A national randomized placebo-controlled double-blind multicenter trial of
LT4/LT3 combination therapy in patients with autoimmune
hypothyroidism.

An underactive thyroid gland leading to a deficiency of thyroid hormones
(hypothyroidism) affects up to 10% of the general population. The thyroid gland
produces the inactive hormone T4, and to a lesser extent the active hormone T3.
Additional production of T3 from T4 takes place in peripheral tissues. Because
thyroid hormone plays an important role in the function of virtually all human
tissues, hypothyroidism causes many complaints, such as fatigue and
neurocognitive complaints. The standard treatment for hypothyroidism is
levothyroxine (LT4), which only contains T4. In most patients with
hypothyroidism, LT4 is an adequate treatment with which the symptoms disappear.
However,10-15% of patients experience persisting complaints, the most important
of which is tiredness, despite normalization of blood thyroid hormone levels.
This can result in decreased quality of life, loss of work and decreased
participation to society. Unfortunately, there is no solution to this problem
yet. An explanation for the aforementioned permanent disabling complaints may
be that therapy with LT4 alone does not mimic physiology. An option is
therefore to add LT3 to LT4 (LT4 / LT3 combination therapy). Although thousands
of patients are currently being treated with this in the Netherlands, it is
unclear whether and which patients benefit from this treatment.

This study has been transitioned to CTIS with ID 2024-513883-24-00 check the CTIS register for the current data.

Primary Objective:
To investigate the effects of LT4/LT3 combination therapy compared to LT4
monotherapy on tiredness in those patients with autoimmune hypothyroidism and
persisting tiredness on LT4 monotherapy, after 1 year of treatment.

In case it is confirmed that LT4/LT3 combination therapy reduces tiredness
compared to LT4 treatment alone, the primary objective includes investigating
simultaneously whether effect sizes are higher in patients with genetic
variation in the type 2 deiodinase (DIO2-rs225014) and effect sizes are higher
in patients with genetic variation in the monocarboxylate transporter 10
(MCT10-rs17606253).


Secondary Objective(s):
1. To investigate other determinants of effects of LT4/LT3 combination therapy
compared to LT4 therapy alone on tiredness.
2. To investigate the (determinants of the) effects of LT4/LT3 combination
therapy compared to LT4 therapy alone on other thyroid related complaints and
quality of life.
3. To explore the (determinants of the) effects of LT4/LT3 combination therapy
compared to LT4 therapy alone on cardiovascular, metabolic, and bone outcomes.
4. To explore the (determinants of the) effects of LT4/LT3 combination therapy
compared to LT4 therapy alone on neurocognitive function.
5. To perform an economic evaluation including cost-effectiveness analysis
comparing LT4/LT3 combination therapy and LT4 monotherapy.
6. To compare the number of adverse events during LT4/LT3 combination therapy
vs LT4 therapy alone.

The study design is: A national multi center double blind randomized placebo
controlled study.

The study starts with a run-in period in which all subjects switch to a generic
LT4 preparation in order to prevent heterogeneity and bias in the RCT. An ECG
is performed at baseline. The run-in period stops when the TSH is normal on
generic LT4 and the patient still suffers from tiredness. The RCT starts 2
months afterwards to also achieve a mental steady state condition. A maximum of
two dose adjustments are possible during the run-in period. The duration of the
run-in period can therefore vary from 4-8 months.
In the RCT, LT3 / LT4 combination therapy is given in a 1:16 ratio,
corresponding to the physiological ratio of T3 and T4. The patients in the LT4
/ placebo arm will receive a placebo in addition to the standard LT4 treatment,
due to the double-blinded nature of the study. The duration of the RCT is 1
year.

During the RCT the following interventions will take place:
- Physical examination (pulse rate/ blood pressure, weight, waist
circumference) at 6 visits.
- TSH is measured at each visit and additional blood is drawn at the start and
at the end of the RCT (genetic, metabolic, bone markers and biobank).
- An ECG will be performed at the start and at the end of the study.
- Questionnaires will be completed at six visits (ThyPRO, EQ-5D-5L, iPCQ and
iMCQ).
- DEXA scans and neurocognitve test will be performed in a subgroup of 200
patients at the start and at the end of the RCT .

The study includes 9-11 visits in 1.5 years, depending on the number of dose
adjustments required in the run-in period, while the normal contact frequency
is ~4-6 times per year. If the subject is referred to a trial center, the
travel time may take longer. The subjects may be confronted with their illness
when completing the questionnaires / neurocognitive tests. The blood drawings
may hurt or cause bruising. A DEXA scan is performed in a subgroup of 200
patients at the start as well as at the end of the RCT. This is a scan with a
very low radiation exposure, which requires the patient to lie still for 10-15
minutes. LT3 is a drug approved by the Dutch Medicines Evaluation Board
authority. The side effects of LT3 are in most cases due to oversupplementation
and disappear after dose reduction.