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

Graves' Disease Clinical Trial

— DAGMAR  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02384668
• Other study ID #: 12122012
• Status: Completed
• Phase: N/A
• Start date: March 24, 2015
• Est. completion date: December 2020

Study information

• Verified date: August 2022
• Source: University of Aarhus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 278
• Est. completion date: December 2020
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Graves Disease
• Graves' Disease

Intervention

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.
• Placebo
One tablet per day. Placebo tablet identical in appearance to cholecalciferol tablet. Duration and cessation of treatment identical to intervention with cholecalciferol.

Locations

Country	Name	City	State
Denmark	Department of Endocrinology and Internal Medicine, Aarhus University Hospital	Aarhus C
Denmark	Gentofte Hospital	Gentofte
Denmark	Department of Internal Medicine, Regionshospitalet Herning	Herning
Denmark	Department of Internal Medicine, Regionshospitalet Holstebro	Holstebro
Denmark	Department of Internal Medicine, Regionshospitalet Horsens	Horsens
Denmark	Department of Internal Medicine, Regionhospitalet Randers	Randers
Denmark	Department of Internal Medicine, Diagnostisk Center, Regionshospitalet Silkeborg	Silkeborg
Denmark	Department of Internal Medicine, Regionshospitalet Viborg	Viborg

Sponsors (8)

Lead Sponsor	Collaborator
University of Aarhus	Aarhus University Hospital, Herning Hospital, Randers Regional Hospital, Regional Hospital Holstebro, Regionshospitalet Horsens, Regionshospitalet Silkeborg, Regionshospitalet Viborg, Skive

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Immune response as measured by flow cytometric analysis of T- and B-cells	In a subcohort of 50 participants blood samples will be investigated by flow cytometry. Lymphocyte subpopulations will be quantified.	First nine months.
Other	Immune response as measured by soluble HLA-G (Human Leukocyte Antigen-G)	In a subcohort of 50 participants soluble HLA-G (Human Leukocyte Antigen-G) will be quantified based on blood samples.	First nine months.
Other	Immune response as measured by membrane-bound HLA-G (Human Leukocyte Antigen-G)	In a subcohort of 50 participants membrane-bound HLA-G (Human Leukocyte Antigen-G) will be quantified based on expression on monocytes.	First nine months.
Other	Immune response assessed by qualitative analysis of regulatory T lymphocytes	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.	First nine months.
Other	Arterial stiffness as measured by tonometry	Indices of arterial stiffness at 3 and 9 months after randomisation in a subcohort of 80 participants	First nine months
Other	Muscle strength and balance as measured by isometric tests and dynamic stability tests.	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	First nine months
Other	Bone density and geometry as measured by DXA and HRpQCT scans	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	First nine months
Other	Effect on thyroid gland size by ultrasound examination	Estimation of thyroid volume by ultrasound examination	First nine months
Other	Proportion of patients with adverse reactions to anti thyroid drugs	Proportion of patients with adverse reactions to anti thyroid drugs measured by regular questionnaires and reported complaints and events in patient journals	From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Other	Proportion of patients with serious adverse events	Based on reports from patients journals and hospitals admissions of agranulocytosis, leukopenia, aplastic anemia, hepatitis, and vasculitis	From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Other	Effects on frequency of infectious disease as measured by use of antibiotics	Data from the Danish prescription database	From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Other	Effects on use of Health care services as measured by hospital admissions and visits to general practitioner	Measured by all cause-hospital admissions and visits to general practitioner	From randomisation until 12 months after cessation of ATD treatment, an expected average of 24 months
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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