Exploring symptoms and signs of mild thyroid overactivity in Dutch primary care

ISRCTN	ISRCTN15496928
DOI	https://doi.org/10.1186/ISRCTN15496928
Secondary identifying numbers	P2365

Submission date: 11/05/2023
Registration date: 25/05/2023
Last edited: 28/10/2024

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

Background and study aims
The aim of this study is to determine how many people in the Netherlands have or develop a condition called subclinical hyperthyroidism and whether they have a higher risk of negative health outcomes, such as fractures or cardiovascular disease. Subclinical hyperthyroidism is when you have low or undetectable thyroid-stimulating hormone (TSH) levels with normal thyroid hormone levels.

Who can participate?
Adults with subclinical hyperthyroidism and adults without thyroid disorders. Data from medical records will be used from the PHARMO database (https://pharmo.nl/).

What does the study involve?
Medical records will be compared between people with subclinical hyperthyroidism and people with normal thyroid function.

What are the possible benefits and risks of participating?
There are no direct benefits or risks to patients whose medical records are included.

Where is the study run from?
Amsterdam University Medical Centers (Amsterdam)

When is the study starting and how long is it expected to run for?
December 2022 to June 2025

Who is funding the study?
Amsterdam University Medical Centers (Netherlands)

Who is the main contact?
1. Dr. Stan Ursem, s.ursem@amsterdamumc.nl
2. Prof. Annemieke Heijboer, a.heijboer@amsterdamumc.nl

Contact information

Dr Stan Ursem
Principal Investigator

Meibergdreef 9
Amsterdam
1105 AZ
Netherlands

ORCID ID	0000-0001-9989-0821
Phone	+31 (0)205666434
Email	s.ursem@amsterdamumc.nl

Study information

Study design	Observational nested case-control study
Primary study design	Observational
Secondary study design	Nested case-control study
Study setting(s)	GP practice
Study type	Other
Participant information sheet	Not available in web format, please use the contact details to request a participant information sheet
Scientific title	Subclinical hyperthyroidism and TSH measurements in primary care in the Netherlands
Study hypothesis	For this observational study, the aim is to investigate the prevalence and incidence of endogenous subclinical hyperthyroidism in the Netherlands in primary care. In addition, the researchers want to assess the natural course, as well as the risk for adverse health outcomes and comorbidities, of patients with subclinical hyperthyroidism in primary care. Hypotheses will be generated using exploratory analysis described under "Intervention".
Ethics approval(s)	This is an anonymized retrospective observational study, which does not require ethics approval under the Dutch law "Wet medisch-wetenschappelijk onderzoek met mensen" 1998. The study has been assessed by the Compliance Committee of PHARMO (https://pharmo.nl/).
Condition	Subclinical hyperthyroidism
Intervention	A dataset will be extracted from the PHARMO general practitioner database (see https://pharmo.nl/) using routine care data. A nested case-control study will be performed. For every case (see inclusion criteria below), four matched controls are included based on age, sex and general practitioner practice. The incidence and prevalence of patients with subclinical hyperthyroidism (SHT) will be compared with the total number of patients with a TSH measurement. Over the years 2010-2021 the researchers want to assess the yearly incidence and prevalence of SHT against the total group of requested TSH measurements (with exclusion criteria applied). For this research question they would not require a dataset. For the other hypotheses the researchers will use a dataset over the last 10 years (2012-2022) to compare a group of patients with SHT and a group of euthyroid patients. First, 25% of the dataset will be used for exploratory analyses and researchers will not have access to the other 75%. After determining hypotheses and establishing an analysis protocol, confirmatory analyses will be performed on the other 75% of the dataset. Differences in proportions between groups (e.g. subclinical hyperthyroidism vs euthyroidism) will be investigated with Chi-square tests (categorical data) and independent t-tests (normally distributed continuous data) or Mann-Whitney U tests (not normally distributed data). Associations between subclinical hyperthyroidism and clinical outcomes (atrial fibrillation, coronary artery disease, heart failure, osteoporosis, fractures, stroke, dementia and mortality) will be investigated with time-to-event analyses (e.g. Cox proportional hazard models and competing risk analysis). Primary analyses will be adjusted for sex and age (since some traditional risk factors may be potential mediators), and then for traditional risk factors, i.e. diabetes, pre-existent cardiovascular disease and medications (lipid-lowering, antihypertensive or anti-osteoporosis treatment).
Intervention type	Other
Primary outcome measure	Cardiovascular comorbidity and bone health. In the exploratory analyses the exact outcomes will be determined by means of International Classification of Primary Care (ICPC) codes, medication use (such as osteoporosis medication or medication used in heart failure) and relevant laboratory data (for example cholesterol and BNP values), the researchers will compare this comorbidity between the subclinical hyperthyroid group and controls using a dataset over the last 10 years (2012-2022).
Secondary outcome measures	Natural course of subclinical hyperthyroidism by TSH and free T4 concentrations using a dataset over the last 10 years (2012-2022)
Overall study start date	16/12/2022
Overall study end date	01/06/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	>200
Participant inclusion criteria	Cases: Patients with TSH concentration below reference range and with fT4 concentration within reference range (at same measurement) or patients with recorded ICPC code A91.07 (subclinical hyperthyroidism). Controls: TSH and fT4 measurement within reference range
Participant exclusion criteria	Cases: 1. In 2 years prior to inclusion use of amiodarone (ATC C01BD01) 2. In 2 years prior to inclusion use of thyroid medication (ATC starting with H03) 3. Ever recorded use of lithium (ATC N05AN01) 4. In 2 years prior to inclusion mention of ICPC T85 (hyperthyroidism), T86 (hypothyroidism), A91.07 (subclinical hyperthyroidism), T71 (thyroid malignancy), A91.06 (subclinical hypothyroidism) Controls: During 5-year follow-up from cohort entry date: 1. TSH or FT4 measurement outside of reference range 2. Mention of ICPC codes (see also above) T85, T86, A91.07, T71, A91.06
Recruitment start date	01/01/2012
Recruitment end date	31/12/2021

Locations

Countries of recruitment

Netherlands

Study participating centre

PHARMO institute

Van Deventerlaan 30-40
Utrecht
3528 AE
Netherlands

Sponsor information

Amsterdam University Medical Centers
Hospital/treatment centre

Meibergdreef 9
Amsterdam
1105 AZ
Netherlands

Phone	+31 (0)205665940
Email	a.heijboer@amsterdamumc.nl
Website	https://www.amsterdamumc.org/research/institutes/cancer-center-amsterdam.htm
"ROR"	https://ror.org/05grdyy37

Funders

Funder type

Hospital/treatment centre

Amsterdam University Medical Centers
Government organisation / Universities (academic only)

Alternative name(s): Amsterdam UMC, Amsterdam University Medical Centres, AUMC
Location: Netherlands

Results and Publications

Intention to publish date	01/06/2025
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal and presentation at relevant scientific conferences.
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon reasonable request for scientific verifications or evaluation of the quality of the research via Dr Stan Ursem (s.ursem@amsterdamumc.nl). These data will be retained for at least 10 years. Personal data from participants cannot be shared and are also unknown to the authors. The other data (year of birth, comorbidity, laboratory data and medication) are available for the above-mentioned requests. PHARMO will be informed of such a request for peer review.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	Protocol and SAP CVD	27/10/2024	28/10/2024	No	No
Protocol file	Protocol and SAP natural course	27/10/2024	28/10/2024	No	No
Statistical Analysis Plan	Protocol and SAP Bone	27/10/2024	28/10/2024	No	No

Additional files

ISRCTN15496928 Protocol and SAP natural course 27-10-2024.pdf: Protocol and SAP natural course
ISRCTN15496928 Protocol and SAP CVD 27-10-2024.pdf: Protocol and SAP CVD
ISRCTN15496928 Protocol and SAP Bone 27-10-2024.pdf: Protocol and SAP Bone

Editorial Notes

28/10/2024: Uploaded protocol and statistical analysis plan files (not peer-reviewed).
16/05/2023: Study's existence confirmed by the Compliance Committee of PHARMO.