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NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation (NOMOTHETICOS)

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ClinicalTrials.gov Identifier: NCT01145040
Recruitment Status : Active, not recruiting
First Posted : June 16, 2010
Last Update Posted : August 31, 2018
Sponsor:
Information provided by (Responsible Party):
PD Dr. Johannes W. Dietrich, MD, Ruhr University of Bochum

Brief Summary:
The NOMOTHETICOS study is a unicentric cross-sectional study for a quantitative analysis of feedback-inhibition in the thyrotropic homeostatic control. Structural parameters are obtained in vivo from open-loop analysis in patients with disconnected feedback, i.e. with overt thyroid dysfunction or full dose substitution therapy with levothyroxine.

Condition or disease
Hypothyroidism Hyperthyroidism

Detailed Description:

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 : March 31, 2019

Resource links provided by the National Library of Medicine


Group/Cohort
Partition 1
Overt primary hypothyroidism
Partition 2
Hypothyroidism with "full dose" levothyroxine substitution therapy (more than 1.75 µg per kg of body mass)
Partition 3
Overt primary hyperthyroidism



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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
Study Population
Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)
Criteria

Inclusion Criteria:

  • Outpatients with disconnected feedback control due to the following conditions:

    • Overt primary hypothyroidism with TSH level over 10 mU/l and FT4 level below 0.5 ng/l (Partition 1)
    • Overt primary hyperthyroidism with TSH level below 0.1 mU/l and FT4 level over 25 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

Information from the National Library of Medicine

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


Locations
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
Sponsors and Collaborators
Ruhr University of Bochum
Investigators
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, M.D. Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

Publications:
Danziger L, Elmergreen GL. The Thyroid-Pituitary Homeostatic Mechanism. Bulletin of Mathematical Biophysics 18 : 1-13, 1956.
Roston S: Mathematical Represention of Some Endocrinological Systems. Bulletin of Mathematical Biophysics, 21:271-282, 1959.
Dietrich JW,Tesche A, Pickardt, CR, Mitzdorf U. Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis. Cybernetics and Systems 35 (4): 315-31, 2004.

Responsible Party: PD Dr. Johannes W. Dietrich, MD, Senior consultant endocrinologist, Ruhr University of Bochum
ClinicalTrials.gov Identifier: NCT01145040     History of Changes
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: August 31, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by PD Dr. Johannes W. Dietrich, MD, Ruhr University of Bochum:
Overt primary hypothyroidism
Overt primary hyperthyroidism
Thyrotropic feedback control
Mathematical modelling
Nonlinear modelling
Thyroid
Pituitary
Physiological cybernetics
Full-dose levothyroxine substitution therapy
Syndrome T

Additional relevant MeSH terms:
Hypothyroidism
Hyperthyroidism
Thyroid Diseases
Endocrine System Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs