NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation (NOMOTHETICOS)
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| ClinicalTrials.gov Identifier: NCT01145040 |
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Recruitment Status : Unknown
Verified October 2020 by PD Dr. Johannes W. Dietrich, MD, Ruhr University of Bochum.
Recruitment status was: Active, not recruiting
First Posted : June 16, 2010
Last Update Posted : October 8, 2020
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| Condition or disease |
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| Hypothyroidism Hyperthyroidism |
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 |
| Observational Model: | Cohort |
| Time Perspective: | Cross-Sectional |
| 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 : | January 31, 2021 |
| Group/Cohort |
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Partition 1
Overt primary hypothyroidism
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Partition 2
Hypothyroidism with "full dose" levothyroxine substitution therapy (more than 1.75 µg per kg of body mass)
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Partition 3
Overt primary hyperthyroidism
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- 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)
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| Ages Eligible for Study: | 14 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Probability Sample |
Inclusion Criteria:
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Outpatients with disconnected feedback control due to the following conditions:
- Overt primary hypothyroidism with TSH level higher than 10 mU/l and FT4 concentration below 7 pmol/L (5.4 ng/L) (Partition 1)
- Overt primary hyperthyroidism with TSH level below 0.1 mU/l and FT4 concentration higher than 18 pmol/L (14 ng/L) (Partition 3)
- All other constellations, if the patient receives substitution therapy with more 1.75 µg Levothyroxin per kg of body mass (Partition 2).
- System in equilibrium (e.g. unchanged substitution dose over the past six weeks)
Exclusion Criteria:
- Pituitary or hypothalamic dysfunction
- Severe illness that may be associated with euthyroid sick syndrome (non-thyroidal illness syndrome)
- Medication influencing pituitary function
- Pregnancy
- Missing consent for participation in the study
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
| Germany | |
| Klinikum Ludwigsburg-Bietigheim | |
| 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 |
| Responsible Party: | PD Dr. Johannes W. Dietrich, MD, Senior consultant endocrinologist, Ruhr University of Bochum |
| ClinicalTrials.gov Identifier: | NCT01145040 |
| Other Study ID Numbers: |
TFC-UK10 3718-10 ( Other Identifier: Ethics commission of the Ruhr University of Bochum ) U1111-1122-3273 ( Registry Identifier: WHO ICTRP Universal Trial Number (UTN) ) DRKS00003153 ( Registry Identifier: DRKS (German Clinical Trials Register) ) |
| First Posted: | June 16, 2010 Key Record Dates |
| Last Update Posted: | October 8, 2020 |
| Last Verified: | October 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Data will be made available upon reasonable request. |
| Supporting Materials: |
Analytic Code |
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Overt primary hypothyroidism Overt primary hyperthyroidism Thyrotropic feedback control Mathematical modelling Nonlinear modelling |
Thyroid Pituitary Physiological cybernetics Full-dose levothyroxine substitution therapy Syndrome T |
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Hypothyroidism Hyperthyroidism Thyroid Diseases Endocrine System Diseases |