The purpose of this study is to determine whether sulodexide is effective in slowing or preventing the progression of diabetic kidney disease.

Condition	Intervention	Phase
Diabetic Nephropathy	Drug: Sulodexide	Phase IV

Further Study Details: 

Primary Outcomes: - Time to doubling of the serum creatinine or ESRD; - Safety and tolerance of sulodexide therapy long-term
Secondary Outcomes: - Change in urinary protein / albumin excretion
Expected Total Enrollment:  2240

Diabetes is now the most common cause of end-stage renal disease (ESRD) in the U.S. and in many other developed nations. Diabetic nephropathy now represents 44% of all new cases of ESRD in the U.S. Despite advances in clinical care, including improvements in glycemic and blood pressure control, the number of new cases of diabetes related ESRD continues to rise. In particular, the incidence of type 2 diabetes mellitus (DM2)-related cases of ESRD is rapidly increasing. From 1993 to 1997, 71% of all diabetes-related ESRD was attributable to DM2 (USRDS 1999). The earliest sign of diabetic kidney disease presents as microalbuminuria, the spilling of small of amounts of blood protein into the urine. Microalbuminuria correlates directly with the subsequent development of more advanced kidney disease. Improved glycemic control and blood pressure control with the use of inhibitors of the renin-angiotensin-aldosterone system can reduce the level of microalbuminuria and overt proteinuria. However, despite these measures, diabetic nephropathy continues to progress, albeit more slowly. Sulodexide belongs to a class of drugs called glycosaminoglycans (GAG). GAG therapy has been shown in animal models to prevent and or induce regression of albuminuria, and the morphologic changes associated with progressive diabetic nephropathy such as glomerular basement thickening, loss of the anionic charge density and mesangial collagen deposition. Sulodexide is approved in Europe to treat vascular indications. It has been utilized in several small phase II studies to treat early diabetic nephropathy, inducing an additional 40-70 % reduction in albuminuria in subjects whose albumin excretion was already reduced with tight glycemic control plus the use of inhibitors of the renin-angiotensin-aldosterone system for blood pressure control.

The purpose of this study is to add to this body of evidence that Sulodexide may offer additional benefit in preventing or ameliorating more advanced diabetic nephropathy manifested as overt proteinuria and reduced GFR. Subjects with type 2 diabetes, moderately elevated serum creatinine and overt proteinuria will be treated with a standardized maximal recommended/tolerated dose of irbesartan 300 mg/day or losartan 100 mg/day plus additional concomitant non-ARB, non-ACEi antihypertensive drugs,for up to 2-3 months to establish adequate and stable blood pressure control and urine protein excretion. After establishing baseline serum creatinine and urine protein excretion they will be randomized to either Sulodexide 200 mg/d or matching placebo. Subjects will be seen every 3 months to monitor safety and efficacy parameters for up to 4 years. The primary outcome is a doubling of baseline serum creatinine (50% loss of kidney function) or end stage kidney disease (ESRD).

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Diagnosis of type 2 diabetes;
• Urine protein to creatinine ratio (PCR) equal to or greater than 900 mg/G (101.7 mg/mmol) in women and equal to or greater than 650 mg/G (73.45 mg/mmol) in men;
• Serum creatinine in women 1.3 - 3.0 mg/dL (115-265 μmol/L), inclusive, and in men 1.5 - 3.0 mg/dL (133-265 μmol/L), inclusive;
• Willing to discontinue antihypertensive medication regimen, if applicable;
• Willing and able to give informed consent.

Exclusion Criteria:

• Type 1 (insulin-dependent; juvenile onset) diabetes;
• Renal disease as follows:

• Patients with known non-diabetic renal disease (nephrosclerosis superimposed on diabetic nephropathy acceptable), or • Renal allograft;

• Absolute requirement for combination therapy of ACEI and ARB;
• Patients who require ACEI, but not ACEI/ARB combination;
• 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/stent within 3 months of study entry; • Transient ischemic attack within 3 months of study entry; • Cerebrovascular accident within 3 months of study entry; • New York Heart Association Functional Class III or IV (Note: if a patient is New York Heart Association Functional Class I or II and requires an ACEI, consult with the Clinical Coordinating Center to obtain permission for the patient to be on an ACEI rather than an ARB); • Obstructive valvular heart disease or hypertrophic cardiomyopathy; or • 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);
• 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;
• History of alcohol or other drug abuse within 12 months of study entry;
• Known human immunodeficiency virus 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 (>35  mol/L) or liver transaminase (aspartate aminotransferase [AST] or alanine transferase [ALT]) >3 times upper limit of normal;
• Anticipate need for surgery;
• Inability to cooperate with study personnel or history of noncompliance to medical regimen;
• Known allergies or intolerance to any heparin-like compound including heparin-induced thrombocytopenia Type II;
• Prior exposure to sulodexide, either in a clinical setting or as a participant in another clinical study.
• Untreated urinary tract infection that would impact urinary protein values.

Please refer to this study by ClinicalTrials.gov identifier  NCT00130312

Richard D Rohde, BS      312-633-4250    drohde@rush.edu
Josephine Volgi, BS, CDE      312-850-8434  Ext. 248    Josephine Volgi/Rush/RSH@RSH

Illinois
      The Collaborative Study Group, Clinical Coordinating Center for U.S. and Canadian clinics, Rush University Medical Center, Chicago,  Illinois,  60612,  United States; Recruiting
Australia, Victoria
      The Collaborative Study Group, Clinical Coordinating Center for the Pacific Region, Monash Medical Center, Clayton, Melbourne,  Victoria,  3168,  Australia; Not yet recruiting
Netherlands
      The Collaborative Study Group, Clinical Coordinating Center for European Clinics, University of Groningen, Groningen,  9713 AV,  Netherlands; Not yet recruiting

Study chairs or principal investigators

Edmund J Lewis, MD,  Study Director,  The Collaborative Study Group, Rush University Medical Center, Chicago, IL USA   
Robert C Atkins, M.D.,  Principal Investigator,  The Collaborative Study Group, Monash Medical Center, Clayton, Victoria, AUSTRALIA   
Dick deZeeuw, M.D.,  Principal Investigator,  The Collaborative Study Group, University of Groningen, NETHERLANDS   
Itamar Raz, M.D.,  Principal Investigator,  The Collaborative Study Group, Hadassah University, Jerusalem, ISRAEL   

Study ID Numbers:  KRX-101-401
Last Updated:  August 16, 2005
Record first received:  August 11, 2005
ClinicalTrials.gov Identifier:  NCT00130312
Health Authority: United States: Food and Drug Administration; Australia: Department of Health and Ageing Therapeutic Goods Administration; Austria: Federal Ministry for Health and Women; Belgium: Directorate general for the protection of Public health: Medicines; Canada: Health Canada; Denmark: Danish Medicines Agency; Finland: National Agency for Medicines; France: Ministry of Health; Hong Kong: Department of Health; Hungary: National Institute of Pharmacy; Ireland: Irish Medicines Board; Israel: Israeli Health Ministry Pharmaceutical Administration; Italy: National Monitoring Centre for Clinical Trials - Ministry of Health; Malaysia: Ministry of Health; Netherlands: The Central Committee on Research Involving Human Subjects (CCMO); New Zealand: Health and Disability Ethics Committees; Poland: Ministry of Health; Portugal: National Pharmacy and Medicines Institute; Singapore: Health Sciences Authority; Spain: Spanish Agency of Medicines; Sweden: Medical Products Agency; Switzerland: Swissmedic; Taiwan: Department of Health; United Kingdom: Medicines and Healthcare Products Regulatory Agency
ClinicalTrials.gov processed this record on 2005-08-23