D-vitamin And Graves' Disease; Morbidity And Relapse Reduction (DAGMAR)

The DAGMAR Study. D-vitamin And Graves' Disease; Morbidity And Relapse Reduction: A Randomised, Clinical Trial.

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.

Study Overview

• Status: Completed
• Conditions: Graves' Disease
• Intervention / Treatment: Dietary supplement: Cholecalciferol; Dietary supplement: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus C, Denmark, 8000
    • Department of Endocrinology and Internal Medicine, Aarhus University Hospital
  • Gentofte, Denmark, 2900
    • Gentofte Hospital
  • Herning, Denmark, 7400
    • Department of Internal Medicine, Regionshospitalet Herning
  • Holstebro, Denmark, 7500
    • Department of Internal Medicine, Regionshospitalet Holstebro
  • Horsens, Denmark, 8700
    • Department of Internal Medicine, Regionshospitalet Horsens
  • Randers, Denmark, 8930
    • Department of Internal Medicine, Regionhospitalet Randers
  • Silkeborg, Denmark, 8600
    • Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg
  • Viborg, Denmark, 8800
    • Department of Internal Medicine, Regionshospitalet Viborg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cholecalciferol; Cholecalciferol 70 mcg per day Other name: Vitamin D3.	Dietary supplement: Cholecalciferol; 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.; Other Names: Vitamin D3
Placebo Comparator: Placebo; 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.	Dietary supplement: Placebo; One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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
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

Other Outcome Measures

Outcome Measure	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)	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

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; Herning Hospital; Regionshospitalet Viborg, Skive; Regionshospitalet Horsens; Regional Hospital Holstebro; Regionshospitalet Silkeborg; Randers Regional Hospital
• Investigators: Principal Investigator: Lars Rejnmark, Professor, Aarhus University Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2015
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): December 1, 2020

Study Registration Dates

• First Submitted: January 9, 2015
• First Submitted That Met QC Criteria: March 4, 2015
• First Posted (Estimate): March 10, 2015

Study Record Updates

• Last Update Posted (Actual): September 1, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Quality of Life; Arterial stiffness; Vitamin D3; Cholecalciferol; Bone density and geometry; Muscle strength and balance
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Eye Diseases; Endocrine System Diseases; Thyroid Diseases; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Graves Disease; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: 12122012