Effect of Sulodexide in Early Diabetic Nephropathy

• ClinicalTrials.gov Identifier: NCT00130208
• Recruitment Status: Completed
• First Posted: August 15, 2005
• Results First Posted: March 23, 2018
• Last Update Posted: March 23, 2018
• Sponsor: Keryx Biopharmaceuticals
• Collaborator: Collaborative Study Group (CSG)
• Information provided by (Responsible Party): Keryx Biopharmaceuticals

Study Description

Brief Summary:

The purpose of the study is to determine whether treatment with sulodexide is effective in reducing the level of urine albumin excretion in patients with early diabetic kidney disease expressed as microalbuminuria.

Condition or disease	Intervention/treatment	Phase
Diabetic Nephropathy	Drug: Sulodexide; Drug: Placebo	Phase 3

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1056 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: The Collaborative Study Group Trial: The Effect of Sulodexide in Patients With Type 2 Diabetes and Microalbuminuria
• Study Start Date: August 2005
• Actual Primary Completion Date: January 2008
• Actual Study Completion Date: February 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sulodexide; Also known as KRX-101. All patients will be on standard of care ACE or ARBs.	Drug: Sulodexide; 100 mg sulodexide gelcaps; Other Name: KRX-101
Placebo Comparator: Placebo; All patients will be on standard of care ACE or ARBs.	Drug: Placebo; 0 mg gelcap; Other Name: Placebo oral gelcap

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria [ Time Frame: 26 Weeks ]
   The primary efficacy variable was the fraction of those patients in the ITT population with valid baseline and Week 26 ACRs in whom "therapeutic success" was achieved at Week 26 measured as a conversion of microalbuminuria to normoalbuminuria and at least a 25% reduction in ACR relative to baseline
2. Number of Subjects With Greater Than 50% Reduction in Microalbuminuria [ Time Frame: 26 Weeks ]
   During the treatment period, KRX-101 is being compared to placebo to assess whether a 50% reduction in microalbuminuria has been achieved.

Secondary Outcome Measures :

1. Change in Serum Albumin From Baseline to End of 26 Weeks [ Time Frame: 26 Weeks ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

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

Melbourne, Victoria, Australia, 3168

Netherlands

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)

Investigators

• Study Director: Edmund J Lewis, M.D.; 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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lewis EJ, Lewis JB, Greene T, Hunsicker LG, Berl T, Pohl MA, de Zeeuw D, Heerspink HL, Rohde RD, Atkins RC, Reutens AT, Packham DK, Raz I; Collaborative Study Group. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Dis. 2011 Nov;58(5):729-36. doi: 10.1053/j.ajkd.2011.06.020. Epub 2011 Aug 26. Erratum in: Am J Kidney Dis. 2012 Feb;59(2):318.

• Responsible Party: Keryx Biopharmaceuticals
• ClinicalTrials.gov Identifier: NCT00130208
• Other Study ID Numbers: KRX-101-301
• First Posted: August 15, 2005
• Results First Posted: March 23, 2018
• Last Update Posted: March 23, 2018
• Last Verified: February 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Keryx Biopharmaceuticals:

Diabetes; Diabetes Mellitus, Type 2; Albuminuria; Diabetic Nephropathy

Additional relevant MeSH terms:

Kidney Diseases; Diabetic Nephropathies; Urologic Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Glucuronyl glucosamine glycan sulfate; Anticoagulants; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Hypoglycemic Agents; Physiological Effects of Drugs