Sulodexide to Treat Type 2 Diabetic Nephropathy

Condition(s) targeted: Overt Type 2 Diabetic Nephropathy; Chronic Kidney Disease; Diabetes Type 2

Intervention: Sulodexide (KRX-101) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall contact:
Lois Jones, R.N., Phone: (602) 200-5213, Email: ljones@mail.nih.gov

This study will evaluate the safety and effectiveness of the experimental drug sulodexide in treating diabetic nephropathy. This is a disorder in which the kidneys leak protein into the urine, potentially leading to end-stage kidney failure and requiring dialysis or transplantation. The protein leak is caused, in part, by changes in the chemical makeup of the filtering membranes within the kidney. Sulodexide may protect the kidneys by preventing these chemical changes. Tests in animals and in people suggest that sulodexide may help prevent further progression of damage to the kidneys caused by diabetic nephropathy because it reduces the amount of protein that leaks into the urine.

Patients 18 years of age and older with diabetic nephropathy may be eligible for this study. Candidates are screened with a medical history, blood and urine tests, and measurement of blood pressure and heart rate. Following a 3- to 7-day screening period, participants undergo the following procedures:

Run-in period

Before beginning the study drug, participants take irbesartan or losartan (blood pressure drugs that belong to a class of medicines called angiotensin II receptor antagonists) until the desired blood pressure is achieved. This may take from 1 to 10 weeks and may require changes in patients' regular blood pressure medications. Patients have three clinic visits during the run-in period for medical and laboratory evaluations, blood pressure measurements and adjustments of the drug dosage.

Drug treatment period

When the desired blood pressure is reached, patients begin taking the study drug or placebo, in addition to irbesartan or losartan. Patients are assigned at random to take either sulodexide twice a day or a placebo (a gel capsule that looks like the sulodexide capsule but has no active ingredient) twice a day. Patients are monitored closely during the treatment period for any drug side effects or health problems and for any worsening of their kidney disease. They are seen in the clinic at the start of sulodexide treatment, 1 month after treatment has started, and then every 3 months until the end of the study. Visits include a physical examination, blood and urine tests, review of medical history and pregnancy tests for women who are able to become pregnant. The treatment period continues for 2 years after the end of the enrollment period or until a Data Safety Monitoring Committee determines that enough information has been gathered to evaluate the role of sulodexide in diabetic neuropathy, at which time the study ends.

Study termination visit

When a decision is made to end the study, participants come to the clinic for a final visit. They have the same tests as those done at the 3-month visits and are then returned to the care of their referring physician.

Official title: The Collaborative Study Group Trial: The Effect of Sulodexide in Overt Type 2 Diabetic Nephropathy

Study design: Treatment, Randomized, Double-Blind, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Doubling of serum creatinine concentration or development of end-stage renal disease

Secondary outcome: Other measures of kidney or cardiovascular disease

Detailed description: Diabetes is the leading cause of kidney failure in the developed world and it is rapidly becoming a leading cause of kidney failure worldwide. A randomized, double-blinded, placebo-controlled clinical trial will be conducted in adults greater than or equal to18 years and older with type two diabetes and chronic kidney disease to determine whether treatment with sulodexide can slow the progression of kidney and cardiovascular disease in patients with diabetic nephropathy due to type 2 diabetes to a greater extent than standard care.

Approximately 2358 patients will be enrolled over a two-year period in approximately 200 centers worldwide. All subjects will be treated with either irbesartan 300 mg/day or losartan 100 mg/day. Patients will be randomized to treatment with either sulodexide 200 mg/day or a placebo of identical appearance. Treatment will continue for two years after the recruitment period and patients will be followed at three-month intervals during treatment.

The primary objective will be to 1) determine whether sulodexide, compared to placebo, will protect the kidneys by increasing the time to the first occurrence of the composite endpoint of a doubling of the serum creatinine concentration from baseline or end-stage renal disease and 2) compare the safety and tolerance of sulodexide with placebo when administered long-term to patients with diabetic nephropathy due to type 2 diabetes. Other measures of kidney and cardiovascular protection will also be assessed as secondary endpoints according to treatment groups.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

Males and post-menopausal, surgically sterile, or non-lactating and non-pregnant females using adequate contraception. All women of child-bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L of beta-HCG) at Visit 1 and within 72 hours prior to the start of study medication.

Diagnosis of type 2 diabetes as defined by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.

Age greater than or equal to 18 years of age. Upper age limit is at the discretion of the investigator and should be based on the judgment of the investigator that the patient is likely to survive at least 2 years.

PCR of the three first void AM urine samples greater than or equal to 900 mg/G (101. 7 mg/mmol) in women and greater than or equal to 650 mg/G (73. 45 mg/mmol) in men at Visit 2

Serum creatinine in women between 1. 3 and 3. 0 mg/dL (115-265 micromoles per liter), inclusive, and in men between 1. 5 and 3. 0 mg/dL (133-265 micromoles per liter), inclusive, at Visit 1. If the screening serum creatinine falls outside the specified creatinine criteria, a patient may enter the Run-in Period if the GFR by the MDRD formula at Visit 1 is between 25 to 45 mL/min.

Willing to discontinue antihypertensive medication regimen, if applicable; and

Willing and able to give informed consent

EXCLUSION CRITERIA:

A patient with any of the following conditions at study entry (Visit 1) cannot be randomized into the study:

Type 1 (insulin-dependent; juvenile onset) diabetes

Renal disease as follows:

- Patients with known non-diabetic renal disease (nephorsclerosis 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, may enter the trial if approved by the Clinical Coordinating Center

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 and 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 artioventricular block not successfully treated with a

pacemaker

Need for chronic (greater than 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 greater than 2. 0 mg/dL (greater than 35 micromoles per liter) or liver transaminase (aspartate aminotransferase (AST)) or alanine transferase (ALT) greater than 3 times upper limit of normal at Screening

Anticipate need for surgery

Inability to cooperate with study personnel or history or 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 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 or other medical condition that may impact urinary protein values. If these medical conditions are treated, the patient can enter and be randomized into the study.

Lois Jones, R.N., Phone: (602) 200-5213, Email: ljones@mail.nih.gov

NIDDK, Phoenix, Phoenix, Arizona 85014, United States; Recruiting

Rush University Medical Center, Chicago, Illinois 60612, United States; Recruiting

Related publications:

Rohrbach R. Reduced content and abnormal distribution of anionic sites (acid proteoglycans) in the diabetic glomerular basement membrane. Virchows Arch B Cell Pathol Incl Mol Pathol. 1986;51(2):127-35.

Starting date: October 2005
Last updated: December 22, 2007