Feasibility Study of 2000 IU Per Day of Vitamin D for the Primary Prevention of Type 1 Diabetes

Study Overview
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Brief Summary
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Type 1 diabetes is a common chronic disease of childhood. It is not yet preventable. Multiple daily injections of insulin, tests of blood sugar, and careful dietary planning are required lifelong to prevent long-term complications such as blindness and kidney failure. Recent studies of potential risk factors in children with diabetes, along with studies revealing the immunologic properties of vitamin D, and experiments in animals suggest higher doses of vitamin D may prevent type 1 diabetes. For proof for human children, a randomized trial will compare groups at risk randomly assigned to receive either the usual vitamin D supplement or a higher amount, 2000 IU daily. This initial study is a small scale test of procedures.

Detailed Description
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Type 1 diabetes is a multifactorial disease with both strong genetic and non-genetic components of disease susceptibility. The uniquely strong genetic risk factor region, the human leukocyte antigen region on chromosome 6p, contributes approximately half of the genetic component and can be used for screening for diabetes risk. For example, individuals with the highest risk compound heterozygote genotype comprise 2% of the general population, but have a twenty fold increased risk for type 1 diabetes with an absolute risk of approximately 7% by age 15 years. Studies of the non-inherited component of diabetes susceptibility implicate external environmental factors operating in the first year of life, suggesting the possibility to reverse the trend with the correct intervention. Recent data suggest that the vitamin D system is a potentially important target for therapeutic intervention to prevent type 1 diabetes. These data include epidemiological studies showing that vitamin D supplementation in infancy is associated with a substantially decreased subsequent risk of the disease, and animal work in the non-obese diabetes mouse model of autoimmune diabetes showing that the incidence of autoimmune diabetes increases when the animals are nutritionally deprived of vitamin D, and that the disease can be prevented using 1,25-dihydroxyvitamin D, and non-hypercalcemic vitamin D analogues. In vitro experiments suggest that the prevention seen in NOD mice may be due to combined effects of vitamin D on antigen presenting cells and activated T-cells. Based on these epidemiological and animal model studies, we hypothesize that administration during infancy of cholecalciferol, the usual nutritional supplement form of vitamin D, at the increased dose of 2000 IU/day (instead of the current practice of 400 IU/day) will prevent type 1 diabetes in children from the general population at increased genetic risk. The main objective of this proposal is to pilot a two-arm randomized controlled trial comparing these two doses. The participants are infants from the general population identified at increased genetic risk for type 1 diabetes by cord blood or filter paper blood spot HLA class II genetic screening. The study will measure key safety, compliance and pharmacokinetic, surrogate efficacy, and process outcomes including growth parameters, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, calcium levels in blood and urine, bone mineral content and body composition by densitometry, diabetes-related autoantibodies markers for beta-cell autoimmunity, and recruitment rates for both the screening and for the intervention trial.

Official Title
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Pilot Trial of Vitamin D for the Prevention of Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Dietary Supplement: vitamin D3
* Dietary Supplement: vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HLA genotypes that increase risk of type 1 diabetes: heterozygous for DRB1*03, DQA1*0501, DQB1*0201 / DRB1*04, DQA1*03011, DQB1*0302 (DRB1*04 ≠ *0403 or related alleles), or homozygous for DRB1*03, DQA1*0501, DQB1*0201, or homozygous for DRB1*04, DQA1*03011, DQB1*0302 (DRB1*04 ≠ *0403 or related alleles). Exclusion Criteria: Premature, low birthweight, or major congenital malformations or serious chronic disease

Ages Eligible for Study
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Maximum Age: 4 Weeks

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin D-higher dose<br>Vitamin D 2000 IU per os once daily | Dietary Supplement: vitamin D3<br>* 2000 IU per day<br>* Other names: cholecalciferol;|
| Active Comparator: Vitamin D-lower dose<br>Vitamin D 400 IU per os once daily | Dietary Supplement: vitamin D3<br>* 400 IU per os once daily<br>* Other names: Cholecalciferol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in 25(OH)D from baseline | 25-hydroxyvitamin D levels | at baseline (1 month of age), 2 months of age, 6 months of age, 9 months of age, 1 year of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| renal ultrasound | to detect nephrocalcinosis | 1 year of age | 
| bone densitometry |  | at 6 months and 1 year of age | 
| diabetes autoantibody levels | GADA, ICA-512, IAA | 1 year of age | 
| recruitment and retention rates |  | 1 year of age | 
| Change from baseline in serum calcium levels |  | at baseline (1 month of age), 2 months of age, 6 months of age, 9 months of age, 1 year of age | 
| changes in urine calcium:creatinine ratio |  | monthly in the first year of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vitamin D, type 1 diabetes, prevention trial