Diabetic Nephropathy
Conditions
Keywords
Diabetes, Diabetes Mellitus, Type 2, Albuminuria, Diabetic Nephropathy
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.
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
Interventions
DRUGSulodexide
100 mg sulodexide gelcaps
DRUGPlacebo
0 mg gelcap
Sponsors
Collaborative Study Group (CSG)
Keryx Biopharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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
| Measure | Time frame |
|---|---|
| Change in Serum Albumin From Baseline to End of 26 Weeks | 26 Weeks |
Countries
Australia, Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sulodexide Also known as KRX-101. All patients will be on standard of care ACE or ARBs.
Sulodexide: 100 mg sulodexide gelcaps | 524 |
| Placebo All patients will be on standard of care ACE or ARBs.
Placebo: 0 mg gelcap | 532 |
| Total | 1,056 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Maintenance Period (26 Weeks) | Adverse Event | 10 | 12 |
| Maintenance Period (26 Weeks) | Lost to Follow-up | 5 | 4 |
| Maintenance Period (26 Weeks) | Other | 1 | 1 |
| Maintenance Period (26 Weeks) | Physician Decision | 0 | 2 |
| Maintenance Period (26 Weeks) | Withdrawal by Subject | 8 | 11 |
| Washout Period (8 Weeks) | Adverse Event | 3 | 6 |
| Washout Period (8 Weeks) | Lost to Follow-up | 0 | 1 |
| Washout Period (8 Weeks) | Other | 1 | 1 |
| Washout Period (8 Weeks) | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Sulodexide |
|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 9.9 | 62.2 years STANDARD_DEVIATION 9.82 | 62.0 years STANDARD_DEVIATION 9.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 59 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 501 Participants | 997 Participants | 496 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 67 Participants | 33 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 67 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 15 Participants | 23 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 451 Participants | 891 Participants | 440 Participants |
| Sex: Female, Male Female | 124 Participants | 254 Participants | 130 Participants |
| Sex: Female, Male Male | 408 Participants | 802 Participants | 394 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 523 | 3 / 532 |
| other Total, other adverse events | 348 / 523 | 358 / 532 |
| serious Total, serious adverse events | 21 / 523 | 33 / 532 |
Outcome results
Primary
Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sulodexide | Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria | 39 Participants |
| Placebo | Number of Subjects With Conversion From Microalbuminuria to Normoalbuminuria | 30 Participants |
Primary
Number of Subjects With Greater Than 50% Reduction in Microalbuminuria
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sulodexide | Number of Subjects With Greater Than 50% Reduction in Microalbuminuria | 76 Participants |
| Placebo | Number of Subjects With Greater Than 50% Reduction in Microalbuminuria | 87 Participants |
Secondary
Change in Serum Albumin From Baseline to End of 26 Weeks
Time frame: 26 Weeks
Population: Participant numbers include those with both baseline and week 26 measurements
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sulodexide | Change in Serum Albumin From Baseline to End of 26 Weeks | -0.02 percent change | Standard Error 0.01 |
| Placebo | Change in Serum Albumin From Baseline to End of 26 Weeks | -0.02 percent change | Standard Error 0.01 |