Effect of Sulodexide in Early Diabetic Nephropathy

• Sponsor: Keryx Biopharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00130208
• Collaborator: Collaborative Study Group (CSG) (Other)
• Enrollment: 1,056
• Locations: 3
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 352
• Patients Per Site Per Month: 11.7

Study Details

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
• 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: Aug 1, 2005
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Feb 1, 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 Names: KRX-101
Placebo Comparator: Placebo All patients will be on standard of care ACE or ARBs.	Drug: Placebo; 0 mg gelcap; Other Names: Placebo oral gelcap

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria [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 [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 [26 Weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	The Collaborative Study Group, Clinical Coordinating Center for U.S. and Canadian Clinics, Rush University Medical Center	Chicago	Illinois	United States	60612
2	The Collaborative Study Group, Clinical Coordinating Center for the Pacific Region, Monash Medical Center	Melbourne	Victoria	Australia	3168
3	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Keryx Biopharmaceuticals
• ClinicalTrials.gov Identifier: NCT00130208
• Other Study ID Numbers: KRX-101-301
• First Posted: Aug 15, 2005
• Last Update Posted: Mar 23, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• 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; Glucuronyl glucosamine glycan sulfate

Study Results

Participant Flow

Arm/Group Title	Sulodexide	Placebo
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps	All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap
Period Title: Maintenance Period (26 Weeks)
STARTED	524	532
Valid Albumin Creatinine Ratio	492	494
COMPLETED	500	502
NOT COMPLETED	24	30
Period Title: Maintenance Period (26 Weeks)
STARTED	500	502
COMPLETED	494	490
NOT COMPLETED	6	12

Baseline Characteristics

Arm/Group Title	Sulodexide	Placebo	Total
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps	All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap	Total of all reporting groups
Overall Participants	524	532	1056
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.0 (9.73)	62.3 (9.90)	62.2 (9.82)
Sex: Female, Male (Count of Participants)
Female	130 24.8%	124 23.3%	254 24.1%
Male	394 75.2%	408 76.7%	802 75.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	28 5.3%	31 5.8%	59 5.6%
Not Hispanic or Latino	496 94.7%	501 94.2%	997 94.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.4%	2 0.4%	4 0.4%
Asian	33 6.3%	34 6.4%	67 6.3%
Native Hawaiian or Other Pacific Islander	1 0.2%	2 0.4%	3 0.3%
Black or African American	39 7.4%	28 5.3%	67 6.3%
White	440 84%	451 84.8%	891 84.4%
More than one race	8 1.5%	15 2.8%	23 2.2%
Unknown or Not Reported	1 0.2%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria
Description	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
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sulodexide	Placebo
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps	All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap
Measure Participants	492	494
Count of Participants [Participants]	39 7.4%	30 5.6%

2. Primary Outcome

Title	Number of Subjects With Greater Than 50% Reduction in Microalbuminuria
Description	During the treatment period, KRX-101 is being compared to placebo to assess whether a 50% reduction in microalbuminuria has been achieved.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sulodexide	Placebo
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps	All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap
Measure Participants	492	494
Count of Participants [Participants]	76 14.5%	87 16.4%

3. Secondary Outcome

Title	Change in Serum Albumin From Baseline to End of 26 Weeks
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Participant numbers include those with both baseline and week 26 measurements

Arm/Group Title	Sulodexide	Placebo
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps	All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap
Measure Participants	489	496
Least Squares Mean (Standard Error) [percent change]	-0.02 (0.01)	-0.02 (0.01)

Adverse Events

Time Frame	Adverse event data was collected for the full duration of the trial (34 weeks)
Adverse Event Reporting Description	The safety population consisted of all patients who were administered at least 1 dose of study medication. There was one patient in the sulodexide group who was randomized but did not receive study medication
Arm/Group Title	Sulodexide		Placebo
Arm/Group Description	Also known as KRX-101. All patients will be on standard of care ACE or ARBs. Sulodexide: 100 mg sulodexide gelcaps		All patients will be on standard of care ACE or ARBs. Placebo: 0 mg gelcap
All Cause Mortality
	Sulodexide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/523 (0.4%)		3/532 (0.6%)
Serious Adverse Events
	Sulodexide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/523 (4%)		33/532 (6.2%)
Blood and lymphatic system disorders
Post-procedural hematoma	1/523 (0.2%)		0/532 (0%)
Cardiac disorders
Atrioventricular block complete	1/523 (0.2%)		0/532 (0%)
Ischaemic Cardiomyopathy	1/523 (0.2%)		0/532 (0%)
Supraventricular Tachycardia	1/523 (0.2%)		0/532 (0%)
Myocardial Infarction	1/523 (0.2%)		0/532 (0%)
Acute Coronary Syndrome	1/523 (0.2%)		1/532 (0.2%)
Aortic Stenosis	1/523 (0.2%)		0/532 (0%)
Aortic Aneurysm	1/523 (0.2%)		0/532 (0%)
Transient ischemic attack	1/523 (0.2%)		0/532 (0%)
Coronary artery disease	0/523 (0%)		1/532 (0.2%)
Carotid Artery Stenosis	0/523 (0%)		1/532 (0.2%)
Cardiac Failure	0/523 (0%)		2/532 (0.4%)
Atrial Fibrillation	0/523 (0%)		1/532 (0.2%)
Cardiomyopathy	0/523 (0%)		1/532 (0.2%)
Cardiac Failure Congestive	0/523 (0%)		2/532 (0.4%)
Acute Myocardial Infarction	1/523 (0.2%)		0/532 (0%)
Gastrointestinal disorders
Intestinal Obstruction	1/523 (0.2%)		0/532 (0%)
Gastritis	0/523 (0%)		1/532 (0.2%)
General disorders
Death	0/523 (0%)		2/532 (0.4%)
Hepatobiliary disorders
Cholecystitis	1/523 (0.2%)		0/532 (0%)
Infections and infestations
Subcutaneous Abscess	1/523 (0.2%)		0/532 (0%)
Pancreatitis	1/523 (0.2%)		0/532 (0%)
Cellulitis	0/523 (0%)		1/532 (0.2%)
Sigmoiditis	1/523 (0.2%)		0/532 (0%)
Septic Shock	0/523 (0%)		1/532 (0.2%)
Osteomyelitis	0/523 (0%)		1/532 (0.2%)
Injury, poisoning and procedural complications
Device Failure	1/523 (0.2%)		0/532 (0%)
Metabolism and nutrition disorders
Diabetic Foot	1/523 (0.2%)		0/532 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/523 (0.2%)		0/532 (0%)
Scoliosis	0/523 (0%)		1/532 (0.2%)
Spinal Cord Stenosis	0/523 (0%)		1/532 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	1/523 (0.2%)		0/532 (0%)
Ovarian Cancer	0/523 (0%)		1/532 (0.2%)
Colon Cancer Metastatic	0/523 (0%)		1/532 (0.2%)
Myelodysplastic syndrome	0/523 (0%)		1/532 (0.2%)
Non-Hodgkins Lymphoma	0/523 (0%)		1/532 (0.2%)
Rectal Cancer	0/523 (0%)		1/532 (0.2%)
Bladder Neoplasm	0/523 (0%)		1/532 (0.2%)
Nervous system disorders
Cerebrovascular Accident	1/523 (0.2%)		3/532 (0.6%)
Hemorhage Intracranial	0/523 (0%)		1/532 (0.2%)
Renal and urinary disorders
Renal Failure Acute	1/523 (0.2%)		1/532 (0.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary edema	1/523 (0.2%)		0/532 (0%)
Lung Disorder	0/523 (0%)		1/532 (0.2%)
Acute Respiratory Distress	0/523 (0%)		1/532 (0.2%)
Obstructive Airways Disorder	0/523 (0%)		1/532 (0.2%)
Sleep Apnea	0/523 (0%)		1/532 (0.2%)
Respiratory Tract Infection	0/523 (0%)		1/532 (0.2%)
Chronic Obstructive Pulmonary Disease	0/523 (0%)		1/532 (0.2%)
Other (Not Including Serious) Adverse Events
	Sulodexide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	348/523 (66.5%)		358/532 (67.3%)
Cardiac disorders
Coronary Artery Disease	6/523 (1.1%)		3/532 (0.6%)
Gastrointestinal disorders
Diarrhea	21/523 (4%)		20/532 (3.8%)
Constipation	10/523 (1.9%)		11/532 (2.1%)
Nausea	10/523 (1.9%)		6/532 (1.1%)
Abdominal Pain	4/523 (0.8%)		6/532 (1.1%)
Dyspepsia	3/523 (0.6%)		6/532 (1.1%)
General disorders
Edema Peripheral	55/523 (10.5%)		65/532 (12.2%)
Edema	13/523 (2.5%)		12/532 (2.3%)
Chest Pain	8/523 (1.5%)		6/532 (1.1%)
Asthenia	9/523 (1.7%)		4/532 (0.8%)
Fatigue	4/523 (0.8%)		9/532 (1.7%)
Infections and infestations
Urinary Tract Infection	16/523 (3.1%)		20/532 (3.8%)
Bronchitis	9/523 (1.7%)		16/532 (3%)
Influenza	8/523 (1.5%)		12/532 (2.3%)
Sinusitis	9/523 (1.7%)		5/532 (0.9%)
Gastroenteritis	3/523 (0.6%)		6/532 (1.1%)
Investigations
Cardiac Murmur	5/523 (1%)		9/532 (1.7%)
Weight Increased	6/523 (1.1%)		4/532 (0.8%)
Blood glucose increased	1/523 (0.2%)		6/532 (1.1%)
Metabolism and nutrition disorders
Hypoglycaemia	10/523 (1.9%)		8/532 (1.5%)
Hyperglycaemia	6/523 (1.1%)		8/532 (1.5%)
Hyperkalaemia	9/523 (1.7%)		5/532 (0.9%)
Musculoskeletal and connective tissue disorders
Back Pain	13/523 (2.5%)		17/532 (3.2%)
Pain in extremities	11/523 (2.1%)		19/532 (3.6%)
Arthralgia	13/523 (2.5%)		13/532 (2.4%)
Muscle Spasms	7/523 (1.3%)		9/532 (1.7%)
Nervous system disorders
Headache	16/523 (3.1%)		17/532 (3.2%)
Dizziness	13/523 (2.5%)		15/532 (2.8%)
Hypoesthesia	2/523 (0.4%)		6/532 (1.1%)
Psychiatric disorders
Depression	2/523 (0.4%)		8/532 (1.5%)
Respiratory, thoracic and mediastinal disorders
Upper Respiratory Tract Infection	18/523 (3.4%)		24/532 (4.5%)
Nasopharyngitis	21/523 (4%)		18/532 (3.4%)
Cough	14/523 (2.7%)		9/532 (1.7%)
Rales	7/523 (1.3%)		11/532 (2.1%)
Dyspnoea	6/523 (1.1%)		8/532 (1.5%)
Epistaxis	6/523 (1.1%)		2/532 (0.4%)
Skin and subcutaneous tissue disorders
Rash	7/523 (1.3%)		9/532 (1.7%)
Vascular disorders
Hypertension	12/523 (2.3%)		15/532 (2.8%)
Hypotension	7/523 (1.3%)		5/532 (0.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.