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

• ClinicalTrials.gov Identifier: NCT02384668
• Recruitment Status: Completed
• First Posted: March 10, 2015
• Last Update Posted: September 1, 2022
• Sponsor: University of Aarhus
• Collaborators: Aarhus University Hospital; Regionshospitalet Silkeborg; Regional Hospital Holstebro; Regionshospitalet Horsens; Randers Regional Hospital; Regionshospitalet Viborg, Skive; Herning Hospital
• Information provided by (Responsible Party): University of Aarhus

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Graves' Disease	Dietary Supplement: Cholecalciferol; Dietary Supplement: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 278 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The DAGMAR Study. D-vitamin And Graves' Disease; Morbidity And Relapse Reduction: A Randomised, Clinical Trial.
• Actual Study Start Date: March 24, 2015
• Actual Primary Completion Date: December 2020
• Actual Study Completion Date: December 2020

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Proportion of participants without relapse within the first year after cessation of ATD treatment. [ Time Frame: 0-12 months 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.

Secondary Outcome Measures :

1. The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period. [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
   The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period.
2. The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy [ Time Frame: 0-12 months after cessation of ATD treatment ]
   The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy
3. 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. [ Time Frame: 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.
4. The proportion of participants who fails to stop ATD treatment within 24 months after initiation of ATD therapy. [ Time Frame: 0-24 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
5. Effects of D-vitamin supplementation according to plasma level of D-vitamin at inclusion to the study. [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
   Sub analysis of all primary and secondary outcome measures will be performed according to this criteria.
6. Proportion of participants without relapse within the first year after cessation of ATD treatment according to baseline use of D-vitamin. [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
   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.
7. Quality of Life as measured by Health questionnaires [ Time Frame: 6 weeks ]

   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)

8. Quality of Life as measured by Health questionnaires [ Time Frame: 3 months ]

   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. Quality of Life as measured by Health questionnaires [ Time Frame: 6 months ]

   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)

10. Quality of Life as measured by Health questionnaires [ Time Frame: 9 months ]

    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)

11. Quality of Life as measured by Health questionnaires [ Time Frame: 12 months ]

    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. Quality of Life as measured by Health questionnaires [ Time Frame: 18 months ]

    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)

13. Quality of Life as measured by Health questionnaires [ Time Frame: 24 months ]

    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)

14. Biomarkers of calcium- and bone metabolism. [ Time Frame: 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months ]
    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.
15. Level of Thyrotropin receptor antibody (TRAb) [ Time Frame: 3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months ]
    Level of TRAb at 3 and 9 months and at end of study period (maximum of 36 months)
16. Level of 25 hydroxy vitamin D [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
    Level of 25 hydroxy vitamin D at 3 and 9 months and at end of study period (maximum of 36 months)

Other Outcome Measures:

1. Immune response as measured by flow cytometric analysis of T- and B-cells [ Time Frame: First nine months. ]
   In a subcohort of 50 participants blood samples will be investigated by flow cytometry. Lymphocyte subpopulations will be quantified.
2. Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G) [ Time Frame: First nine months. ]
   In a subcohort of 50 participants soluble HLA-G (Human Leukocyte Antigen-G) will be quantified based on blood samples.
3. Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G) [ Time Frame: First nine months. ]
   In a subcohort of 50 participants membrane-bound HLA-G (Human Leukocyte Antigen-G) will be quantified based on expression on monocytes.
4. Immune response assessed by qualitative analysis of regulatory T lymphocytes [ Time Frame: First nine months. ]
   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.
5. Arterial stiffness as measured by tonometry [ Time Frame: First nine months ]
   Indices of arterial stiffness at 3 and 9 months after randomisation in a subcohort of 80 participants
6. Muscle strength and balance as measured by isometric tests and dynamic stability tests. [ Time Frame: First nine months ]
   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
7. Bone density and geometry as measured by DXA and HRpQCT scans [ Time Frame: First nine months ]
   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
8. Effect on thyroid gland size by ultrasound examination [ Time Frame: First nine months ]
   Estimation of thyroid volume by ultrasound examination
9. Proportion of patients with adverse reactions to anti thyroid drugs [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
   Proportion of patients with adverse reactions to anti thyroid drugs measured by regular questionnaires and reported complaints and events in patient journals
10. Proportion of patients with serious adverse events [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
    Based on reports from patients journals and hospitals admissions of agranulocytosis, leukopenia, aplastic anemia, hepatitis, and vasculitis
11. Effects on frequency of infectious disease as measured by use of antibiotics [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
    Data from the Danish prescription database
12. Effects on use of Health care services as measured by hospital admissions and visits to general practitioner [ Time Frame: From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months ]
    Measured by all cause-hospital admissions and visits to general practitioner

Eligibility Criteria

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

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.

Contacts and Locations

Locations

Denmark

Department of Endocrinology and Internal Medicine, Aarhus University Hospital

Aarhus C, Denmark, 8000

Gentofte Hospital

Gentofte, Denmark, 2900

Department of Internal Medicine, Regionshospitalet Herning

Herning, Denmark, 7400

Department of Internal Medicine, Regionshospitalet Holstebro

Holstebro, Denmark, 7500

Department of Internal Medicine, Regionshospitalet Horsens

Horsens, Denmark, 8700

Department of Internal Medicine, Regionhospitalet Randers

Randers, Denmark, 8930

Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg

Silkeborg, Denmark, 8600

Department of Internal Medicine, Regionshospitalet Viborg

Viborg, Denmark, 8800

Sponsors and Collaborators

University of Aarhus

Aarhus University Hospital

Regionshospitalet Silkeborg

Regional Hospital Holstebro

Regionshospitalet Horsens

Randers Regional Hospital

Regionshospitalet Viborg, Skive

Herning Hospital

Investigators

• Principal Investigator: Lars Rejnmark, Professor; Aarhus University Hospital

  Study Documents (Full-Text)

Documents provided by University of Aarhus:

Study Protocol and Statistical Analysis Plan  [PDF] May 11, 2017

Informed Consent Form  [PDF] January 25, 2013

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Aarhus
• ClinicalTrials.gov Identifier: NCT02384668
• Other Study ID Numbers: 12122012
• First Posted: March 10, 2015
• Last Update Posted: September 1, 2022
• Last Verified: August 2022

Keywords provided by University of Aarhus:

Cholecalciferol; Vitamin D3; Arterial stiffness; Quality of Life; Bone density and geometry; Muscle strength and balance

Additional relevant MeSH terms:

Graves Disease; Exophthalmos; Orbital Diseases; Eye Diseases; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases; Vitamin D; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents