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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Graves' Disease

Intervention / Treatment
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* Dietary Supplement: Cholecalciferol
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cholecalciferol<br>Cholecalciferol 70 mcg per day Other name: Vitamin D3. | Dietary Supplement: Cholecalciferol<br>* 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.<br>* Other names: Vitamin D3;|
| Placebo Comparator: Placebo<br>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<br>* One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholecalciferol, Vitamin D3, Arterial stiffness, Quality of Life, Bone density and geometry, Muscle strength and balance