Paricalcitol and Endothelial Function in Chronic Kidney Disease Patients (the PENNY Study)
Condition: Chronic Kidney Disease.
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Study type: Interventional
Phase: Phase 3

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Paracalcitol; placebo
Intervention type(s): Drug; Drug
Intervention description(s): Patients in the experimental arm received 2 micrograms Paricalcitol capsules daily, for 12 weeks. This dose was adjusted based on clinical laboratory parameters and the maximum dose was 2 micrograms daily.
Other intervention name(s): Active form of Vitamin D.
Intervention MeSH terms: Vitamin D
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Vitamin D; Paracalcitol; Chronic kidney disease; Endothelial dysfunction; Flow mediated vasodilation