search
Back to results

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

Primary Purpose

Graves' Disease

Status
Completed
Phase
Not Applicable
Locations
Denmark
Study Type
Interventional
Intervention
Cholecalciferol
Placebo
Sponsored by
University of Aarhus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graves' Disease focused on measuring Cholecalciferol, Vitamin D3, Arterial stiffness, Quality of Life, Bone density and geometry, Muscle strength and balance

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Department of Endocrinology and Internal Medicine, Aarhus University Hospital
  • Gentofte Hospital
  • Department of Internal Medicine, Regionshospitalet Herning
  • Department of Internal Medicine, Regionshospitalet Holstebro
  • Department of Internal Medicine, Regionshospitalet Horsens
  • Department of Internal Medicine, Regionhospitalet Randers
  • Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg
  • Department of Internal Medicine, Regionshospitalet Viborg

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Cholecalciferol

Placebo

Arm Description

Cholecalciferol 70 mcg per day Other name: Vitamin D3.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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
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.
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
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.
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.
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)
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)
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)
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)
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)
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)
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)
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.
Level of Thyrotropin receptor antibody (TRAb)
Level of TRAb at 3 and 9 months and at end of study period (maximum of 36 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)

Full Information

First Posted
January 9, 2015
Last Updated
August 26, 2022
Sponsor
University of Aarhus
Collaborators
Aarhus University Hospital, Regionshospitalet Silkeborg, Regional Hospital Holstebro, Regionshospitalet Horsens, Randers Regional Hospital, Regionshospitalet Viborg, Skive, Herning Hospital
search

1. Study Identification

Unique Protocol Identification Number
NCT02384668
Brief Title
D-vitamin And Graves' Disease; Morbidity And Relapse Reduction
Acronym
DAGMAR
Official Title
The DAGMAR Study. D-vitamin And Graves' Disease; Morbidity And Relapse Reduction: A Randomised, Clinical Trial.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2022
Overall Recruitment Status
Completed
Study Start Date
March 24, 2015 (Actual)
Primary Completion Date
December 2020 (Actual)
Study Completion Date
December 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
Collaborators
Aarhus University Hospital, Regionshospitalet Silkeborg, Regional Hospital Holstebro, Regionshospitalet Horsens, Randers Regional Hospital, Regionshospitalet Viborg, Skive, Herning Hospital

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graves' Disease
Keywords
Cholecalciferol, Vitamin D3, Arterial stiffness, Quality of Life, Bone density and geometry, Muscle strength and balance

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
278 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cholecalciferol
Arm Type
Active Comparator
Arm Description
Cholecalciferol 70 mcg per day Other name: Vitamin D3.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Cholecalciferol
Other Intervention Name(s)
Vitamin D3
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol.
Primary Outcome Measure Information:
Title
Proportion of participants without relapse within the first year after cessation of ATD treatment.
Description
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.
Time Frame
0-12 months after cessation of ATD treatment
Secondary Outcome Measure Information:
Title
The proportion of participants who has been referred to radioactive iodine or thyroid surgery at any time during the entire intervention period.
Description
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
Title
The proportion of participants who have relapse of hyperthyroidism (TSH<0.1) after cessation of ATD therapy
Description
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
Title
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.
Description
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
Title
The proportion of participants who fails to stop ATD treatment within 24 months after initiation of ATD therapy.
Description
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
Time Frame
0-24 months after initiation of ATD therapy
Title
Effects of D-vitamin supplementation according to plasma level of D-vitamin at inclusion to the study.
Description
Sub analysis of all primary and secondary outcome measures will be performed according to this criteria.
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Proportion of participants without relapse within the first year after cessation of ATD treatment according to baseline use of D-vitamin.
Description
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.
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
6 weeks
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
3 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
6 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
9 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
12 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
18 months
Title
Quality of Life as measured by Health questionnaires
Description
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)
Time Frame
24 months
Title
Biomarkers of calcium- and bone metabolism.
Description
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.
Time Frame
3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Level of Thyrotropin receptor antibody (TRAb)
Description
Level of TRAb at 3 and 9 months and at end of study period (maximum of 36 months)
Time Frame
3 months, 9 months and 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Level of 25 hydroxy vitamin D
Description
Level of 25 hydroxy vitamin D at 3 and 9 months and at end of study period (maximum of 36 months)
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Other Pre-specified Outcome Measures:
Title
Immune response as measured by flow cytometric analysis of T- and B-cells
Description
In a subcohort of 50 participants blood samples will be investigated by flow cytometry. Lymphocyte subpopulations will be quantified.
Time Frame
First nine months.
Title
Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G)
Description
In a subcohort of 50 participants soluble HLA-G (Human Leukocyte Antigen-G) will be quantified based on blood samples.
Time Frame
First nine months.
Title
Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G)
Description
In a subcohort of 50 participants membrane-bound HLA-G (Human Leukocyte Antigen-G) will be quantified based on expression on monocytes.
Time Frame
First nine months.
Title
Immune response assessed by qualitative analysis of regulatory T lymphocytes
Description
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.
Time Frame
First nine months.
Title
Arterial stiffness as measured by tonometry
Description
Indices of arterial stiffness at 3 and 9 months after randomisation in a subcohort of 80 participants
Time Frame
First nine months
Title
Muscle strength and balance as measured by isometric tests and dynamic stability tests.
Description
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
Time Frame
First nine months
Title
Bone density and geometry as measured by DXA and HRpQCT scans
Description
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
Time Frame
First nine months
Title
Effect on thyroid gland size by ultrasound examination
Description
Estimation of thyroid volume by ultrasound examination
Time Frame
First nine months
Title
Proportion of patients with adverse reactions to anti thyroid drugs
Description
Proportion of patients with adverse reactions to anti thyroid drugs measured by regular questionnaires and reported complaints and events in patient journals
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Proportion of patients with serious adverse events
Description
Based on reports from patients journals and hospitals admissions of agranulocytosis, leukopenia, aplastic anemia, hepatitis, and vasculitis
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Effects on frequency of infectious disease as measured by use of antibiotics
Description
Data from the Danish prescription database
Time Frame
From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Title
Effects on use of Health care services as measured by hospital admissions and visits to general practitioner
Description
Measured by all cause-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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lars Rejnmark, Professor
Organizational Affiliation
Aarhus University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Endocrinology and Internal Medicine, Aarhus University Hospital
City
Aarhus C
ZIP/Postal Code
8000
Country
Denmark
Facility Name
Gentofte Hospital
City
Gentofte
ZIP/Postal Code
2900
Country
Denmark
Facility Name
Department of Internal Medicine, Regionshospitalet Herning
City
Herning
ZIP/Postal Code
7400
Country
Denmark
Facility Name
Department of Internal Medicine, Regionshospitalet Holstebro
City
Holstebro
ZIP/Postal Code
7500
Country
Denmark
Facility Name
Department of Internal Medicine, Regionshospitalet Horsens
City
Horsens
ZIP/Postal Code
8700
Country
Denmark
Facility Name
Department of Internal Medicine, Regionhospitalet Randers
City
Randers
ZIP/Postal Code
8930
Country
Denmark
Facility Name
Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg
City
Silkeborg
ZIP/Postal Code
8600
Country
Denmark
Facility Name
Department of Internal Medicine, Regionshospitalet Viborg
City
Viborg
ZIP/Postal Code
8800
Country
Denmark

12. IPD Sharing Statement

Citations:
PubMed Identifier
35018442
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.
Results Reference
derived
PubMed Identifier
31910101
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.
Results Reference
derived
PubMed Identifier
31280470
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.
Results Reference
derived

Learn more about this trial

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

We'll reach out to this number within 24 hrs