The Use of Cilostazol in Patients With Diabetic Nephropathy

Study Overview
=================
Brief Summary
-----------------
Patients with type 2 diabetes have a long duration of disease for the development of complications. Among all complications, microangiopathic complications are major causes of mortality and morbidity in diabetic patients. In Asia, patients with type 2 diabetes are particularly susceptible to the development of kidney disease. Patients with diabetic kidney disease have more adverse metabolic profiles and increased risk of having other complications such as blindness, stroke, heart attack and nerve damage than those without. Despite receiving the best of care, the combined event rate of death, cardiovascular disease and end stage kidney disease in diabetic patients with renal impairment remained as high as 10% per year. Cilostazol reduces platelet aggregation and prevents formation of blood clots. Furthermore, cilostazol treatment has been shown to reduce serum triglyceride concentrations and increase HDL-cholesterol levels. In this randomized placebo-controlled, double-blinded study, the investigators hypothesize that Cilostazol may reduce the rate of decline in renal function in Chinese patients with type 2 diabetes and mild to moderate renal impairment. Sixty patients will be randomised to receive either Cilostazol 100 mg twice daily or placebo for 12 months. The effect of Cilostazol on the progression of diabetic nephropathy, as defined by rates of decline in glomerular filtration rate, serum creatinine and urinary albumin excretion rate will be measured. The results will provide additional insight on the management of diabetic kidney disease which is prevalent among Chinese diabetic patients in Hong Kong.

Detailed Description
-----------------
Hypothesis: Cilostazol reduces the rate of decline in renal function in Chinese patients with type 2 diabetes and mild to moderate renal impairment secondary to diabetic nephropathy. Objectives: To assess the suppressive effect of Cilostazol on the progression of diabetic nephropathy, as defined by rates of decline in glomerular filtration rate, serum creatinine and urinary albumin excretion rate. The rising prevalence of diabetes in Asia imposes a heavy burden on the health care system. Given the increasingly early onset of disease, patients with type 2 diabetes have long duration of disease for the development of complications. Among all complications, microangiopathic complications are major causes of mortality and morbidity in diabetic patients. In Asia, patients with type 2 diabetes are particularly susceptible to the development of nephropathy. Among dialysis patients, the primary disease is diabetic nephropathy in about 40 to 50 % of patients. Despite the inhibition of the renin angiotensin system using either ACE inhibitor or AII receptor blocker (ARB) as well as introduction of tight glycaemic and blood pressure control, the prevalence of diabetic nephropathy remains high. More importantly, patients with nephropathy have more adverse metabolic profiles and increased risk of having other complications such as retinopathy, macrovascular diseases and neuropathy than those without. Indeed, according to the RENAAL Study, despite receiving the best of care, the combined event rate of death, cardiovascular disease and end stage renal disease in diabetic patients with renal impairment remained as high as 10% per year. Cilostazol exerts antiplatelet, antithrombotic and vasodilating effects by inhibiting phosphodiesterase type 3 in platelets and vascular smooth muscle cells. Furthermore, cilostazol treatment has been shown to reduce serum triglyceride concentrations and increase HDL-cholesterol levels. In Japanese patients with type 2 diabetes, cilostazol therapy was associated with regression of carotid intimal media thickness and could prevent the onset of silent brain infarction. On the other hand, abnormal metabolism of prostaglandins in renal glomeruli has been postulated to modulate renal haemodynamics. Elevated levels of platelet-derived microparticles and soluble adhesion molecules may further contribute to the development of diabetic nephropathy. Cilostazol treatment had been shown to reduce serum levels of PMP, activated platelet subsets, soluble adhesion molecules and urinary excretion of thromboxane B2 in patients with type 2 diabetes. These changes were accompanied by a reduction in urinary albumin excretion and an increase in creatinine clearance.

Official Title
-----------------
A Randomised, Double-Blind, Placebo-Controlled Study of Cilostazol 100 mg Twice Daily in the Treatment of Diabetic Nephropathy in Hong Kong Chinese

Conditions
-----------------
Diabetes Mellitus, Type 2, Diabetes Complications

Intervention / Treatment
-----------------
* Drug: Cilostazol
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients aged between 20 and 70 years Patients with Type 2 diabetic mellitus A fasting urinary albumin/creatinine ratio greater than or equal to 30 mg/mmol or 24 hour urinary albumin excretion greater than or equal to 300 mg/day in two urine collections during the baseline period Two consecutive serum creatinine levels during baseline period which meet the following requirements: Women: between 80 umol/l and 250 umol/l (inclusive) Men: between 105 umol/l and 250 umol/l (inclusive) Written informed consent Exclusion Criteria: Pregnancy Known allergy to cilostazol or aspirin Congestive heart failure (NYHA class III to IV) Severe liver impairment (greater than or equal to 3 times ULN of ALT) Serum potassium levels greater than or equal to 5.5 mmol/l on 2 consecutive specimens

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cilostazol<br>Cilostazol 100 mg twice daily | Drug: Cilostazol<br>* Cilostazol 100 mg twice daily<br>* Other names: Pletaal;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 1 tablet twice daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Doubling of serum creatinine level |  | 1 year | 
| 50% reduction in GFR (estimated by MDRD equation) |  | 1 year | 
| GFR less than 15 ml/min/1.73m2 |  | 1 year | 
| Need for dialysis |  | 1 year | 
| Death related to renal causes |  | 1 year | 
| Fatal or severe bleeding |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite cardiovascular endpoints (acute myocardial infarction, revascularisation procedures, heart failure or unstable angina or arrhythmia) requiring hospital admissions, lower extremity amputation) |  | 1 year | 
| Number of hospital admissions, total number of days of hospital stay and attendance at the Accident and Emergency Department |  | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic nephropathy, Macroalbuminuria, Pletaal