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

This study is enrolling participants by invitation only.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01145040
First Posted: June 16, 2010
Last Update Posted: April 25, 2017
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.
Information provided by (Responsible Party):
Johannes W. Dietrich, MD, Ruhr University of Bochum
June 14, 2010
June 16, 2010
April 25, 2017
June 2010
December 31, 2017   (Final data collection date for primary outcome measure)
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.
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 modelling of the pituitary response with different models (logarithmic, polynomial, non-competitive divisive inhibiton). Selection of one out of different possible mathematical models that suffices an optimal combination of

  1. best nonlinear fit (minimal p-value),
  2. minimal entropy (as expressed by minimal values for Akaike information criterion, Bayesian information criterion and Hannan-Quinn information criterion) and
  3. best compatibility with biochemical mechanisms.
Complete list of historical versions of study NCT01145040 on ClinicalTrials.gov Archive Site
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)
Same as current
Not Provided
Not Provided
 
NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation
NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation. A Correlation Study
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.

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.

Observational
Observational Model: Cohort
Time Perspective: Cross-Sectional
Not Provided
Not Provided
Probability Sample
Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)
  • Hypothyroidism
  • Hyperthyroidism
Not Provided
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Enrolling by invitation
100
March 31, 2018
December 31, 2017   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
14 Years and older   (Child, Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Germany
 
 
NCT01145040
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) )
Yes
Not Provided
Not Provided
Johannes W. Dietrich, MD, Ruhr University of Bochum
Ruhr University of Bochum
Not Provided
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
Ruhr University of Bochum
April 2017