Clinical trial NCT00745225: Peroxisome Proliferator-Activated Receptor-Gamma Activation in Peritoneal Dialysis Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: End-stage Renal Disease
Keywords: peritoneal dialysis, cardiovascular, PPAR-gamma
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Baxter Healthcare Corporation
First posted: 2008-09-03
Enrollment: 160
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind randomized placebo-controlled trial
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in carotid intima-media thickness
timeFrame: over 48 weeks
measure: change in flow mediated dilatation (marker of endothelial function)
timeFrame: over 48 weeks
Secondary outcomes:
measure: change in aortic pulse wave velocity
timeFrame: over 96 weeks
measure: change in augmentation index-heart rate adjusted
timeFrame: over 96 weeks
measure: change in nitroglycerin-mediated dilatation
timeFrame: over 48 weeks
measure: change in coronary artery calcium score
timeFrame: over 96 weeks
measure: change in heart valves calcium score
timeFrame: over 96 weeks
measure: change in carotid artery calcium score
timeFrame: over 96 weeks
measure: change in abdominal visceral fat
timeFrame: over 96 weeks
measure: change in subcutaneous fat
timeFrame: over 96 weeks
measure: change in blood pressure
timeFrame: over 96 weeks
measure: change in C-reactive protein
timeFrame: over 96 weeks
measure: change in residual kidney function
timeFrame: over 96 weeks
measure: change in HOMA index (among those not on insulin)
timeFrame: over 96 weeks
measure: change in D/P creatinine ratio
timeFrame: over 96 weeks
measure: change in peritoneal ultrafiltration with 2.5% during PET
timeFrame: over 96 weeks
measure: change in handgrip strength
timeFrame: over 96 weeks
measure: Change in cardiac biomarkers
timeFrame: over 96 weeks
measure: change in insulin dose (among those on insulin)
timeFrame: over 96 weeks
measure: change in endothelial progenitor cells
timeFrame: over 96 weeks
measure: change in central systolic blood pressure
timeFrame: over 96 weeks
measure: Change in central diastolic blood pressure
timeFrame: over 96 weeks
measure: change in glycemic control (fasting glucose, and glycosylated hemoglobin)
timeFrame: over 96 weeks
Other outcomes:
measure: overall survival
timeFrame: over 96 weeks
measure: major adverse cardiovascular event-free survival
timeFrame: over 96 weeks
measure: Fluid overload/heart failure event-free survival
timeFrame: over 96 weeks
measure: myocardial infarction event-free survival
timeFrame: over 96 weeks
measure: 3 point major adverse cardiovascular event-free survival
timeFrame: over 96 weeks
measure: 4 point major adverse cardiovascular event-free survival
timeFrame: over 96 weeks
Locations:
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital, Tung Wah Hospital
Study officials:
affiliation: University of Hong Kong, Queen Mary Hospital
name: Angela YM Wang, MD, PhD, FRCP
role: PRINCIPAL_INVESTIGATOR
References: