- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01493050
The Effects of Sevelamer Carbonate on Diabetic Nephropathy
Multi-Center Study of the Effect of Sevelamer Carbonate (Renvela®) on Metabolic/Inflammatory/ROS in Diabetics With Nephropathy
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Advanced glycation end products (AGEs) levels are elevated in diabetic patients and in patients with chronic kidney disease (CKD) and may contribute to the excessive cardiovascular disease in this population, by promoting oxidant stress and chronic vascular inflammation. It has recently been recognized that AGEs in the body originate not only endogenously, but also from the ingestion of preformed AGEs in the diet. We have shown that reduction of dietary AGE intake leads to significant reductions of circulating AGEs and insulin levels as well as levels of markers of oxidative stress and inflammation in both diabetic and CKD patients. Thus, the increased inflammation and oxidative stress (Infl/OS) in stable diabetes mellitus (DM) are largely due to advanced glycation end products (AGEs) from food, and restricting AGEs-intake reduces these risk factors in DM. High circulating AGEs and TNFR1/2 have been shown to be associated with progression in diabetic nephropathy. Ideally, a compound that binds food AGEs within the lumen of the intestine should have the same effect as dietary restriction of AGEs and could become an important therapeutic tool in the clinical care of these patients. We found that Sevelamer binds AGEs in vitro in a pH dependent manner. This led us to hypothesize that sevelamer carbonate, but not calcium carbonate, would sequester AGEs in the gut and reduce Infl/OS, including circulating AGEs and TNFα, in T2DM with Stage 2-4 CKD. This hypothesis was tested in a Pilot Study (GCO-08-0976) we designed as a proof-of-concept trial to determine if a larger and longer trial is indicated. We conducted a randomized, open-label, intention-to-treat, two-month crossover study to compare stable diabetic patients with stage 2-4 CKD treated with either Sevelamer carbonate or calcium carbonate for 2 months, a 1 week wash-out, and then the opposite drug for 2 months. There were no changes in medications and food intake. We found that urinary phosphate excretion was decreased by both Sevelamer carbonate and calcium carbonate. Serum AGEs, lipids, HbA1c, FGF23, and 8-isoprostanes were reduced by Sevelamer carbonate compared to calcium carbonate. In addition, PMNC levels of AGER1, SIRT1 and TNFα were also decreased by Sevelamer carbonate, compared to calcium carbonate. We concluded that Sevelamer carbonate reduces HbA1c, FGF23, lipids, and TNFα via reduced inflammation and OS in stage 2-4 diabetic CKD. These changes were not seen with calcium carbonate. Since we found that sevelamer carbonate bound AGE-BSA (but not BSA) at pH 7.0, but not at pH 1.0 in vitro, we proposed that the mechanism action is sequestration of dietary AGEs and GI elimination. Based on these data, we concluded that a larger and longer trial is indicated to confirm these results.
The current study proposes to confirm that Sevelamer Carbonate, an agent known to prevent the gastrointestinal absorption of phosphates, is also able to block the absorption of AGEs and improve certain aspects of diabetes and chronic renal disease in a larger group of patients who will be followed for a longer period of time.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
New York
-
New York, New York, United States, 10003
- Beth Israel Medical Center
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New York, New York, United States, 10029
- Icahn School of Medicine at Mount Sinai
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age > 18 years
- Evidence of CKD Stages II, III or IV
- Stage II CKD; eGFR 60-89 ml/min
- Stage III CKD: eGFR 30-59 ml/min
- Stage IV CKD: eGFR 15-29 ml/min
- Proteinuria (>200 mg/day or 300 mg/gm creatinine on a spot urine) on urinalysis on two occasions within 18 months of recruitment
- Diagnosis of diabetes and receiving at least one medication for diabetes mellitus
- HbA1c>6.5%
Exclusion criteria:
- Age <18
- Patients receiving active treatment for hyperphosphatemia
- Biopsy proven renal disease other than diabetic nephropathy
- Hypophosphatemia
- Hypercalcemia
- Any history of significant gastrointestinal disorders
- Any history of significant gastrointestinal surgery such as ileostomy, colostomy and colectomy.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Sevelamer Carbonate
1600 mg (two 800 mg in the form of tablets or powder to be diluted in water) TID with meals for 26 weeks
|
1600 mg (two 800 mg in the form of tablets or powder to be diluted in water) TID with meals for 26 weeks
|
Active Comparator: calcium carbonate
1200 mg of calcium carbonate TID with meals for 26 weeks
|
1200 mg of calcium carbonate TID with meals for 26 weeks
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
glucose metabolism
Time Frame: baseline
|
HbA1C and serum AGE levels
|
baseline
|
glucose metabolism
Time Frame: at 3 months
|
HbA1C and serum AGE levels
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at 3 months
|
glucose metabolism
Time Frame: at 6 months
|
HbA1C and serum AGE levels
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at 6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
markers of inflammation and oxidative stress
Time Frame: baseline
|
baseline
|
|
markers of inflammation and oxidative stress
Time Frame: at 3 months
|
at 3 months
|
|
markers of inflammation and oxidative stress
Time Frame: at 6 months
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at 6 months
|
|
serum lipid levels
Time Frame: baseline
|
baseline
|
|
serum lipid levels
Time Frame: at 3 months
|
at 3 months
|
|
serum lipid levels
Time Frame: at 6 months
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at 6 months
|
|
serum phosphate level
Time Frame: at one week
|
to check for hypophosphatemia
|
at one week
|
serum phosphate level
Time Frame: at two weeks
|
to check for hypophosphatemia
|
at two weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Gary Striker, MD, Icahn School of Medicine at Mount Sinai
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Urologic Diseases
- Endocrine System Diseases
- Diabetes Complications
- Diabetes Mellitus
- Kidney Diseases
- Diabetic Nephropathies
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Gastrointestinal Agents
- Calcium-Regulating Hormones and Agents
- Chelating Agents
- Sequestering Agents
- Antacids
- Calcium
- Sevelamer
- Calcium Carbonate
Other Study ID Numbers
- GCO 11-0973
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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