Effect of Sulodexide in Overt Diabetic Nephropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00130312
Recruitment Status : Terminated (No difference in protein excretion at 6&12 months. No safety issues.)
First Posted : August 15, 2005
Last Update Posted : May 5, 2015
Collaborative Study Group (CSG)
Information provided by (Responsible Party):
Keryx Biopharmaceuticals

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

Condition or disease Intervention/treatment Phase
Diabetic Nephropathy Drug: Sulodexide Phase 4

Detailed Description:

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).

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1248 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Collaborative Study Group Trial: The Effect of Sulodexide in Overt Type 2 Diabetic Nephropathy
Study Start Date : August 2005
Actual Primary Completion Date : March 2008
Actual Study Completion Date : March 2008

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Sulodexide
Also known as KRX-101. These patients are also on standard of care ACEs and ARBs.
Drug: Sulodexide
Other Name: KRX-101

Placebo Comparator: Placebo
These patients were on standard of care ACEs and ARBs.

Primary Outcome Measures :
  1. Time to doubling of the serum creatinine or end stage kidney disease (ESRD) [ Time Frame: Time in study depended on time to doubling of serum creatinine ]
    Time in study depended on time to doubling of serum creatinine and when the patient was enrolled in the trial.

  2. Safety and tolerance of sulodexide therapy long-term [ Time Frame: Time in study depended on time to doubling of serum creatinine ]
    Review of laboratory parameters, adverse events, physical examinations, etc. were made to evaluate patient safety.

Secondary Outcome Measures :
  1. Change in urinary protein/albumin excretion [ Time Frame: Time in study depended on time to doubling of serum creatinine ]
    Review of urinary protein and albumin excretion was made as an additional assessment of kidney function.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (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 micromol/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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00130312

United States, Illinois
The Collaborative Study Group, Clinical Coordinating Center for U.S. and Canadian clinics, Rush University Medical Center
Chicago, Illinois, United States, 60612
Australia, Victoria
The Collaborative Study Group, Clinical Coordinating Center for the Pacific Region, Monash Medical Center
Clayton / Melbourne, Victoria, Australia, 3168
The Collaborative Study Group, Clinical Coordinating Center for European Clinics, University of Groningen
Groningen, Netherlands, 9713 AV
Sponsors and Collaborators
Keryx Biopharmaceuticals
Collaborative Study Group (CSG)
Study Director: Edmund J Lewis, MD The Collaborative Study Group, Rush University Medical Center, Chicago, IL USA
Principal Investigator: Robert C Atkins, M.D. The Collaborative Study Group, Monash Medical Center, Clayton, Victoria, AUSTRALIA
Principal Investigator: Dick deZeeuw, M.D. The Collaborative Study Group, University of Groningen, NETHERLANDS
Principal Investigator: Itamar Raz, M.D. The Collaborative Study Group, Hadassah University, Jerusalem, ISRAEL

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Keryx Biopharmaceuticals Identifier: NCT00130312     History of Changes
Obsolete Identifiers: NCT00342238
Other Study ID Numbers: KRX-101-401
First Posted: August 15, 2005    Key Record Dates
Last Update Posted: May 5, 2015
Last Verified: April 2015

Keywords provided by Keryx Biopharmaceuticals:
Diabetic Nephropathy

Additional relevant MeSH terms:
Kidney Diseases
Diabetic Nephropathies
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Glucuronyl glucosamine glycan sulfate
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Hypoglycemic Agents
Physiological Effects of Drugs