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| Name | Class |
|---|---|
| Aarhus University Hospital | OTHER |
| Regionshospitalet Silkeborg | OTHER |
| Regional Hospital Holstebro | OTHER |
| Regionshospitalet Horsens |
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The purpose of this study is to investigate the effects of vitamin D supplementation on morbidity and risk of relapse in patients with Graves' disease.
In a multicentre trial, 260 patients with newly diagnosed Graves ' disease will be randomized to cholecalciferol 70 mcg/day or placebo in a parallel Group design. Drop outs prior to 31th of December 2017 will be replaced. The intervention will continue during treatment with antithyroid drugs (ATD), and for a period of 12 months after cessation of ATD. Blood samples will be collected at study entry, at 3 and 9 months, and at end of study. QoL questionnaires on nine occasions through out the study period. In a subcohort of 80 participants detailed examinations of bone density and geometry, muscle strength and postural balance, immune tests (N=50), and measurements of arterial stiffness will be performed at study entry, and at 3 and 9 months after randomisation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cholecalciferol | Active Comparator | Cholecalciferol 70 mcg per day Other name: Vitamin D3. |
|
| Placebo | Placebo Comparator | Placebo tablets are identical in regards to size and appearance to the experimental intervention tablet. The placebo regimen is identical to the vitamin D3 regimen. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cholecalciferol | Dietary Supplement | One tablet per day. The duration of the intervention period is between 24-36 months. This is defined by the time of ATD treatment withdrawal, which is scheduled between approximately 12-18(-24) months after randomisation. Vitamin D supplementation will continue 12 months after withdrawal of ATD treatment or until relapse of Graves' Disease if this occurs prior. |
| Measure | Description | Time Frame |
|---|---|---|
| Proportion of participants without relapse within the first year after cessation of ATD treatment. | A relapse is defined as: The participant has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period; or The participant has hyperthyroidism (TSH<0.1) at 12 months (+/- 1 months) after cessation of ATD treatment; or ATD is re-initiated within 12 months after cessation of initial ATD treatment; or The participant fails to stop ATD treatment within 24 months after initiation of ATD treatment. | 0-12 months after cessation of ATD treatment |
| Measure | Description | Time Frame |
|---|---|---|
| The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period. | The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period. | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Immune response as measured by flow cytometric analysis of T- and B-cells | In a subcohort of 50 participants blood samples will be investigated by flow cytometry. Lymphocyte subpopulations will be quantified. | First nine months. |
| Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lars Rejnmark, Professor | Aarhus University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Endocrinology and Internal Medicine, Aarhus University Hospital | Aarhus C | 8000 | Denmark | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39264438 | Derived | Grove-Laugesen D, Ebbehoj E, Watt T, Hansen KW, Rejnmark L. Changes in bone density and microarchitecture following treatment of Graves' disease and the effects of vitamin D supplementation. A randomized clinical trial. Osteoporos Int. 2024 Dec;35(12):2153-2164. doi: 10.1007/s00198-024-07241-y. Epub 2024 Sep 12. | |
| 37218433 | Derived |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 11, 2017 | Aug 21, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 25, 2013 | Aug 25, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D006111 | Graves Disease |
| ID | Term |
|---|---|
| D005094 | Exophthalmos |
| D009916 | Orbital Diseases |
| D005128 | Eye Diseases |
| D006042 | Goiter |
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| ID | Term |
|---|---|
| D002762 | Cholecalciferol |
| ID | Term |
|---|---|
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| OTHER |
| Randers Regional Hospital | OTHER |
| Regionshospitalet Viborg, Skive | OTHER |
| Herning Hospital | OTHER |
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|
|
| Placebo | Dietary Supplement | One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol. |
|
| The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy | The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy | 0-12 months after cessation of ATD treatment |
| The proportion of participants who re-initiates ATD treatment or is referred to radioactive iodine or thyroid surgery due to hyperthyroidism within 12 months after cessation of initial ATD treatment. | The proportion of participants who re-initiates ATD treatment or is referred to radioactive iodine or thyroid surgery due to hyperthyroidism within 12 months after cessation of initial ATD treatment. | 0-12 months after cessation of ATD treatment |
| The proportion of participants who fails to stop ATD treatment within 24 months after initiation of ATD therapy. | In a pre-planned sub-analysis participants on sustained ATD treatment for more than 24 months after initiation of ATD therapy because of Graves' orbitopathy will be excluded | 0-24 months after initiation of ATD therapy |
| Effects of D-vitamin supplementation according to plasma level of D-vitamin at inclusion to the study. | Sub analysis of all primary and secondary outcome measures will be performed according to this criteria. | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Proportion of participants without relapse within the first year after cessation of ATD treatment according to baseline use of D-vitamin. | Sub analysis of baseline "users" versus "non-users" of D-vitamin supplementation with regards to effects of intervention on all primary and secondary outcome measures. | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 6 weeks |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 3 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 6 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 9 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 12 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 18 months |
| Quality of Life as measured by Health questionnaires | Thyroid specific QoL as measured by the global score in the thyPRO questionnaire. Hyperthyroid symptoms (thyPRO subscale) Proportion of patients with eye symptoms (thyPRO subscale) | 24 months |
| Biomarkers of calcium- and bone metabolism. | Effects of intervention on biochemical markers of calcium and bone metabolism, such as calcium, phosphate, parathyroid hormone, calcitriol, vitamin D-binding protein, bone-specific alkaline phosphatase, osteocalcin, and N-terminal propeptide of type 1 procollagen (P1NP). Also C-terminal telopeptide of type 1 collagen (CTX) and N-telopeptide of type 1 collagen (NTX) among others. | 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months |
| Level of Thyrotropin receptor antibody (TRAb) | Level of TRAb at 3 and 9 months and at end of study period (maximum of 36 months) | 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months |
| Level of 25 hydroxy vitamin D | Level of 25 hydroxy vitamin D at 3 and 9 months and at end of study period (maximum of 36 months) | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
In a subcohort of 50 participants soluble HLA-G (Human Leukocyte Antigen-G) will be quantified based on blood samples. |
| First nine months. |
| Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G) | In a subcohort of 50 participants membrane-bound HLA-G (Human Leukocyte Antigen-G) will be quantified based on expression on monocytes. | First nine months. |
| Immune response assessed by qualitative analysis of regulatory T lymphocytes | In a subcohort of 50 participants functional analysis of the suppressive capacity of regulatory T lymphocytes will be measured at 3 and 9 months after randomisation. | First nine months. |
| Arterial stiffness as measured by tonometry | Indices of arterial stiffness at 3 and 9 months after randomisation in a subcohort of 80 participants | First nine months |
| Muscle strength and balance as measured by isometric tests and dynamic stability tests. | Effects on muscle strength (isometric tests of flexion and extension of thigh and hand), two function-tests (timed up-and go and timed stand-and-sit), and postural stability at 3 and 9 months after randomisation in a subcohort of 80 participants | First nine months |
| Bone density and geometry as measured by DXA and HRpQCT scans | Bone density, geometry, and quality as assessed by dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT)-scans 9 months months after randomisation in a subcohort of 80 participants | First nine months |
| Effect on thyroid gland size by ultrasound examination | Estimation of thyroid volume by ultrasound examination | First nine months |
| Proportion of patients with adverse reactions to anti thyroid drugs | Proportion of patients with adverse reactions to anti thyroid drugs measured by regular questionnaires and reported complaints and events in patient journals | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Proportion of patients with serious adverse events | Based on reports from patients journals and hospitals admissions of agranulocytosis, leukopenia, aplastic anemia, hepatitis, and vasculitis | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Effects on frequency of infectious disease as measured by use of antibiotics | Data from the Danish prescription database | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Effects on use of Health care services as measured by hospital admissions and visits to general practitioner | Measured by all cause-hospital admissions and visits to general practitioner | From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months |
| Gentofte Hospital |
| Gentofte Municipality |
| 2900 |
| Denmark |
| Department of Internal Medicine, Regionshospitalet Herning | Herning | 7400 | Denmark |
| Department of Internal Medicine, Regionshospitalet Holstebro | Holstebro | 7500 | Denmark |
| Department of Internal Medicine, Regionshospitalet Horsens | Horsens | 8700 | Denmark |
| Department of Internal Medicine, Regionhospitalet Randers | Randers | 8930 | Denmark |
| Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg | Silkeborg | 8600 | Denmark |
| Department of Internal Medicine, Regionshospitalet Viborg | Viborg | 8800 | Denmark |
| Grove-Laugesen D, Ebbehoj E, Watt T, Riis AL, Ostergard T, Bruun BJ, Juel Christiansen J, Hansen KW, Rejnmark L. Effect of Vitamin D Supplementation on Graves' Disease: The DAGMAR Trial. Thyroid. 2023 Sep;33(9):1110-1118. doi: 10.1089/thy.2023.0111. Epub 2023 Jun 26. |
| 35018442 | Derived | Bislev LS, Wamberg L, Rolighed L, Grove-Laugesen D, Rejnmark L. Effect of Daily Vitamin D3 Supplementation on Muscle Health: An Individual Participant Meta-analysis. J Clin Endocrinol Metab. 2022 Apr 19;107(5):1317-1327. doi: 10.1210/clinem/dgac004. |
| 31910101 | Derived | Grove-Laugesen D, Cramon PK, Malmstroem S, Ebbehoj E, Watt T, Hansen KW, Rejnmark L. Effects of Supplemental Vitamin D on Muscle Performance and Quality of Life in Graves' Disease: A Randomized Clinical Trial. Thyroid. 2020 May;30(5):661-671. doi: 10.1089/thy.2019.0634. Epub 2020 Feb 7. |
| 31280470 | Derived | Grove-Laugesen D, Malmstroem S, Ebbehoj E, Riis AL, Watt T, Hansen KW, Rejnmark L. Effect of 9 months of vitamin D supplementation on arterial stiffness and blood pressure in Graves' disease: a randomized clinical trial. Endocrine. 2019 Nov;66(2):386-397. doi: 10.1007/s12020-019-01997-8. Epub 2019 Jul 6. |
| D013959 |
| Thyroid Diseases |
| D004700 | Endocrine System Diseases |
| D006980 | Hyperthyroidism |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011083 |
| Polycyclic Compounds |
| D013261 | Sterols |
| D014807 | Vitamin D |
| D012632 | Secosteroids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |