DAGMAR: D-vitamin And Graves' Disease; Morbidity And Relapse Reduction
Study Details
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 |
|---|---|---|
|
N/A |
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
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 Names:
|
| 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
- Proportion of participants without relapse within the first year after cessation of ATD treatment. [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
- 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 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 [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
- 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 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. [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
- Effects of D-vitamin supplementation according to plasma level of D-vitamin at inclusion to the study. [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.
- Proportion of participants without relapse within the first year after cessation of ATD treatment according to baseline use of D-vitamin. [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.
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Quality of Life as measured by Health questionnaires [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)
- Biomarkers of calcium- and bone metabolism. [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.
- Level of Thyrotropin receptor antibody (TRAb) [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)
- Level of 25 hydroxy vitamin D [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
- Immune response as measured by flow cytometric analysis of T- and B-cells [First nine months.]
In a subcohort of 50 participants blood samples will be investigated by flow cytometry. Lymphocyte subpopulations will be quantified.
- Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G) [First nine months.]
In a subcohort of 50 participants soluble HLA-G (Human Leukocyte Antigen-G) will be quantified based on blood samples.
- Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G) [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.
- Immune response assessed by qualitative analysis of regulatory T lymphocytes [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.
- Arterial stiffness as measured by tonometry [First nine months]
Indices of arterial stiffness at 3 and 9 months after randomisation in a subcohort of 80 participants
- Muscle strength and balance as measured by isometric tests and dynamic stability tests. [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
- Bone density and geometry as measured by DXA and HRpQCT scans [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
- Effect on thyroid gland size by ultrasound examination [First nine months]
Estimation of thyroid volume by ultrasound examination
- Proportion of patients with adverse reactions to anti thyroid drugs [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
- Proportion of patients with serious adverse events [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
- Effects on frequency of infectious disease as measured by use of antibiotics [From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months]
Data from the Danish prescription database
- Effects on use of Health care services as measured by hospital admissions and visits to general practitioner [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
Criteria
Inclusion Criteria:
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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:
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Previously diagnosed hyperthyroidism
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ATD treatment initiated more than 3 months prior to inclusion
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Planned ablative therapy (radioactive iodine or thyroid surgery)
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Intake of more than 10 µg D-vitamin/day that the participant wishes to continue.
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Chronic granulomatous illness
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Persistent hypercalcemia (plasma calcium > 1.40 mmol/L)
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Reduced kidney function (eGFR < 45 ml/min)
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Treatment with immunomodulatory drugs
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Active malignant disease
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Alcohol or drug abuse
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Pregnancy at inclusion
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Major comorbidity, making the participant unlikely to continuously receive trial intervention.
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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
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Department of Endocrinology and Internal Medicine, Aarhus University Hospital | Aarhus C | Denmark | 8000 | |
| 2 | Gentofte Hospital | Gentofte | Denmark | 2900 | |
| 3 | Department of Internal Medicine, Regionshospitalet Herning | Herning | Denmark | 7400 | |
| 4 | Department of Internal Medicine, Regionshospitalet Holstebro | Holstebro | Denmark | 7500 | |
| 5 | Department of Internal Medicine, Regionshospitalet Horsens | Horsens | Denmark | 8700 | |
| 6 | Department of Internal Medicine, Regionhospitalet Randers | Randers | Denmark | 8930 | |
| 7 | Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg | Silkeborg | Denmark | 8600 | |
| 8 | 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)
None provided.More Information
Publications
None provided.- 12122012