Paricalcitol and Endothelial Function in Chronic Kidney Disease Patients (the PENNY Study) (PENNY)

October 1, 2012 updated by: Carmine Zoccali, Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

88

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Reggio Calabria, Italy, 89124
        • Nephrology, Dialysis and Transplantation Unit

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with iPTH level > 65 pg/ml; Ca between 8.4- 10.00 mg/dL and P between 2.9-4.5
  • Negative serum pregnancy test for female subjects of childbering potential.
  • Informed consent.

Exclusion Criteria:

  • Use vitamin D supplements.
  • Altered liver function tests (bilirubin, aminotransferases and total alkaline phosphatase > 3 times the upper limit of normal ranges).
  • Sympthomatic cardiovascular disease on the basis of clinical history. Cancer.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Placebo capsules daily for 12 weeks.
Drug: placebo
Experimental: Paracalcitol
see "Intervention description" for details.
Drug: Paracalcitol
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 Names:
  • Active form of Vitamin D.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endothelial function measurement
Time Frame: 12 weeks from baseline
Endothelial-dependent and independent vasodilation was assessed by a Toshiba Nemia XG Echo-Doppler applying a 7.5 MHz transducer that was fixed by an adjustable stereotactic clamp to warrant image stability. After baseline recording (1 min) a standard sphygmomanometer was placed on the right forearm 2 cm below the elbow and the cuff was inflated to 250 mmHg for 5 min. Recordings were performed during the 4 min following cuff deflation to estimate endothelium-dependent FMD. In studies of endothelium-independent vasodilatation recording times were 1 min for the baseline assessment and 5 min for changes in arterial diameter brought about by GTN. An interval of at least 1h was set between the last FMD assessment and GTN administration. All scans were recorded, stored and analyzed off-line. FMD and GTN were computed as the maximal % increase in diameter over baseline by an automatic edge detection system.
12 weeks from baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endothelial function and plasma/serum and genetic biomarkers of bone mineral disorders in CKD (BMD-CKD) and renin angiotensin-aldosteron system (RAS).
Time Frame: 12 weeks from baseline
The investigators will analyze 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).
12 weeks from baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy

Investigators

  • Study Director: Giuseppe Curatola, MD, Nephrology, Dialysis and Transplantation Unit

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2011

Primary Completion (Actual)

August 1, 2012

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

August 30, 2012

First Submitted That Met QC Criteria

September 6, 2012

First Posted (Estimate)

September 7, 2012

Study Record Updates

Last Update Posted (Estimate)

October 2, 2012

Last Update Submitted That Met QC Criteria

October 1, 2012

Last Verified

October 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Oct2010PENNYStudy

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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