Early Risk Stratification of Thyroid Eye Disease in Newly Diagnosed Graves' Disease

NCT07812194 | Not Yet Recruiting

• 4 other identifiers: p-2026-21969150,000 DKK930,000250,000 DKK
• Study Type: observational
• Target: 430
• Locations: 1 country
• Sites: 1

Brief Summary

The aim of this observational study is to investigate why some people with newly diagnosed Graves' disease (GD) develop thyroid eye disease (TED), also known as Graves' orbitopathy, while others do not. The main questions the study aims to answer are:

• Answer questions about their symptoms and quality of life
• Undergo a standardized eye examination and have clinical photographs taken of their eyes
• Provide blood samples, tear-fluid samples, and a small swab sample from the ocular surface The study will also include healthy volunteers and participants with moderate-to-severe TED. Participants in these comparison groups will attend one study visit. Researchers will compare findings across the groups to better understand the early clinical and biological changes associated with thyroid eye disease. The long-term aim is to improve the early detection and follow-up of people with GD who may be at increased risk of developing TED.

Conditions

Graves' Orbitopathy; Thyroid Eye Disease, TED; Graves' Disease

Keywords

Risk stratification; Quality of Life; Tear Fluid Biomarkers; Early Detection; Prospective Cohort Study; Ocular Surface Microbiome

Outcome Measures

Primary Outcomes (1)

• Incidence of Thyroid Eye Disease (TED) within 12 months

  Proportion of participants with newly diagnosed Graves' Disease (GD) who develop TED of any grade during the 12-month follow-up period. TED status is determined by standardized clinical and ophthalmological assessments using the established European Group on Graves' Orbitopathy (EUGOGO) criteria. Reported as a percentage (%) of participants.

  Baseline to 12 months

Secondary Outcomes (18)

• Prevalence of TED at baseline assessment

  Baseline

• Area Under the Receiver Operating Characteristic curve (AUROC) of the multivariable TED prediction model

  Baseline to 12 months

• Change from baseline in Clinical Activity Score (CAS points)

  Baseline to 12 months

• Change from baseline in proptosis

  Baseline to 12 months

• Change from baseline in Gorman Diplopia Score

  Baseline to 12 months

Study Arms (3)

Newly Diagnosed Graves' Disease Cohort

Adults with newly diagnosed Graves' disease with residence in and/or clinical management within the Capital Region of Denmark. Participants will be followed from baseline to approximately 12 months to assess the development of thyroid eye disease and associated clinical, ophthalmological, and biological markers. Standard clinical and ophthalmological evaluations, including fundoscopy, Optical Coherence Tomography (OCT), and Clinical Activity Score (CAS) assessment, are performed at baseline to characterize the cohort.

Other: Study-related ophthalmological assessment and biospecimen collection; Other: Blood biomarkers and standardized blood samples including thyroid function status

Healthy Control Group

40 healthy control participants without known Graves' disease or thyroid dysfunction. Participants will undergo one study visit for comparison of ophthalmological findings, biomarker profiles, and ocular surface microbiome characteristics.

Other: Study-related ophthalmological assessment and biospecimen collection

Moderate-to-Severe Thyroid Eye Disease Group

40 age- and sex-matched control group consisting of patients with moderate-to-severe thyroid eye disease requiring advanced medical treatment. Participants will undergo one study visit for comparison of ophthalmological findings, biomarker profiles, and ocular surface microbiome characteristics.

Other: Study-related ophthalmological assessment and biospecimen collection

Interventions

Blood biomarkers and standardized blood samples including thyroid function status OTHER

No experimental or therapeutic interventions are administered. Participants undergo routine blood sampling (including thyroid function, biochemistry, hematology, lipids, and liver function markers) solely to gather baseline predictors for the TED prediction model

Also known as: thyroid function, biochemistry, hematology, lipids, and liver function markers

Newly Diagnosed Graves' Disease Cohort

Study-related ophthalmological assessment and biospecimen collection OTHER

Participants are not assigned to any treatment or therapeutic intervention as part of the study. Study-related procedures include standardized ophthalmological assessments, patient-reported outcome measures, blood sampling, tear-fluid collection using Schirmer strips, and conjunctival ocular surface swab sampling for ocular microbiome profiling. Standard clinical care is not altered by study participation.

Also known as: Standardized ophthalmological assessment, Biospecimen collection, Tear-fluid sampling, Ocular surface swab sampling, Patient-reported outcome assessment, Quality of life questionnaires, Ocular symptom questionnaires

Healthy Control Group; Moderate-to-Severe Thyroid Eye Disease Group; Newly Diagnosed Graves' Disease Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Newly diagnosed GD cohort: Potential participants will be identified through approved recruitment reports based on EPIC/Sundhedsplatformen and laboratory data. Reports will identify adults referred to endocrinology outpatient clinics in the Capital Region of Denmark with first-time TRAb \>1.5 IU/L and TSH \<0.01 mU/L, and no previous TRAb \>1.5 IU/L. Participants may also be recruited through public announcements. Moderate-to-severe TED group: Participants will be identified among patients followed at the Endocrinology Outpatient Clinic, Herlev Hospital, and approached during a scheduled visit. Healthy control group: Participants will be recruited through staff advertisements at Herlev and Gentofte Hospital and public announcements.

You may qualify if:

• Newly Diagnosed Graves' Disease (GD) Cohort:
• Age 18 years or older
• Newly diagnosed GD
• Positive TSH receptor antibodies, defined as TRAb \>1.5 IU/L
• Biochemical hyperthyroidism, defined as TSH \<0.01 mIU/L
• Residence in and/or clinical management within the Capital Region of Denmark, including Hvidovre Hospital, Rigshospitalet, Amager Hospital, Nordsjællands Hospital, Herlev Hospital, and Bispebjerg Hospital.
• Ability to provide oral and written informed consent
• Healthy Control Group:
• Age 18 years or older
• No known history of GD
• No previous positive TRAb measurement
• No known thyroid dysfunction requiring antithyroid drug therapy or thyroid hormone replacement therapy
• Ability to provide oral and written informed consent
• Moderate-to-Severe Thyroid Eye Disease (TED) Group:
• Age 18 years or older

You may not qualify if:

• Newly Diagnosed GD Cohort:
• Age below 18 years
• Previous documented TRAb measurement \>1.5 IU/L prior to the current diagnostic episode
• Inability to provide informed consent
• Inability to complete the baseline assessment within the predefined study timeframe
• Healthy Control Group:
• Age below 18 years
• Known Graves' disease or previous positive TRAb measurement
• Known thyroid dysfunction requiring antithyroid drug therapy or thyroid hormone replacement therapy
• Inability to provide informed consent
• Moderate-to-Severe TED Group:
• Age below 18 years
• Inability to provide informed consent
• Inability to complete the planned study assessment

Sponsors & Collaborators

• University of Copenhagen: lead
• Department of Medicine, Endocrine Unit Herlev University Hospital, Herlev, Denmark: collaborator
• Rigshospitalet, Denmark: collaborator

Study Sites (1)

Department of Medical Diseases, Endocrinology Unit, Herlev-Gentofte Hospital

Herlev, 2730, Denmark

Location

Related Publications (6)

• Burlacu MC, Bednarczuk T, Lee V, Perros P. Mild Thyroid Eye Disease-The Most Common yet the Least Studied Presentation of Thyroid Eye Disease. Thyroid. 2026 Aug;36(8):817-826. doi: 10.1177/10507256261464556. Epub 2026 Jun 29.

  PMID: 42370743 BACKGROUND

• Ji X, Dong K, Pu J, Yang J, Zhang Z, Ning X, Ma Q, Kang Z, Xu J, Sun B. Comparison of the ocular surface microbiota between thyroid-associated ophthalmopathy patients and healthy subjects. Front Cell Infect Microbiol. 2022 Jul 26;12:914749. doi: 10.3389/fcimb.2022.914749. eCollection 2022.

  PMID: 35959376 BACKGROUND

• Neset MT, Nilsen RM, Lovas K, Halsoy K, Reikvam H, Stokland AM, Ueland GA, Wolff ASB, Aass HCD, Reppe S, Husebye ES, Rodahl E, Utheim TP, Ueland HO. Exploring tear fluid biomarkers and the ocular surface in thyroid eye disease. Acta Ophthalmol. 2026 Feb;104(1):e28-e38. doi: 10.1111/aos.17556. Epub 2025 Jul 7.

  PMID: 40622704 BACKGROUND

• Boulakh L, Nygaard B, Bek T, Faber J, Heegaard S, Toft PB, Poulsen HE, Toft-Petersen AP, Hesgaard HB, Ellervik C. Nationwide Incidence of Thyroid Eye Disease and Cumulative Incidence of Strabismus and Surgical Interventions in Denmark. JAMA Ophthalmol. 2022 Jul 1;140(7):667-673. doi: 10.1001/jamaophthalmol.2022.1002.

  PMID: 35588051 BACKGROUND

• Wiersinga W, Zarkovic M, Bartalena L, Donati S, Perros P, Okosieme O, Morris D, Fichter N, Lareida J, von Arx G, Daumerie C, Burlacu MC, Kahaly G, Pitz S, Beleslin B, Ciric J, Ayvaz G, Konuk O, Toruner FB, Salvi M, Covelli D, Curro N, Hegedus L, Brix T; EUGOGO (European Group on Graves' Orbitopathy). Predictive score for the development or progression of Graves' orbitopathy in patients with newly diagnosed Graves' hyperthyroidism. Eur J Endocrinol. 2018 Jun;178(6):635-643. doi: 10.1530/EJE-18-0039. Epub 2018 Apr 12.

  PMID: 29650691 BACKGROUND

• Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marino M, Vaidya B, Wiersinga WM; EUGOGO dagger. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021 Aug 27;185(4):G43-G67. doi: 10.1530/EJE-21-0479.

  PMID: 34297684 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Tear fluid will be collected using Schirmer strips for analyses of inflammatory and molecular biomarkers associated with TED. Conjunctival samples will be collected from the inferior fornix using sterile, single-use swabs. The samples may contain proteins, metabolites, and microbial DNA. Ocular surface microbial composition will be characterized using 16S rRNA gene amplicon sequencing. Statistical analyses will be planned and conducted in collaboration with an experienced biostatistician. No human genetic analyses will be performed.

MeSH Terms

Conditions

Graves Ophthalmopathy; Graves Disease

Interventions

Hematologic Tests; Lipids

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Floriana Bytyqi, M.D

  Herlev Hospital

  STUDY DIRECTOR

• Birte Nygaard, M.D., Ph.D.

  Herlev Hospital

  PRINCIPAL INVESTIGATOR

• Jens Pedersen, M.D., Ph.D.

  Herlev Hospital

  STUDY DIRECTOR

Central Study Contacts

Birte Nygaard, M.D., Ph.D

CONTACT

+4538689527; birte.nygaard@regionh.dk

Jens Pedersen, M.D., Ph.D

CONTACT

38688583; jens.pedersen@regionh.dk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Associate Professor, Ph.D., Chief Physician

Study Record Dates

• First Submitted: August 26, 2026
• First Posted: September 10, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): August 31, 2028
• Study Completion (Estimated): September 1, 2029
• Last Updated: September 10, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)