HypothyroidismNOMOTHETICOSNCT01145040
NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation
An observational study of Hypothyroidism and Hyperthyroidism, run by Ruhr University of Bochum at 3 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 14 years and older
- Conditions the study is for
- Hypothyroidism, Hyperthyroidism
- How many people
- 138 participants
- Where
- 3 sitesGermany
- Study dates
- 1 Jun 2010to 31 Jan 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 14 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
3 sites in 1 country.
Germany3 sites
Klinikum Ludwigsburg-Bietigheim
Bietigheim, Baden-Wurttemberg, D-74321
Institute for diagnostical radiology, interventional radiology and nuclear medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum
Bochum, North Rhine-Westphalia, D-44789
Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Bochum, North Rhine-Westphalia, D-44789
About this study
Official title: 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.
Read the 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.
- Conditions
- Hypothyroidism, Hyperthyroidism
- Keywords
- Overt primary hypothyroidism, Overt primary hyperthyroidism, Thyrotropic feedback control, Mathematical modelling, Nonlinear modelling, Thyroid, Pituitary, Physiological cybernetics, Full-dose levothyroxine substitution therapy, Syndrome T
- Medical subject headings
- Hypothyroidism, Hyperthyroidism, Thyroid Diseases, Pituitary Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 being measured
The primary outcome is the main question the study is designed to answer.
Nonlinear correlation of thyrotropin levels with peripheral levothyroxine levels.
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.
Measured: 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 outcomes (1)
Parameters of feedback inhibition.
Extraction of structural parameters out of the model that has been selected (see primary outcome measure)
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2010 (estimated)
- Study start1 Jun 2010
- Primary completion31 Jul 2018
- Study completion31 Jan 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for HypothyroidismStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 138 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ruhr University of Bochum
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, PD Dr. Johannes W. Dietrich, MD, Ruhr University of Bochum
- Investigators
- Johannes W Dietrich, M.D., Principal investigator, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of BochumHarald H Klein, M.D., Study chair, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of BochumJohannes W Dietrich, M.D., Study director, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of BochumBojana Bazika-Gerasch, M.D., Principal investigator, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01145040
- Sponsor's protocol ID
- TFC-UK10
- Other IDs
- 3718-10, U1111-1122-3273, DRKS00003153
- Acronym
- NOMOTHETICOS
- Status last verified
- Oct 2020
- First submitted
- 14 Jun 2010
- Last updated
- 8 Oct 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Data will be made available upon reasonable request.
Publications
Norwich KH, Reiter R. Homeostatic control of thyroxin concentration expressed by a set of linear differential equations. Bull Math Biophys. 1965 Jun;27(2):133-44. doi: 10.1007/BF02498768. No abstract available.
PubMed 5832691DiStefano JJ 3rd, Stear EB. Neuroendocrine control of thyroid secretion in living systems: a feedback control system model. Bull Math Biophys. 1968 Mar;30(1):3-26. doi: 10.1007/BF02476936. No abstract available.
PubMed 4969955DiStefano JJ 3rd. A model of the normal thyroid hormone glandular secretion mechanism. J Theor Biol. 1969 Mar;22(3):412-7. doi: 10.1016/0022-5193(69)90013-7. No abstract available.
PubMed 5803330Saratchandran P, Carson ER, Reeve J. An improved mathematical model of human thyroid hormone regulation. Clin Endocrinol (Oxf). 1976 Sep;5(5):473-83. doi: 10.1111/j.1365-2265.1976.tb01976.x.
PubMed 825330Li G, Liu B, Liu Y. A dynamical model of the pulsatile secretion of the hypothalamo-pituitary-thyroid axis. Biosystems. 1995;35(1):83-92. doi: 10.1016/0303-2647(94)01484-o.
PubMed 7772725Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Math Biosci. 2008 Mar;212(1):22-53. doi: 10.1016/j.mbs.2007.10.009. Epub 2007 Nov 6.
PubMed 18291425Dietrich JW, Brisseau K, Boehm BO. [Absorption, transport and bio-availability of iodothyronines]. Dtsch Med Wochenschr. 2008 Aug;133(31-32):1644-8. doi: 10.1055/s-0028-1082780. German.
PubMed 18651367Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab. 1997 May;82(5):1608-14. doi: 10.1210/jcem.82.5.3945.
PubMed 9141558Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene. J Clin Endocrinol Metab. 1999 Nov;84(11):3919-28. doi: 10.1210/jcem.84.11.6080.
PubMed 10566629Jostel A, Ryder WD, Shalet SM. The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index. Clin Endocrinol (Oxf). 2009 Oct;71(4):529-34. doi: 10.1111/j.1365-2265.2009.03534.x. Epub 2009 Feb 18.
PubMed 19226261Jonklaas J, Soldin SJ. Tandem mass spectrometry as a novel tool for elucidating pituitary-thyroid relationships. Thyroid. 2008 Dec;18(12):1303-11. doi: 10.1089/thy.2008.0155.
PubMed 19067639Danziger 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.
Hoermann R, Eckl W, Hoermann C, Larisch R. Complex relationship between free thyroxine and TSH in the regulation of thyroid function. Eur J Endocrinol. 2010 Jun;162(6):1123-9. doi: 10.1530/EJE-10-0106. Epub 2010 Mar 18.
PubMed 20299491
Study at a glance
From the registry record, last updated by the sponsor on 8 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones' Effect on Thyrotropin Incretion in Confirmed Open-loop Situation. A Correlation Study
- ClinicalTrials.gov ID
- NCT01145040
- Acronym / sponsor ID
- NOMOTHETICOS / TFC-UK10
- Conditions
- Hypothyroidism, Hyperthyroidism
- Keywords
- Overt primary hypothyroidism, Overt primary hyperthyroidism, Thyrotropic feedback control, Mathematical modelling, Nonlinear modelling, Thyroid, Pituitary, Physiological cybernetics
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 138 participants (actual)
- Lead sponsor
- Ruhr University of BochumUniversity, hospital or other
- Study start
- 1 Jun 2010 (actual)
- Primary completion
- 31 Jul 2018 (actual)
- Study completion
- 31 Jan 2021 (estimated)
- First posted
- 16 Jun 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 14 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Outpatients with "open-loop" thyrotropic feedback control (disconnection at the site of the thyroid)
Key inclusion criteria (5 listed)
- Outpatients with disconnected feedback control due to the following conditions:
- System in equilibrium (e.g. unchanged substitution dose over the past six weeks)
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
1 secondary outcome
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.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2020.
- Background: PubMed 5832691Norwich KH, Reiter R. Homeostatic control of thyroxin concentration expressed by a set of linear differential equations. Bull Math Biophys. 1965 Jun;27(2):133-44. doi: 10.1007/BF02498768. No abstract available.
- Background: PubMed 4969955DiStefano JJ 3rd, Stear EB. Neuroendocrine control of thyroid secretion in living systems: a feedback control system model. Bull Math Biophys. 1968 Mar;30(1):3-26. doi: 10.1007/BF02476936. No abstract available.
- Background: PubMed 5803330DiStefano JJ 3rd. A model of the normal thyroid hormone glandular secretion mechanism. J Theor Biol. 1969 Mar;22(3):412-7. doi: 10.1016/0022-5193(69)90013-7. No abstract available.
- Background: PubMed 825330Saratchandran P, Carson ER, Reeve J. An improved mathematical model of human thyroid hormone regulation. Clin Endocrinol (Oxf). 1976 Sep;5(5):473-83. doi: 10.1111/j.1365-2265.1976.tb01976.x.
- Background: PubMed 7772725Li G, Liu B, Liu Y. A dynamical model of the pulsatile secretion of the hypothalamo-pituitary-thyroid axis. Biosystems. 1995;35(1):83-92. doi: 10.1016/0303-2647(94)01484-o.
- Background: PubMed 18291425Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Math Biosci. 2008 Mar;212(1):22-53. doi: 10.1016/j.mbs.2007.10.009. Epub 2007 Nov 6.
- Background: PubMed 18651367Dietrich JW, Brisseau K, Boehm BO. [Absorption, transport and bio-availability of iodothyronines]. Dtsch Med Wochenschr. 2008 Aug;133(31-32):1644-8. doi: 10.1055/s-0028-1082780. German.
- Background: PubMed 9141558Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab. 1997 May;82(5):1608-14. doi: 10.1210/jcem.82.5.3945.
- Background: PubMed 10566629Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene. J Clin Endocrinol Metab. 1999 Nov;84(11):3919-28. doi: 10.1210/jcem.84.11.6080.
- Background: PubMed 19226261Jostel A, Ryder WD, Shalet SM. The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index. Clin Endocrinol (Oxf). 2009 Oct;71(4):529-34. doi: 10.1111/j.1365-2265.2009.03534.x. Epub 2009 Feb 18.
- Background: PubMed 19067639Jonklaas J, Soldin SJ. Tandem mass spectrometry as a novel tool for elucidating pituitary-thyroid relationships. Thyroid. 2008 Dec;18(12):1303-11. doi: 10.1089/thy.2008.0155.
- BackgroundDanziger L, Elmergreen GL. The Thyroid-Pituitary Homeostatic Mechanism. Bulletin of Mathematical Biophysics 18 : 1-13, 1956.
- Individual participant dataSharing planned: Yes. Data will be made available upon reasonable request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Johannes W Dietrich, M.D. principal investigator
Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Harald H Klein, M.D. study chair
Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
Johannes W Dietrich, M.D. study director
Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hypothyroidism and Hyperthyroidism, run by Ruhr University of Bochum at 3 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the 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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01145040, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2020.