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Completed

NCT Number: NCT02384668

D-vitamin And Graves' Disease; Morbidity And Relapse Reduction

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.

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Key information

Conditions

Graves' Disease Autoimmune Diseases Endocrine System Diseases Exophthalmos Eye Diseases Goiter Graves Disease Hyperthyroidism Immune System Diseases Orbital Diseases Thyroid Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

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.

Other names: Vitamin D3

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.

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

University of Aarhus

Other

Collaborators

  • Aarhus University Hospital
  • Herning Hospital
  • Randers Regional Hospital
  • Regional Hospital Holstebro
  • Regionshospitalet Horsens
  • Regionshospitalet Silkeborg
  • Regionshospitalet Viborg, Skive

Registry information

Official study title

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

Acronym: DAGMAR

Important dates

Study start
2015
Primary completion
2020
Study completion
2020
First posted
Mar 10, 2015
Registry last updated
Sep 1, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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