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

October 6, 2020 updated by: PD Dr. Johannes W. Dietrich, MD, Ruhr University of Bochum

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.

Study Overview

Status

Unknown

Conditions

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

Enrollment (Actual)

138

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • BW
      • Bietigheim, BW, Germany, D-74321
        • Klinikum Ludwigsburg-Bietigheim
    • NRW
      • 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
        • Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)

Description

Inclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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)
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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-Gerasch, M.D., Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 1, 2010

Primary Completion (ACTUAL)

July 31, 2018

Study Completion (ANTICIPATED)

January 31, 2021

Study Registration Dates

First Submitted

June 14, 2010

First Submitted That Met QC Criteria

June 15, 2010

First Posted (ESTIMATE)

June 16, 2010

Study Record Updates

Last Update Posted (ACTUAL)

October 8, 2020

Last Update Submitted That Met QC Criteria

October 6, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TFC-UK10
  • 3718-10 (OTHER: Ethics commission of the Ruhr University of Bochum)
  • U1111-1122-3273 (REGISTRY: WHO ICTRP Universal Trial Number (UTN))
  • DRKS00003153 (REGISTRY: DRKS (German Clinical Trials Register))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be made available upon reasonable request.

IPD Sharing Supporting Information Type

  • ANALYTIC_CODE

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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