NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation (NOMOTHETICOS)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01145040|
Recruitment Status : Active, not recruiting
First Posted : June 16, 2010
Last Update Posted : April 10, 2020
|Condition or disease|
Control of thyroid hormone homeostasis is essential for function and development of the organism and hence for individual health. It is therefore not surprising that the thyroid's function is controlled by a complex, multi-loop feedback control system.
Today, the central component of the thyrotropic feedback control system is still poorly understood on a physiological level. Therefore, in mathematical models different functional relations describing the feedback-inhibition of thyrotropin incretion by thyroid hormones have been suggested [Danziger and Elmergreen 1956, Roston 1959, Norwich and Reiter 1965, DiStefano and Stear 1968, DiStefano 1969, Saratchandran et al. 1973, Li et al. 1995, Dietrich et al. 2004, Degon et al. 2008, Jonklaas and Soldin 2008, Hörmann et al. 2010]. Most of these models fail in delivering biochemical explanations for the functional interrelations they postulate.
Nevertheless, some clinical applications of these models have been developed, although their diagnostical potential is usually rather limited [Yagi et al. 1997, Pohlenz et al. 1999, Jostel et al. 2009].
Assuming that the pituitary's response to peripheral thyroid hormones is determined by active transmembrane thyroxine transport mechanisms [Dietrich et al. 2008], intracellular deiodination of thyroxine (T4), binding of resulting triiodothyronine (T3) to iodothyronine receptors and, finally, their inhibiting effect on mRNA expression, translation and release of TRH, a novel, physiologically motivated model has been developed that is based on compartment-analytical approaches, Michaelis-Menten kinetics and non competitive divisive inhibition [Dietrich et al 2004]. However, this model has not been sufficiently evaluated in a clinical context.
It is the aim of the NOMOTHETICOS study to deliver new systems-level insights into the pituitary's thyrotropic function. This unicentric cross-sectional study compares different models of feedback-inhibition by means of modern statistical methods like nonlinear regression and Akaike information criterion. Structural parameters are obtained in vivo from open-loop analysis in patients with disconnected feedback in equilibrium.
These parameters can serve as theoretical basis for possible future trials developing advanced diagnostical evaluation methods of thyrotropic pituitary function.
|Study Type :||Observational|
|Actual Enrollment :||138 participants|
|Official Title:||NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation. A Correlation Study|
|Actual Study Start Date :||June 1, 2010|
|Actual Primary Completion Date :||July 31, 2018|
|Estimated Study Completion Date :||July 31, 2020|
Overt primary hypothyroidism
Hypothyroidism with "full dose" levothyroxine substitution therapy (more than 1.75 µg per kg of body mass)
Overt primary hyperthyroidism
- Nonlinear correlation of thyrotropin levels with peripheral levothyroxine levels. [ Time Frame: Data of individual patients are obtained one work day after consultation (to allow for laboratory investigations). Model comparison will take place immediately after the inclusion of the 100th patient. ]
Nonlinear modeling of the pituitary response with different models (logarithmic, polynomial, non-competitive divisive inhibition). Selection of one out of different possible mathematical models that suffices an optimal combination of
- best nonlinear fit (minimal p-value),
- minimal entropy (as expressed by minimal values for Akaike information criterion, Bayesian information criterion and Hannan-Quinn information criterion) and
- best compatibility with biochemical mechanisms.
- Parameters of feedback inhibition. [ Time Frame: Data of individual patients are obtained one work day after consultation (to allow for laboratory investigations). Parameter estimation will take place immediately after the inclusion of the 100th patient. ]Extraction of structural parameters out of the model that has been selected (see primary outcome measure)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01145040
|Bietigheim, BW, Germany, D-74321|
|Institute for diagnostical radiology, interventional radiology and nuclear medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum|
|Bochum, NRW, Germany, D-44789|
|Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum|
|Bochum, NRW, Germany, D-44789|
|Principal Investigator:||Johannes W Dietrich, M.D.||Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum|
|Study Chair:||Harald H Klein, M.D.||Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum|
|Study Director:||Johannes W Dietrich, M.D.||Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum|
|Principal Investigator:||Bojana Bazika-Gerasch, M.D.||Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum|