Graves' Disease
Conditions
Keywords
Cholecalciferol, Vitamin D3, Arterial stiffness, Quality of Life, Bone density and geometry, Muscle strength and balance
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.
Interventions
DIETARY_SUPPLEMENTCholecalciferol
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.
DIETARY_SUPPLEMENTPlacebo
One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol.
Sponsors
Aarhus University Hospital
Regionshospitalet Silkeborg
Regional Hospital Holstebro
Regionshospitalet Horsens
Randers Regional Hospital
Regionshospitalet Viborg, Skive
Herning Hospital
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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) |
| 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) |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
Countries
Denmark
Outcome results
None listed