Peroxisome Proliferator-Activated Receptor-Gamma Activation in Peritoneal Dialysis Patients (PPAR)

Targeting Peroxisome Proliferator-Activated Receptor-Gamma in Peritoneal Dialysis Patients - Will it Reduce Inflammation, Atherosclerosis, Calcification and Improve Survival of Peritoneal Dialysis Patients? (PROOF Trial)

To study whether peroxisome proliferator-activated receptor-gamma activation in peritoneal dialysis patients will reduce inflammation, atherosclerosis, calcification and improve survival of peritoneal dialysis patients

Study Overview

• Status: Completed
• Conditions: End-stage Renal Disease
• Intervention / Treatment: Drug: Pioglitazone; Drug: placebo comparator

Detailed Description

Peritoneal dialysis patients are at increased risk of cardiovascular morbidity and mortality and are related to the presence of accelerated atherosclerosis. Other than the traditional cardiovascular risk factors, there is increasing evidence that inflammation is associated with the development of atherosclerosis and cardiovascular events in both the general and dialysis population. C-reactive protein is predictive of higher all-cause mortality and cardiovascular mortality, independent of other cardiovascular risk factors and atherosclerotic vascular disease. As a considerable proportion of peritoneal dialysis patients showed elevated C-reactive protein, it raises an important question as to whether lowering C-reactive protein will have any cardiovascular and survival benefit in these patients. On the other hand, insulin resistance with associated hyperinsulinemia is frequently observed in chronic renal failure and dialysis patients. Although the exact mechanism of insulin resistance needs further evaluation, studies indicated that insulin resistance is an important cardiovascular risk factor and outcome predictor in the general and dialysis population. Moreover, recent evidence indicates an association between chronic inflammation and insulin resistance although the exact interrelationship remains unclear. The peroxisome proliferator-activated receptor-gamma (PPAR-g) is a member of the nuclear receptor family of ligand-dependent transcription factors. PPAR-g is highly expressed in adipose tissue and clinical study has confirmed efficacy of the specific ligands for PPAR-gamma, namely thiazolidinediones (TZD), in improving insulin sensitivity. Recent experimental and clinical studies demonstrated that TZD has anti-inflammatory and anti-atherosclerotic properties other than insulin sensitizing effect in type 2 diabetics. We hypothesize that modulation of the PPAR-g activity may be a novel therapeutic strategy for reducing inflammation and improving insulin sensitivity and may retard the progression of atherosclerosis and possibly reduce mortality of our peritoneal dialysis patients.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong, 0000
    • Queen Mary Hospital, Tung Wah Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Both prevalent patients or patients newly started on continuous peritoneal dialysis, with or without diabetes mellitus will be considered eligible for study entry.
• For patients newly started on chronic peritoneal dialysis, they will be suitable for recruitment into the study after one month on peritoneal dialysis.
• Patients who provide informed consent for the study

Exclusion Criteria:

• Patients with underlying active malignancy
• Patients with chronic liver disease or liver cirrhosis
• Patients with active infections
• Patients with other chronic active inflammatory disease such as systemic lupus erythematosus, rheumatoid arthritis
• Patients who refuse study participation
• Patients with underlying congenital heart disease or rheumatic heart disease
• Patients with poor general condition
• Patients with plans for living related kidney transplant within 2 years
• Female patients with pregnancy
• Patients with history of recurrent hypoglycemia
• Patients with Class III and IV congestive heart failure
• Patients already receiving glitazones treatment at the screening visit

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active intervention arm; Peroxisome proliferator activator receptor gamma treatment, Pioglitazone	Drug: Pioglitazone; pioglitazone 15mg daily for 12 weeks, then 30mg daily for 84 weeks; Other Names: Actos
Placebo Comparator: placebo pill; placebo comparator	Drug: placebo comparator; 1 capsule daily, 96 weeks.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in carotid intima-media thickness	Change in carotid intima-media thickness	over 48 weeks
change in flow mediated dilatation (marker of endothelial function)	change in flow mediated dilatation (marker of endothelial function)	over 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in aortic pulse wave velocity	change in aortic pulse wave velocity	over 96 weeks
change in augmentation index-heart rate adjusted	change in augmentation index-heart rate adjusted	over 96 weeks
change in nitroglycerin-mediated dilatation	change in nitroglycerin-mediated dilatation	over 48 weeks
change in coronary artery calcium score	change in coronary artery calcium score	over 96 weeks
change in heart valves calcium score	change in heart valves calcium score	over 96 weeks
change in carotid artery calcium score	change in carotid artery calcium score	over 96 weeks
change in abdominal visceral fat	change in abdominal visceral fat	over 96 weeks
change in subcutaneous fat	change in subcutaneous fat	over 96 weeks
change in blood pressure	change in blood pressure	over 96 weeks
change in C-reactive protein	change in C-reactive protein	over 96 weeks
change in residual kidney function	change in residual kidney function	over 96 weeks
change in HOMA index (among those not on insulin)	Change in insulin resistance index	over 96 weeks
change in D/P creatinine ratio	Change in peritoneal solute transport parameter	over 96 weeks
change in peritoneal ultrafiltration with 2.5% during PET	Change in peritoneal ultrafiltration volume	over 96 weeks
change in handgrip strength	change in handgrip strength	over 96 weeks
Change in cardiac biomarkers	change in cardiac biomarkers	over 96 weeks
change in insulin dose (among those on insulin)	change in insulin dose	over 96 weeks
change in endothelial progenitor cells	change in endothelial progenitor cells	over 96 weeks
change in central systolic blood pressure	change in central systolic blood pressure	over 96 weeks
Change in central diastolic blood pressure	change in central diastolic blood pressure	over 96 weeks
change in glycemic control (fasting glucose, and glycosylated hemoglobin)	change in glycemic control	over 96 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	Hard outcome	over 96 weeks
major adverse cardiovascular event-free survival	hard outcome	over 96 weeks
Fluid overload/heart failure event-free survival	hard outcome	over 96 weeks
myocardial infarction event-free survival	hard outcome	over 96 weeks
3 point major adverse cardiovascular event-free survival	Hard outcome	over 96 weeks
4 point major adverse cardiovascular event-free survival	Hard outcome	over 96 weeks

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: Baxter Healthcare Corporation
• Investigators: Principal Investigator: Angela YM Wang, MD, PhD, FRCP, University of Hong Kong, Queen Mary Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2006
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: September 1, 2008
• First Submitted That Met QC Criteria: September 2, 2008
• First Posted (Estimate): September 3, 2008

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 1, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: peritoneal dialysis, cardiovascular, PPAR-gamma
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Pioglitazone
• Other Study ID Numbers: A111-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No