Clinical trial NCT02384668: D-vitamin And Graves' Disease; Morbidity And Relapse Reduction
Official title: The DAGMAR Study. D-vitamin And Graves' Disease; Morbidity And Relapse Reduction: A Randomised, Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Graves' Disease
Keywords: Cholecalciferol
Vitamin D3
Arterial stiffness
Quality of Life
Bone density and geometry
Muscle strength and balance
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Regionshospitalet Silkeborg
name: Regional Hospital Holstebro
name: Regionshospitalet Horsens
name: Randers Regional Hospital
name: Regionshospitalet Viborg, Skive
name: Herning Hospital
First posted: 2015-03-10
Enrollment: 278
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* A first time diagnosis of Graves' hyperthyroidism within the last three months, confirmed by TSH below 0.01 IU/L, and T3 or T4 levels above the reference interval necessitating ATD therapy
* Positive TRAb
* Speak and read Danish
* Written informed consent

Exclusion Criteria:

* Previously diagnosed hyperthyroidism
* ATD treatment initiated more than 3 months prior to inclusion
* Planned ablative therapy (radioactive iodine or thyroid surgery)
* Intake of more than 10 µg D-vitamin/day that the participant wishes to continue.
* Chronic granulomatous illness
* Persistent hypercalcemia (plasma calcium \> 1.40 mmol/L)
* Reduced kidney function (eGFR \< 45 ml/min)
* Treatment with immunomodulatory drugs
* Active malignant disease
* Alcohol or drug abuse
* Pregnancy at inclusion
* Major comorbidity, making the participant unlikely to continuously receive trial intervention.
* Allergy towards the components in the D-vitamin or the placebo pills.
* Unable to read and understand Danish
* Lack of informed consent.

Primary outcomes:
measure: Proportion of participants without relapse within the first year after cessation of ATD treatment.
timeFrame: 0-12 months after cessation of ATD treatment
Secondary outcomes:
measure: The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period.
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy
timeFrame: 0-12 months after cessation of ATD treatment
measure: 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.
timeFrame: 0-12 months after cessation of ATD treatment
measure: The proportion of participants who fails to stop ATD treatment within 24 months after initiation of ATD therapy.
timeFrame: 0-24 months after initiation of ATD therapy
measure: Effects of D-vitamin supplementation according to plasma level of D-vitamin at inclusion to the study.
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Proportion of participants without relapse within the first year after cessation of ATD treatment according to baseline use of D-vitamin.
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 6 weeks
measure: Quality of Life as measured by Health questionnaires
timeFrame: 3 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 6 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 9 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 12 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 18 months
measure: Quality of Life as measured by Health questionnaires
timeFrame: 24 months
measure: Biomarkers of calcium- and bone metabolism.
timeFrame: 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Level of Thyrotropin receptor antibody (TRAb)
timeFrame: 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Level of 25 hydroxy vitamin D
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Other outcomes:
measure: Immune response as measured by flow cytometric analysis of T- and B-cells
timeFrame: First nine months.
measure: Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G)
timeFrame: First nine months.
measure: Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G)
timeFrame: First nine months.
measure: Immune response assessed by qualitative analysis of regulatory T lymphocytes
timeFrame: First nine months.
measure: Arterial stiffness as measured by tonometry
timeFrame: First nine months
measure: Muscle strength and balance as measured by isometric tests and dynamic stability tests.
timeFrame: First nine months
measure: Bone density and geometry as measured by DXA and HRpQCT scans
timeFrame: First nine months
measure: Effect on thyroid gland size by ultrasound examination
timeFrame: First nine months
measure: Proportion of patients with adverse reactions to anti thyroid drugs
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Proportion of patients with serious adverse events
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Effects on frequency of infectious disease as measured by use of antibiotics
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
measure: Effects on use of Health care services as measured by hospital admissions and visits to general practitioner
timeFrame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Locations:
city: Aarhus C
country: Denmark
facility: Department of Endocrinology and Internal Medicine, Aarhus University Hospital
city: Gentofte
country: Denmark
facility: Gentofte Hospital
city: Herning
country: Denmark
facility: Department of Internal Medicine, Regionshospitalet Herning
city: Holstebro
country: Denmark
facility: Department of Internal Medicine, Regionshospitalet Holstebro
city: Horsens
country: Denmark
facility: Department of Internal Medicine, Regionshospitalet Horsens
city: Randers
country: Denmark
facility: Department of Internal Medicine, Regionhospitalet Randers
city: Silkeborg
country: Denmark
facility: Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg
city: Viborg
country: Denmark
facility: Department of Internal Medicine, Regionshospitalet Viborg
Study officials:
affiliation: Aarhus University Hospital
name: Lars Rejnmark, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.