The T3-4-Hypo trial

[helvella]

I think this has previously been mentioned.

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.

t3-4-hypotrial.nl/english/

I note that the very first thing they are doing is getting all patients onto the same make of levothyroxine. And I want to shout "See! They are not all the same!!!!"

Clearly, if trialling T3, then eliminating differences from the various T4 products makes a lot of sense. Imagine being on product A then switching to a combination of product B plus T3 or a placebo? A to B could jeopardise the results.

Stage 1

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.

[diogenes Remembering]

This trial is both useful and problematic. At least it tries to separate out those patients who are still tired on T4 only, as subjects for the combination trial. But it still relies on TSH in the initial T4-treatment arm as a control. I would much rather not use tiredness as a choice of subject, but measure FT4 and FT3 on T4 only to select out those with FT4/FT3 ratios 4.5/1 or greater and forget the TSH. The positioning of this parameter will be very crude, given TSH test's high sensitivity and big changes on small doses. Also I wonder if during the combination trial they insist on keeping reference-range TSH. But one thing stands out at least. They now believe presumably from our work of the importance of direct thyroidal T3 production and the reason why some people with lost thyroids cannot adequately deal with T4 alone. It might be best to try to get an FT4/FT3 ratio at around 3/1 to 3.8/1 ie like euthyroidism with full thyroid activity.

[Zephyrbear]

By the sounds of it they are tying one hand behind the patients’ backs before they even start by requiring them all to be:

a) on the same brand of T4 which will carry its own implications, and,

b) have a TSH within a ‘normal’ range.

I’d say this is a project set up to fail, especially if ‘tiredness’ is going to be the governing factor and I would probably have nothing to do with it, speaking as a patient who got my life back after my endo provided me with T3 based on what symptoms I reported back to him.

[helvella Administrator Thyroid UK in reply to Zephyrbear]

I think the same brand of T4 at the start is reasonable. (Though it will obviously make participation more of an issue than otherwise.)

But the TSH issues are questionable.

[Zephyrbear]

Well, let’s hope they don’t put everyone on TEVA!