Lessons From Randomised Clinical Trials with T4/T3 Combination Thyroid Treatment – Research

There is a new research paper from Hoermann, Midgley, Larisch and Deitrich.

This research study shows that the previous research that concluded that T4/T3 combination therapy has little or no benefit was flawed in its design.

It also points out the problems with using TSH or FT4 and their reference ranges to manage thyroid treatment.

The paper lays out what a good clinical trial has to do to be unbiased and not flawed.

It points to a better way to manage thyroid treatment that is more focused on the patient, and on the patient’s response to treatment.

It finally puts a bullet into the incorrect conclusion that T3 does not have a benefit. This conclusion is held as gospel by so many doctors and endocrinologists.

My book, The Thyroid Patient’s Manual  is highly consistent with the new paradigm of thyroid treatment that the authors believe is absolutely necessary in order to relieve patient symptoms. 

The following text comes directly from Dr. Midgley, who is a co-author of the new research paper:

“The essential problem is that the implications of our physiological studies are lethal to the acceptability of randomized clinical trials. This is as true of comparing T4 only v T4/T3 combination responses, or TSH, FT4, and osteoporosis, or TSH, FT4, and atrial fibrillation.

The paper by Fisher et al is a complete rejection of the validity of most medical clinical trials based on RCTs (Randomised Crossover Trials), in whatever discipline. I cannot emphasise enough how great a paper, Fisher’s is. Our paper in the Journal of Thyroid Research follows exactly the same path in thyroidology and draws exactly the same conclusions.

It follows that no longer can one link parameters such as TSH and FT4 to osteoporosis and atrial fibrillation in a generalised fashion. The whole corpus of so-called ‘knowledge’ on which these conclusions rest is essentially swept away – there is no other conclusion, however strongly objectors may complain.

All thinking based on these trials has to be completely revisited.

The new paradigm is a return to individualised diagnosis and treatment, and not assessing patients by their placement within or without a particular reference range.

Thyroid diagnosis can no longer be a parameter-based acceptance of normal ranges but the examination of the particular and unique position that a patient occupies, perhaps in some cases outside the range, and their individual presentation. No longer simple biochemistry, but real medicine is needed. This conclusion has only gradually emerged as the disjoint between physiological and clinical trial implications has become clear.”

This is a short excerpt from the paper by Fisher et al.:

“That is, even in the best-case scenario, we should not think of a correlation in group data as an estimate that generalizes to any given individual in the population. Stated bluntly, this implies that the temptation to use aggregate estimates to draw inferences at the basic unit of social and psychological organization—the person—is far less accurate or valid than it may appear in the literature. Indeed, even the best-case scenario is quite alarming: Only 68% of all individual correlational values fall within a range that would be predicted by group data to cover 99.7% of all possible correlations—a discrepancy of nearly 32%. The worst-case scenario is clearly dire: It is plausible that inattention to nonergodicity and a lack of group-to-individual generalizability threaten the veracity of countless studies, conclusions, and best-practice recommendations.”

A strong statement indeed!

NB Ergodicity is a term that states that variability within an individual is equivalent to that within a group. Non-ergodicity is when this doesn’t happen, as in thyroid clinical trials.

Here are the relevant research papers (the second one needs to be paid for, but on accessing the link you can read the abstract and get a good sense of the nature of the paper):

“Lessons from Randomised Clinical Trials for Triiodothyronine Treatment of Hypothyroidism: Have They Achieved Their Objectives?”
Journal of Thyroid Research.  Research Article | Open Access
Volume 2018 |Article ID 3239197 | 9 pages https://doi.org/10.1155/2018/3239197
Rudolf Hoermann, John E. M. Midgley, Rolf Larisch, and Johannes W. Dietrich.


Although not based on thyroid research it does explain the problems of clinical trials:

“Lack of group-to-individual generalizability is a threat to human subjects research”
Aaron J. Fisher, John D. Medaglia, and  Bertus F. Jeronimus
PNAS July 3, 2018 115 (27) E6106-E6115; first published June 18, 2018 https://doi.org/10.1073/pnas.1711978115

I hope you enjoy the new research and see the significance.

Very well done to the authors of both the new papers!

Best wishes,


P.s. Thank you to my friend Paul R Lundy for drawing my attention to this new resarch paper!

(Updated in February 2019)

Paul Robinson

Paul Robinson is a British author and thyroid patient advocate. The focus of his books and work is on helping patients recover from hypothyroidism. Paul has accumulated a wealth of knowledge on thyroid and adrenal dysfunction and their treatment. His three books cover all of this.

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