Chronic Kidney Disease. Clinical Trial
Official title:
Effect of Paricalcitol on Endothelial Function in Chronic Kidney Disease (CKD) Patients (the PENNY Study)
The primary aim of this study was to test the hypothesis that Paricalcitol, an active form of vitamin D, improved endothelial function in stage 3-4 chronic kidney disease (CKD) patients. A secondary aim of this trial was to study the relationship between endothelial function and plasma/serum and genetic biomarkers of bone mineral disorders in CKD (BMD-CKD) and renin angiotensin-aldosteron system (RAS) (angiotensin II and plasma renin activity).
Primary objective: Test the hypothesis that Paricalcitol, an active form of vitamin D
improves endothelial function in stage 3-4 chronic kidney disease (CKD) patients.
Secondary analysis: Study the relationship between endothelial function and plasma/serum and
genetic biomarkers of bone mineral disorders in CKD (BMD-CKD) and renin
angiotensin-aldosteron system (RAS) (angiotensin II and plasma renin activity).
Background:
Endothelial function is altered in patients with CKD. Factors responsible for disturbed
endothelium-dependent vasodilatation in CKD include reduced bioactivity of the nitric oxide
(NO) pathway with decreased endothelial NO synthase (NOS) activity or inhibition via
accumulation of endogenous inhibitors. In patients with CKD and in those on dialysis serum
25(OH)D3 and 1,25(OH)2D3 levels are associated with FMD. Vitamin D receptors and 1
-hydroxylase activity are present in endothelial and vascular smooth muscle cells and
1,25(OH)2D3 stimulates vascular endothelial growth factor and prostacyclin production by
vascular smooth muscle cells. These biological observations may have clinical implications
because paricalcitol treatment predicts longer survival in ESRD patients and very recent
data link vitamin D to progression to ESRD in patients with stage 3-5 CKD. Furthermore, a
previous study by us has shown that the BMSI polymorphism of the vitamin D receptor gene is
associated with LVH and LVH progression in ESRD patients.
Study population: Patients with stage 3-4 CKD of both sexes in the age range 18-80 years.
Patients taking vitamin D supplements, with abnormal liver function tests, symptomatic
cardiovascular disease, diabetes or cancer and those whose medications changed during the
study were excluded.
Design and Methods: The study was a double-blind, randomized, parallel groups trial. After
baseline measurements, patients with iPTH level > 65 pg/ml; Ca between 8.4- 10.00 mg/dL and
P between 2.9-4.5 were randomized to receive 2 micrograms Paricalcitol capsules (or matching
placebo) daily, for 12 weeks. This doses was adjusted based on clinical laboratory
parameters and the maximum dose was 2 micrograms daily.
During the study if a subject experienced over suppression of serum iPTH (defined as a serum
iPTH <15 pg/mL), or hypercalcemia (defined as Ca > 11.0 mg/dL), the subject continued to
take study drug at reduced dosage 1 mcg any other day and returned in 2 weeks for an
unscheduled visit. If the values from the unscheduled visit serum iPTH and/or Ca did not
returned to > 15 pg/mL and/or <11.0 mg/dL, respectively, the drug was discontinued.
Flow mediated vasodilatation was measured according to a validated protocol developed at the
coordinating center of a national (Italian)working group of vascular function testing.
Primary end-point: Change in Flow Mediated Dilatation (FMD) induced by Paricalcitol in
comparison to Placebo.
Study power: To detect a 2% difference (standard deviation: ± 3.0%) in the change in FMD
between Paracalcitol treated and untreated patients with a power of 80 %, a confidence level
using a two-tailed test of 5% and a potential attrition rate of 15%, at least 44 patients
per group were required (88 patients in total).
Statistical analysis: Data will be summarized as mean ± standard deviation (normally
distributed data), median and inter-quartile range (non normally distributed data) or as
percent frequency, and comparison between groups will be made by independent T-Test,
Mann-Whitney Test, or Chi Square test, as appropriate. Within patients comparisons will be
done by statistical tests for paired observations. Data analysis of the primary outcome will
be performed by comparing the changes in FMD in Paracalcitol treated and untreated patients
by using the T-Test for independent observations. Possible differences in risk factors at
baseline not controlled by randomization (i.e. differences due to chance) will be accounted
for by using multivariate regression analyses.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT02074618 -
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|
N/A | |
| Withdrawn |
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Phase 4 |