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

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
Johannes W. Dietrich, Ruhr University of Bochum
ClinicalTrials.gov Identifier:
NCT01145040
First received: June 14, 2010
Last updated: February 4, 2013
Last verified: February 2013
  Purpose

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
Hypothyroidism
Hyperthyroidism

Study Type: Observational
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Ruhr University of Bochum:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]

    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:
  • 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. ] [ Designated as safety issue: No ]
    Extraction of structural parameters out of the model that has been selected (see primary outcome measure)


Estimated Enrollment: 100
Study Start Date: June 2010
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
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

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.

  Eligibility

Ages Eligible for Study:   14 Years and older
Genders Eligible for Study:   Both
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01145040

Locations
Germany
Klinikum Ludwigsburg-Bietigheim
Bietigheim, BW, Germany, D-74321
Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Bochum, NRW, Germany, D-44789
Institute for diagnostical radiology, interventional radiology and nuclear medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum
Bochum, NRW, Germany, D-44789
Department for visceral surgery, 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
  More Information

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: Johannes W. Dietrich, Senior consultant endocrinologist, Ruhr University of Bochum
ClinicalTrials.gov Identifier: NCT01145040     History of Changes
Other Study ID Numbers: TFC-UK10, 3718-10, U1111-1122-3273, DRKS00003153
Study First Received: June 14, 2010
Last Updated: February 4, 2013
Health Authority: Germany: Ärztekammer Westfalen-Lippe
Germany: Ethics Commission of the Ruhr-University of Bochum
Germany: The Ministry of Work, Health and Social Affairs of the State North Rhine-Westphalia

Keywords provided by 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

Additional relevant MeSH terms:
Hyperthyroidism
Hypothyroidism
Thyroid Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on July 23, 2014