DIVINE: Dialysis Infection and Vitamin D In New England

Study Overview
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Brief Summary
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Infection is the second-leading cause of death in individuals requiring dialysis treatment for kidney failure. New research suggests the high risk of infection may be due in part to low levels of vitamin D, which are extremely common in kidney disease. This study is designed to determine safe and effective ways to raise vitamin D levels while monitoring effects on the immune system.

Detailed Description
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We hypothesize that a profound deficiency of nutritional vitamin D (25-hydroxyvitamin D, 25D) in end-stage renal disease (ESRD) leads to an altered immune response, predisposing to early morbidity and mortality from infection, the second-leading cause of death in ESRD. In addition to impaired renal synthesis of the hormonal form of vitamin D (1,25-dihydroxyvitamin D; 1,25D), ESRD is accompanied by near universal insufficiency of 25D. In-vitro, ex-vivo, and retrospective human studies by our group and others suggest that 25D (and not 1,25D) is intimately linked to immune defense via alterations in the production of inflammatory cytokines and critical antimicrobial peptides including cathelicidin, which we have shown to identify ESRD subjects at risk for infection-related mortality. Ergocalciferol, which is rapidly converted to 25D, is the most widely available form of nutritional vitamin D in the US, yet guidelines to treat ESRD patients with nutritional vitamin D are absent because of limited data supporting its efficacy, safety, and biological effects in this population. To determine effective and safe doses of ergocalciferol in ESRD, we will perform a double blind placebo controlled randomized trial in 120 incident hemodialysis patients (40/arm x 3) with 25D levels < 30ng/ml, comparing two ergocalciferol dosing regimens (50,000 IU/week and 50,000 IU/month) and an identically appearing placebo. The primary outcome will be correction of vitamin D insufficiency (25D >30 ng/ml) at 12 weeks. Serum calcium and phosphate levels will be measured every 4 weeks to assess safety, and blood cytokine and cathelicidin levels will be measured every 4 weeks to determine biological responses. To examine biological effects in greater detail, a subset of subjects from each arm of the study will be further analyzed with serial macrophage gene expression profiles and whole blood cytokine profiles following ex-vivo stimulation with pro-inflammatory mediators (e.g., killed S. aureus). These experiments will inform us on how individuals with ESRD, based on their vitamin D status and the treatment they receive, may respond to infection. Laboratory measures will continue for 12 weeks. Clinical follow-up and monitoring for infection-associated events (including antibiotic use, rates of bacteremia, and sepsis) will continue for 20 weeks. This pilot trial addressing a significant unmet need in nephrology will involve basic, translational, and clinical investigators experienced in vitamin D research, infection and inflammation, and in trials involving ESRD subjects. These data will provide an important foundation for designing future clinical trials rigorously assessing the effect of nutritional vitamin D on infectious and other outcomes in ESRD.

Official Title
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DIVINE: Dialysis Infection and Vitamin D In New England

Conditions
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End Stage Renal Disease

Intervention / Treatment
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* Drug: Ergocalciferol
* Drug: Ergocalciferol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age ≥ 18 years Initiating chronic hemodialysis 3x/wk at Massachusetts General Hospital, Brigham and Women's Hospital or Beth Israel Deaconess Medical Center with planned transfer to Massachusetts chronic facility Serum 25D < 32 ng/ml Corrected serum calcium < 10.2 mg/dl Serum phosphate < 5.5 mg/dl Serum albumin > 3 g/dL Informed consent Exclusion Criteria Pregnant or breastfeeding Women of childbearing potential not practicing one of the following measures of birth control: double-barrier method, hormonal contraceptives for at least 3 months prior to and during study, monogamous relationship with vasectomized partner, total abstinence from sexual intercourse with men during study. HIV positive History of allergic reaction to ergocalciferol Investigator considers subject unsuitable for any reason

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Ergocalciferol<br>Receives 50,000 IU of ergocalciferol weekly | Drug: Ergocalciferol<br>* 50,000 IU tablet given weekly<br>* Other names: vitamin D;|
| Experimental: Low Dose Ergocalciferol<br>Receives 50,000 IU of ergocalciferol per month | Drug: Ergocalciferol<br>* 50,000 IU tablet given monthly<br>* Other names: Vitamin D;|
| Placebo Comparator: Placebo<br>Receives no ergocalciferol | Other: Placebo<br>* Placebo equivalent of ergocalciferol, given weekly as one tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum 25D Level |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Calcium | serum calcium levels (mg/dL) | every 4 weeks for 12 weeks | 
| Serum Phosphate | serum phosphate levels (mmol/L) | every 4 weeks for 12 weeks | 
| Serum 25-OH Vitamin D | serum 25-OH vitamin D levels (ng/mL) | every 4 weeks for 12 weeks | 
| Serum 1,25(OH)2 Levels | serum 1,25(OH) vitamin D levels (pg/mL) | At week 12 | 
| Parathyroid Hormone | serum PTH levels (pg/mL) | every 4 weeks for 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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end stage renal disease, hemodialysis