Effect of Sulodexide in Early Diabetic Nephropathy

Diabetic nephropathy is an important cause of morbidity and mortality in patients with either
type 1 or type 2 diabetes mellitus. The pathogenesis and natural history of diabetic
nephropathy is characterized initially by microalbuminuria followed by a progressive decline
in glomerular function. An emerging body of evidence supports the notion that glomerular
capillary wall and mesangial alterations in diabetic nephropathy involve pathobiochemical
alterations of glycoproteins in these structures. Evidence, in experimental animals rendered
diabetic, reveals that the administration of heparin and other anionic glycoproteins (GAG)
can effectively prevent the biochemical alterations which are responsible for albuminuria.
Sulodexide, an orally active agent which does not have anticoagulant properties associated
with its oral dose range, is comprised of three naturally occurring glycosaminoglycan (GAG)
polysaccharide components isolated from porcine intestinal mucosa. Small clinical studies
employing sulodexide, have shown that albuminuria is significantly diminished in patients
with diabetic nephropathy, even when these patients are receiving angiotensin II receptor
blockers (ARB) or angiotensin converting enzyme inhibitors (ACEI), agents already proven to
reduce albuminuria and slow progressive diabetic nephropathy.

This study is designed to evaluate whether sulodexide is safe and effective in treating
subjects with type 2 diabetic nephropathy. Subjects with type 2 diabetes and microalbuminuria
(defined as a urinary albumin to creatinine ratio,(ACR)in men 35-200 mg/G and in women 45-200
mg/G) who are also receiving either irbesartan 300 mg/day, losartan 100 mg/day, or a maximum
approved dose of an angiotensin receptor blocker (ARB) or angiotensin converting enzyme
inhibitor (ACEI) will be enrolled in the study. The study will consist of the following
periods:

- Screening: of 1-2 weeks for assessing basic eligibility/exclusion criteria

- Run-in: of up to 16 weeks on maximal dose of ARB or ACE with stable blood pressure
control

- Qualifying visit: qualifying patients are on maximal dose of ARB or ACE for a minimum of
4 months with stable BP control, SBP <150 mmHg, DBP <90 mmHg and albumin to creatinine
ratio, (ACR) between in men 35-200 mg/G and in women 45-200 average of 3 first morning
voids

- Randomization: patients are randomized to sulodexide 100 mg or matching placebo
administered orally twice a day.

- Maintenance: 26 week maintenance period, with 4 visits to monitor safety and ACR

- Washout Period: 8 week washout period, with 2 visits to monitor safety and ACR

Inclusion Criteria:

- Diagnosis of type 2 diabetes

- Serum creatinine equal to or less than 1.5 mg/dL

- Microalbuminuria, defined by a urine albumin/creatinine ratio in men; 35- 200 mg
albumin/G creatinine, in women; 45-200 mg albumin/G creatinine

- Blood pressure controlled to less than 150/90 mmHg

- Willing to change antihypertensive medication regimen if necessary

Exclusion Criteria:

- Age of onset of type 2 diabetes <18 years;

- HbA1C >10.0%;

- Morbid obesity defined as a body mass index (BMI) >= 45 kg/m2;

- Type 1 (insulin-dependent; juvenile onset) diabetes;

- Renal disease as follows:

- Patients with known non-diabetic renal disease

- Renal allograft

- Absolute requirement for combination therapy of angiotensin converting enzyme
inhibitors (ACEI) and angiotensin receptor blockers (ARB);

- Cardiovascular disease as follows:

- Unstable angina pectoris within 3 months of study entry;

- Myocardial infarction, coronary artery bypass graft surgery, or percutaneous
transluminal coronary angioplasty or stent placement within 3 months of study
entry;

- Transient ischemic attack within 3 months of study entry;

- Cerebrovascular accident within 3 months of study entry;

- Symptomatic heart failure requiring ACE inhibition;

- New York Heart Association Functional Class III or IV heart failure;

- Obstructive valvular heart disease or hypertrophic cardiomyopathy;

- Second or third degree atrioventricular block not successfully treated with a
pacemaker

- Need for chronic (>2 weeks) immunosuppressive therapy, including corticosteroids
(excluding inhaled or nasal steroids);

- History of multiple drug allergies;

- New diagnosis of cancer or recurrent cancer within 5 years of screening ( (except
non-melanoma skin cancer);

- Psychiatric disorder that interferes with the patient's ability to comply with the
protocol;

- Inability to tolerate oral medication or a history of significant malabsorption;

- Inability to remain on a stable dose of the following class of medications 30 days
prior to randomization and throughout the study:

- 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins);

- Peroxisome proliferator-activated receptor gamma (PPAR gamma inhibitors
(glitazones);

- Cyclooxygenase-2 inhibitors (COX-2 inhibitors); or

- Non-steroidal anti-inflammatory drugs (NSAIDS);

- History of alcohol or other drug abuse within 12 months of study entry;

- Known human immunodeficiency virus (HIV) disease;

- Any other medical condition which renders the patient unable to or unlikely to
complete the study, or which would interfere with optimal participation in the study
or produce significant risk to the patient;

- Receipt of any investigational drugs (including placebo) within 30 days of enrollment;

- Evidence of hepatic dysfunction including total bilirubin >2.0 mg/dL or liver
transaminase (AST or ALT) >3 times upper limit of normal;

- Anticipated surgery within trial period;

- Inability to cooperate with study personnel or history of noncompliance to medical
regimen (i.e., patients who would be expected to comply poorly with treatment);

- Known allergies or intolerance to any heparin-like compound;

- Untreated urinary tract infection that would impact urinary protein values; or

- Prior exposure to sulodexide, either in a clinical setting or as a participant in
another clinical study.