
breakfast group or to the fasting group. Participants who had one or two TSH
levels outside the reference range before study enrolment, will first enter a
run-in period of maximum three months to achieve a TSH level within the normal
range before entering the study. Participants who do not achieve a TSH level
within the normal range during the run-in period, are not eligible for this
study and will be excluded. When participants of the breakfast group reach two,
consecutive stable TSH levels (defined as a maximum deviation of plus or minus
1 mIU/L compared to TSH level at baseline of that specific participant) after
LT4 dose adjustments with an interval of six weeks, their study period ends and
they can continue LT4 ingestion with breakfast. When participants of the
fasting group reach two, consecutive stable TSH levels with an interval of six
weeks, their study period also ends and they have to continue fasting ingestion
of LT4. The study period will thus take at least three months (t=0, t=6 and
t=12 weeks), but can be longer for participants in whom TSH levels remain
outside the predefined stable range (t=18 or t=24 weeks). Participants in whom
TSH levels remain outside the predefined reference range after six months of
LT4 with breakfast ingestion, despite LT4 dose optimalisation (at t=6, t=12,
t=18 and t=24 weeks), have to go back to the fasting regimen. Their study
period will end when normal TSH levels are reached under the conventional
fasting regimen. For participants of the breakfast group follow-up will take
place after six and twelve months to investigate how many of them have been
able to continue LT4 intake with breakfast.

Participants of the intervention group have to take their LT4 with breakfast
after a minimum dose increase of LT4 (*the breakfast group*), while
participants of the control group have to take their LT4 conventionally on an
empty stomach at least 30 minutes prior to breakfast (*the fasting group*). The
intervention will be an alteration of the timing of levothyroxine ingestion
from fasting intake to intake with breakfast for participants of the breakfast
group. It will thus be an alteration in the behavior for participants of the
breakfast group. Furthermore, for participants of the breakfast group a minimal
dose increase of 15% relative to their levothyroxine dose at baseline will be
performed to correct for impaired levothyroxine absorption. LT4 dose
adjustments will be performed if necessary based on blood results in both the
breakfast and the fasting group.

We do not expect that alterting the timing of LT4 ingestion for participants of
the breakfast group will be a significant burden. A burden for participants of
both groups can be that participants have to physically visit our hospital at
least three times and that blood samples will be drawn at least three times.
Besides that, a smaller burden can be that during the study participants will
be asked to keep a small food diary in which they have to report daily the
timing of their LT4 ingestion and the timing of their breakfast and they have
to report whether their breakfast consisted of certain food or beverages (dairy
products with calcium, coffee, fiber or soy products) during 12 weeks.

Theoretically there can be a risk of overreplacement of LT4. Previous study
results showed that LT4 ingestion with breakfast will lead to an impaired LT4
absorption measured as increased TSH values (of approximately 0.99 - 1.87
mIU/L), although mean TSH values remained within the therapeutic range. To
avoid the occurrence of under-replacement and thus hypothyroidism, we will
perform a minimum LT4 dose increase of 15% relative to their own dose (rounded
to the nearest, available LT4 dosage) at baseline only for participants of the
breakfast group. Theoretically there can be a very small risk of
over-replacement of LT4 and thus developing mild hyperthyroidism for
participants of the breakfast group. A possible, non-expected consequence of
over-replacement is a non-well feeling of the participant due to hyperthyroid
symptoms (such as: nervousness, palpitations, weight loss, increased bowel
movements, diarrhea). Although when LT4 dose is not increased at baseline,
participants will have a much higher risk of developing hypothyroidism by
expected malabsorption of LT4. Besides that, participants will be strictly
controlled within a short interval of only six weeks thus when a participant
develops biochemical hyperthyroidism, a decrease in LT4 dose can be very
rapidly performed. Participants will also be instructed to contact us directly
when they experience signs indicating hypo- or hyperthyroidism.