The T3-4-Hypo trial
A Dutch national randomized placebo-controlled double-blind multicenter trial of LT4/LT3 combination therapy in patients with autoimmune hypothyroidism.
Hypothyroidism is common, affecting 5% of the general population, for which levothyroxine (LT4) monotherapy is the standard treatment. Despite normalized serum thyroid hormone levels, 10-15% of LT4 (levothyroxine) treated patients have various persistent complaints, the most important of which is tiredness. This often leads to a poor quality of life, with withdrawal from society and work. The explanation for the persistent complaints could be that physiological T4/T3 ratios cannot be reached with LT4 monotherapy, as in a healthy individual T3 is not only derived from T4/T3 conversion but is also directly produced by the thyroid itself. Studies have reported contradicting results as to whether addition of liothyronine (LT4/LT3 combination therapy) in patients with persistent tiredness on LT4 monotherapy is effective or not.
This problem is a top prioritized knowledge gap on the national research agenda of the Dutch Society of Internal Medicine (NIV), as endorsed by both the Dutch Endocrine Society (NVE) and the Dutch thyroid disease patient organization SON (Schildklier Organisatie Nederland).
To investigate whether addition of liothyronine (LT4/LT3 combination therapy) in patients with persistent tiredness on LT4 (levothyroxine) monotherapy is effective or not in relieving tiredness.
Inclusion and exclusion criteria are:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- Age 18 years or older;
- Overt or subclinical hypothyroidism*;
- LT4 monotherapy for at least 6 months;
- LT4 monotherapy dose of 75-225 microg, with at least a dose of 1.2 microg/kg;
- TSH levels within the assay-specific reference ranges for at least 3 months;
- Severe tiredness with a large negative impact on daily life for at least 6 months, with or without other persisting complaints, based on the patient’s own experience, without judgment of the treating physician;
- Sufficiently fluent in Dutch and able to read Dutch.
*Thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibody positivity is not a requirement as these have frequently not been determined. Instead, we ensure that we only include patients with autoimmune hypothyroidism by excluding other causes of hypothyroidism (see exclusion criteria).
A Dutch national randomized placebo-controlled double-blind multicenter trial. Six hundred adult patients with autoimmune hypothyroidism will be included who despite biochemical euthyroidism on LT4 (levothyroxine) monotherapy have persistent tiredness with a negative impact on daily life.
Switch to generic LT4
In this run-in stage all patients switch to blinded generic LT4. This is because there are multiple LT4 preparations available with different pharmacokinetic properties, which would otherwise introduce substantial bias in the trial. Previous research has shown that 36% of patients need dose adjustments when switching to other LT4 preparations. Therefore, serum TSH levels are measured every 8 weeks, and medication dosages adjusted if needed, in order to obtain serum TSH levels within the assay-specific reference range. For trial feasibility, patients will be excluded and referred back to their referring physician when a normal TSH cannot be reached with a maximum of two dose adjustments. Once a normal TSH has been measured, the final run-in TSH measurement will be performed 8 weeks later. This is because we want to ensure that we only enrol patients with a stable (i.e. normal) TSH on a stable dose of generic LT4, as recent dose adjustments could otherwise impact the tiredness questionnaire scores at the start of the trial. Patients on generic LT4 will enter Stage 2 (randomized controlled trial) when they have a normal TSH, no ECG abnormalities, and indicate they have persistent tiredness. Patients not fulfilling these criteria will be excluded from this study and referred back to their referring physician. The expected duration of the run-in period will be 4-8 months, depending on the number of dose adjustments.
: Neurocognitive test
|Dr. M. Medici
|Dr. R.T. Netea-Maier
|Dr. S. Roerink
|Dr. W. Zandee
|Dr. B. Havekes
|Drs. S.M. van der Leij
|Leids Universitair Medisch Centrum
|Dr. M. Snel
|Amsterdam UMC, locatie AMC
|Dr. E. Bruinstroop
|Franciscus Vlietland ziekenhuis
|Dr. M.E. Kevenaar
|Dr. C. van Noord
|Máxima Medisch Centrum
|Dr. P.C.M. Wouters-van Poppel
|Admiraal De Ruyter Ziekenhuis
|Dr. C.K.A. van den Berge
|Albert Schweitzer Ziekenhuis
|Dr. R.M. Kiewiet-Kemper
|Van Weel-Bethesda Ziekenhuis
|Drs. E. van Schaik
|Zuyderland Medisch Centrum
|Dr. R. Bianchi