Heart Failure
Conditions
Keywords
Vitamin D, Systolic failure, Genomics, Biomarkers, Exercise, Quality of Life
Brief summary
The central objective of this proposal is to establish that vitamin D supplementation in heart failure patients with low vitamin D levels will have improved outcomes compared to placebo. In addition the investigators will also evaluate the role of genetics in regard to vitamin D and heart failure. The investigators will be evaluating what is currently a novel approach of identifying patients with low vitamin D and treating this low vitamin D level. The investigators will be able to evaluate the importance of vitamin D supplementation in these patients and the role of genetics on our defined outcomes.
Detailed description
Primary Objective To determine how rapid vitamin D supplementation affects biomarkers and submaximal exercise capacity in systolic HF patients with low vitamin D status. Working Hypothesis 1: HF patients when supplemented with vitamin D for 6 months will have lower measures of inflammation and extracellular-matrix remodeling compared with placebo. Working Hypothesis 2: HF patients when supplemented with vitamin D for 6 months will have longer 6-minute walk length compared with placebo. Secondary Objectives To establish a relationship between the CYP2R1 variant and surrogate markers in systolic HF patients. Working Hypothesis 3: HF patients with the CYP2R1 G allele will have higher measures of inflammation and extracellular-matrix remodeling compared to AA subjects. This relationship will also be seen in subjects with the CYP2R1 TagSNP variants. Working Hypothesis 4: HF patients with CYP2R1 variant alleles will have shorter 6-minute walk length compared to subjects without these variants. To genotype HF subjects for the VDR variants and additional tag SNPs, to ascertain the relationship between VDR genetic variation and surrogate markers in systolic HF patients. Working Hypothesis 5: HF patients with VDR variants will have greater measures of inflammation and extracellular-matrix remodeling compared to subjects without VDR variants. Working Hypothesis 6: HF patients with VDR variants will have a shorter 6-minute walk length compared to subjects without these variants.
Interventions
DRUGVitamin D3
Vitamin D supplementation will be an oral load of 100,000 IU then 2000 IU by mouth daily of vitamin D3 (cholecalciferol)for 6 months
DRUGPlacebo
A placebo loading dose will be given followed by 2 placebo tablets daily for 6 months.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HF patients with LV systolic dysfunction of ischemic or non-ischemic origin and an LVEF \<40% using nuclear ventriculography or echocardiography within the last 6 months. * Attempts should have been made at optimizing medical therapy and the participant should be stable on these medications for at least 3 months. * Patients with a 25(OH)D level between 10-25 ng/ml
Exclusion criteria
* Inability to give informed consent * Patients with sarcoidosis or other granulomatous disease that can alter vitamin D metabolism * Patients with primary valvular HF, hypertrophic cardiomyopathy, and drug-induced HF * Renal dysfunction defined as serum creatinine \> 2.5 mg/dl * Pregnant women * Patients \<18 years of age * Patients on vitamin D supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biomarkers | 6 months | Biomarkers - C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), propeptide procollagen type I, plasma procollagen III, matrix metalloproteinase 2 (MMP-2), MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exercise Capacity Measured by 6 Minute Walk Test | 6 months | — |
| Quality of Life Measured by Kansas City Cardiomyopathy Questionnaire | 6 months | Kansas City Cardiomyopathy Questionnaire for quality of life is measured on a scale of 0 - 100, with 100 being best. |
| Vitamin D Genomics | Baseline | Genotyped for the restricted fragment length polymorphism at the BsmI site. In addition CYP2R1, CYP27B1, CYP24 will also be genotyped. |
Countries
United States
Participant flow
Pre-assignment details
16 consented participants were not randomized due to screen fails.
Participants by arm
| Arm | Count |
|---|---|
| Vitamin D Vitamin D supplementation will be an oral load of 100,000 IU then 2000 IU by mouth daily of vitamin D3 (cholecalciferol)for 6 months
Vitamin D3: Vitamin D supplementation will be an oral load of 100,000 IU then 2000 IU by mouth daily of vitamin D3 (cholecalciferol)for 6 months | 6 |
| Placebo A placebo loading dose will be given followed by two placebo tablets daily for 6 months.
Placebo: A placebo loading dose will be given followed by 2 placebo tablets daily for 6 months. | 6 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | LVAD Placement | 0 | 2 |
Baseline characteristics
| Characteristic | Vitamin D | Placebo | Total |
|---|---|---|---|
| Age, Customized 46 - 78 Years | 6 participants | 6 participants | 12 participants |
| Baseline Vit D level (ng/mL) | 16.3 ng/mL STANDARD_DEVIATION 5 | 19.6 ng/mL STANDARD_DEVIATION 3 | 17.8 ng/mL STANDARD_DEVIATION 4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 6 | 0 / 6 |
| serious Total, serious adverse events | 2 / 6 | 0 / 6 |
Outcome results
Primary
Biomarkers
Biomarkers - C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), propeptide procollagen type I, plasma procollagen III, matrix metalloproteinase 2 (MMP-2), MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1).
Time frame: 6 months
Population: Because enrollment was less than 30% of original goal (6 vs 4 subjects) and therefore would not have scientific validity and would be a waste of financial resources, this outcome was not analyzed.
Secondary
Exercise Capacity Measured by 6 Minute Walk Test
Time frame: 6 months
Population: Because enrollment was less than 30% of original goal (6 vs 4 patients) and therefore would not have scientific validity and no conclusions could be determined, this outcome was not analyzed.
Secondary
Quality of Life Measured by Kansas City Cardiomyopathy Questionnaire
Kansas City Cardiomyopathy Questionnaire for quality of life is measured on a scale of 0 - 100, with 100 being best.
Time frame: 6 months
Population: Because enrollment was less than 30% of original goal (6 vs 4 patients) and therefore would not have scientific validity and no conclusions could be determined, this outcome was not analyzed.
Secondary
Vitamin D Genomics
Genotyped for the restricted fragment length polymorphism at the BsmI site. In addition CYP2R1, CYP27B1, CYP24 will also be genotyped.
Time frame: Baseline
Population: Because enrollment was less than 30% of original goal (6 vs 4 patients) and therefore would not have scientific validity, in addition there is significant time and costs associated with this measurement which would result in data that would lead to no conclusions, this outcome was not analyzed.