DIVINE: Dialysis Infection and Vitamin D In New England

• ClinicalTrials.gov Identifier: NCT00892099
• Recruitment Status: Completed
• First Posted: May 4, 2009
• Results First Posted: June 8, 2015
• Last Update Posted: April 20, 2018
• Sponsor: Massachusetts General Hospital
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Ravi Thadhani, Massachusetts General Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
End Stage Renal Disease	Drug: Ergocalciferol; Other: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: DIVINE: Dialysis Infection and Vitamin D In New England
• Study Start Date: November 2009
• Actual Primary Completion Date: October 2014
• Actual Study Completion Date: October 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Serum 25D Level [ Time Frame: 12 weeks ]

Secondary Outcome Measures :

1. Serum Calcium [ Time Frame: every 4 weeks for 12 weeks ]
   serum calcium levels (mg/dL)
2. Serum Phosphate [ Time Frame: every 4 weeks for 12 weeks ]
   serum phosphate levels (mmol/L)
3. Serum 25-OH Vitamin D [ Time Frame: every 4 weeks for 12 weeks ]
   serum 25-OH vitamin D levels (ng/mL)
4. Serum 1,25(OH)2 Levels [ Time Frame: At week 12 ]
   serum 1,25(OH) vitamin D levels (pg/mL)
5. Parathyroid Hormone [ Time Frame: every 4 weeks for 12 weeks ]
   serum PTH levels (pg/mL)

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Sponsors and Collaborators

Massachusetts General Hospital

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Ravi Thadhani, MD MPH; Massachusetts General Hospital

More Information

Publications of Results:

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)

Other 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.

• Responsible Party: Ravi Thadhani, Director of Clinical Research in Nephrology, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00892099
• Other Study ID Numbers: 2009P-000398; R01DK084974 ( U.S. NIH Grant/Contract )
• First Posted: May 4, 2009
• Results First Posted: June 8, 2015
• Last Update Posted: April 20, 2018
• Last Verified: March 2018

Keywords provided by Ravi Thadhani, Massachusetts General Hospital:

end stage renal disease; hemodialysis

Additional relevant MeSH terms:

Kidney Diseases; Kidney Failure, Chronic; Urologic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Vitamin D; Ergocalciferols; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents