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DIVINE: Dialysis Infection and Vitamin D In New England

Sponsor
Massachusetts General Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT00892099
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
105
Enrollment
3
Locations
3
Arms
59
Duration (Months)
35
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

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
N/A

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
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 :
Nov 1, 2009
Actual Primary Completion Date :
Oct 1, 2014
Actual Study Completion Date :
Oct 1, 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 Names:
  • vitamin D

    		•
    Experimental: Low Dose Ergocalciferol

    Receives 50,000 IU of ergocalciferol per month

    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

    Outcome Measures

    Primary Outcome Measures

    1. Serum 25D Level [12 weeks]

    Secondary Outcome Measures

    1. Serum Calcium [every 4 weeks for 12 weeks]

      serum calcium levels (mg/dL)

    2. Serum Phosphate [every 4 weeks for 12 weeks]

      serum phosphate levels (mmol/L)

    3. Serum 25-OH Vitamin D [every 4 weeks for 12 weeks]

      serum 25-OH vitamin D levels (ng/mL)

    4. Serum 1,25(OH)2 Levels [At week 12]

      serum 1,25(OH) vitamin D levels (pg/mL)

    5. Parathyroid Hormone [every 4 weeks for 12 weeks]

      serum PTH levels (pg/mL)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02114
    2 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02115
    3 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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Ravi Thadhani, Director of Clinical Research in Nephrology, Massachusetts General Hospital
    ClinicalTrials.gov Identifier:
    NCT00892099
    Other Study ID Numbers:
    • 2009P-000398
    • R01DK084974
    First Posted:
    May 4, 2009
    Last Update Posted:
    Apr 20, 2018
    Last Verified:
    Mar 1, 2018
    Keywords provided by Ravi Thadhani, Director of Clinical Research in Nephrology, Massachusetts General Hospital
    end stage renal disease
    hemodialysis
    Additional relevant MeSH terms:
    Kidney Diseases
    Kidney Failure, Chronic
    Vitamin D
    Ergocalciferols
    Cholecalciferol
    Vitamins

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Period Title: Overall Study
    STARTED 36 33 36
    COMPLETED 31 32 29
    NOT COMPLETED 5 1 7

    Baseline Characteristics

    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo Total
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet Total of all reporting groups
    Overall Participants 36 33 36 105
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    53
    (17)
    58
    (16)
    59
    (17)
    57
    (17)
    Sex: Female, Male (Count of Participants)
    Female
    11
    30.6%
    5
    15.2%
    7
    19.4%
    23
    21.9%
    Male
    25
    69.4%
    28
    84.8%
    29
    80.6%
    82
    78.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    4
    11.1%
    5
    15.2%
    6
    16.7%
    15
    14.3%
    Not Hispanic or Latino
    32
    88.9%
    28
    84.8%
    30
    83.3%
    90
    85.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    2
    6.1%
    4
    11.1%
    6
    5.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    13
    36.1%
    9
    27.3%
    9
    25%
    31
    29.5%
    White
    23
    63.9%
    21
    63.6%
    22
    61.1%
    66
    62.9%
    More than one race
    0
    0%
    1
    3%
    1
    2.8%
    2
    1.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    25(OH) vitamin D (ng/ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ng/ml]
    21.8
    (7)
    22.3
    (6.5)
    21.7
    (7.3)
    21.9
    (6.9)

    Outcome Measures

    1. Primary Outcome
    Title Serum 25D Level
    Description
    Time Frame 12 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Mean (Standard Deviation) [ng/ml]
    49.8
    (2.3)
    38.3
    (2.4)
    27.3
    (2.3)
    2. Secondary Outcome
    Title Serum Calcium
    Description serum calcium levels (mg/dL)
    Time Frame every 4 weeks for 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Subject receiving treatment
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Visit 1
    8.8
    (0.1)
    8.7
    (0.1)
    8.8
    (0.1)
    Visit 2
    9.1
    (0.1)
    8.9
    (0.1)
    9.0
    (0.1)
    Visit 3
    9.3
    (0.1)
    9.1
    (0.1)
    9.3
    (0.1)
    Visit 4
    9.1
    (0.1)
    9.1
    (0.1)
    9.1
    (0.1)
    3. Secondary Outcome
    Title Serum Phosphate
    Description serum phosphate levels (mmol/L)
    Time Frame every 4 weeks for 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Subject receiving treatment
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Visit 1
    4.2
    (0.2)
    4.2
    (0.2)
    4.1
    (0.2)
    Visit 2
    4.7
    (0.3)
    4.7
    (0.3)
    4.8
    (0.3)
    Visit 3
    4.9
    (0.3)
    5.2
    (0.3)
    5
    (0.4)
    Visit 4
    4.7
    (0.3)
    5.4
    (0.3)
    4.9
    (0.3)
    4. Secondary Outcome
    Title Serum 25-OH Vitamin D
    Description serum 25-OH vitamin D levels (ng/mL)
    Time Frame every 4 weeks for 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Subject receiving treatment
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Visit 1
    21.8
    (1.2)
    21.7
    (1.2)
    22.3
    (1.2)
    Visit 2
    42.2
    (2.0)
    33.6
    (2)
    27.6
    (1.9)
    Visit 3
    48.9
    (2.2)
    35.6
    (2.2)
    27
    (2.1)
    Visit 4
    49.8
    (2.3)
    38.3
    (2.4)
    27.4
    (2.3)
    5. Secondary Outcome
    Title Serum 1,25(OH)2 Levels
    Description serum 1,25(OH) vitamin D levels (pg/mL)
    Time Frame At week 12

    Outcome Measure Data

    Analysis Population Description
    Subject receiving treatment
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Median (Inter-Quartile Range) [pg/mL]
    95
    100
    120
    6. Secondary Outcome
    Title Parathyroid Hormone
    Description serum PTH levels (pg/mL)
    Time Frame every 4 weeks for 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Subject receiving treatment
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    Measure Participants 36 33 36
    Visit 1
    281
    (1)
    214
    (1)
    243
    (1)
    Visit 2
    253
    (1)
    195
    (1)
    243
    (1)
    Visit 3
    255
    (1)
    195
    (1)
    196
    (1)
    Visit 4
    245
    (1.1)
    216
    (1)
    215
    (1)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Arm/Group Description Receives 50,000 IU of ergocalciferol weekly Ergocalciferol: 50,000 IU tablet given weekly Receives 50,000 IU of ergocalciferol per month Ergocalciferol: 50,000 IU tablet given monthly Receives no ergocalciferol Placebo: Placebo equivalent of ergocalciferol, given weekly as one tablet
    All Cause Mortality
    High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/36 (0%) 0/33 (0%) 0/36 (0%)
    Other (Not Including Serious) Adverse Events
    High Dose Ergocalciferol Low Dose Ergocalciferol Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 33/36 (91.7%) 26/33 (78.8%) 28/36 (77.8%)
    Cardiac disorders
    Cardiovascular 6/36 (16.7%) 6 2/33 (6.1%) 2 3/36 (8.3%) 3
    Fluid overload 1/36 (2.8%) 1 0/33 (0%) 0 2/36 (5.6%) 2
    Hypotension 0/36 (0%) 0 3/33 (9.1%) 3 2/36 (5.6%) 2
    Hypertension 1/36 (2.8%) 1 0/33 (0%) 0 0/36 (0%) 0
    Endocrine disorders
    Elevated PTH 6/36 (16.7%) 6 2/33 (6.1%) 2 4/36 (11.1%) 4
    Gastrointestinal disorders
    Constipation 2/36 (5.6%) 2 0/33 (0%) 0 1/36 (2.8%) 1
    Nausea/vomiting/diarrhea 2/36 (5.6%) 2 4/33 (12.1%) 4 3/36 (8.3%) 3
    General disorders
    Other 4/36 (11.1%) 4 2/33 (6.1%) 2 2/36 (5.6%) 2
    Infections and infestations
    Infection 11/36 (30.6%) 11 11/33 (33.3%) 11 8/36 (22.2%) 8
    Metabolism and nutrition disorders
    Low albumin 0/36 (0%) 0 0/33 (0%) 0 1/36 (2.8%) 1
    Musculoskeletal and connective tissue disorders
    Fall 3/36 (8.3%) 3 3/33 (9.1%) 3 1/36 (2.8%) 1
    Renal and urinary disorders
    Elevated phosphorus 13/36 (36.1%) 13 13/33 (39.4%) 13 15/36 (41.7%) 15
    Elevated calcium 2/36 (5.6%) 2 1/33 (3%) 1 1/36 (2.8%) 1
    Elevated potassium 0/36 (0%) 0 0/33 (0%) 0 3/36 (8.3%) 3
    Elevated white blood count 0/36 (0%) 0 0/33 (0%) 0 1/36 (2.8%) 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory 3/36 (8.3%) 3 2/33 (6.1%) 2 3/36 (8.3%) 3
    Surgical and medical procedures
    Hospitalization 14/36 (38.9%) 14 11/33 (33.3%) 11 13/36 (36.1%) 13

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Ishir Bhan
    Organization Massachusetts General Hospital
    Phone 617-726-3934
    Email ibhan@mgh.harvard.edu
    Responsible Party:
    Ravi Thadhani, Director of Clinical Research in Nephrology, Massachusetts General Hospital
    ClinicalTrials.gov Identifier:
    NCT00892099
    Other Study ID Numbers:
    • 2009P-000398
    • R01DK084974
    First Posted:
    May 4, 2009
    Last Update Posted:
    Apr 20, 2018
    Last Verified:
    Mar 1, 2018