DIVINE: Dialysis Infection and Vitamin D In New England

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.

Study Overview

• Status: Completed
• Conditions: End Stage Renal Disease
• Intervention / Treatment: Drug: Ergocalciferol; Drug: Ergocalciferol; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Ravi Thadhani, MD MPH, Massachusetts General Hospital

Publications and helpful links

General Publications

• Bhan I, Camargo CA Jr, Wenger J, Ricciardi C, Ye J, Borregaard N, Thadhani R. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol. 2011 May;127(5):1302-4.e1. doi: 10.1016/j.jaci.2010.12.1097. Epub 2011 Feb 9. No abstract available.
• Ishir Bhan, Dorothy A Dobens, Caitlin A. Trottier, Julia Beth Wenger, Hector Tamez, Joseph James Deferio, Kathryn J. Lucchesi, Ravi I. Thadhani. The DIVINE Trial: Dialysis Infection and Vitamin D in New England J. Am. Soc. Nephrol 24:2013 (Abstract: SA-PO1082)

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: April 30, 2009
• First Submitted That Met QC Criteria: May 1, 2009
• First Posted (Estimate): May 4, 2009

Study Record Updates

• Last Update Posted (Actual): April 20, 2018
• Last Update Submitted That Met QC Criteria: March 21, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: hemodialysis; end stage renal disease
• Additional Relevant MeSH Terms: Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Kidney Failure, Chronic; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: 2009P-000398; R01DK084974 (U.S. NIH Grant/Contract)