Effect of Sevelamer Carbonate on Oxidative Stress in Patients With Diabetic Nephropathy

NCT ID: NCT00967629

Last Updated: 2011-11-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2010-02-28

Brief Summary

The purpose of this study is to determine whether oral sevelamer carbonate binds advanced glycation end products (AGEs) in the gastrointestinal (GI) tract of patients with diabetic nephropathy leading to decrease body AGE load and therefore decreases the inflammation and oxidative stress in these patients.

Detailed Description

Traditional vascular risk factors alone cannot account for the elevated cardiovascular risk in patients with chronic kidney disease (CKD). In addition to a high prevalence of hypertension and diabetes, patients with CKD have elevated levels of inflammatory markers and OS, which are emerging as important risk factors for cardiovascular disease (CVD). Patients with CKD are also known to have elevated levels of circulating advanced glycation end products (AGE's), which have been shown to induce OS and to play a central role in the development of diabetic microvascular and macrovascular complications. In CKD patients, AGE's accumulate secondary to decreased renal clearance and increased endogenous production in the setting of high levels of OS. Efforts to understand relationships between the multiple vascular risk factors in chronic kidney disease may lead to reduced morbidity and mortality in this population of patients.

Sevelamer Hydrochloride is an anion exchange resin composed of multiple positively charged amine groups indicated for the treatment of hyperphosphatemia in patients with stage V CKD. The positively charged amine groups bind negatively charged dietary phosphate preventing systemic absorption. Sevelamer Hydrochloride has been shown to have the added benefits of lowering LDL levels, lowering highly sensitive C-reactive protein (hsCRP) levels, and improving insulin resistance. Patients treated with Sevelamer Hydrochloride have also been shown to have improved vascular compliance and reduced progression of coronary vascular calcification. Since AGE's are mostly negatively charged compounds, Sevelamer Carbonate by analogy, may have anti-AGE effects which could reduce inflammation and oxidative stress. Sevelamer Carbonate would have a major advantage over Calcium Carbonate-based phosphate binders, based on the fact that it would have the added advantage of reducing the levels of AGEs. The resultant reduction of both OS and inflammation would be expected to have an independent beneficial effect on the rate of progression of CKD and CVD.

We have shown in CKD patients and in animal models that AGE's correlate with levels of OS, LDL, hsCRP, and insulin resistance. Additionally, these factors can be remediated in CKD and non-CKD diabetics by decreasing overall AGE load, particularly in the diet. To date, the effect of Sevelamer Hydrochloride or Sevelamer Carbonate on OS and circulating AGE levels has not been studied. The anti-inflammatory and lipid-lowering effects of Sevelamer Hydrochloride may occur through lowering serum AGE levels and OS. Sevelamer Carbonate is an improved form of Sevelamer Hydrochloride that has been shown to be a safe and effective alternative to calcium carbonate in the treatment of hyperphosphatemia in the earlier sta'ges of CKD without causing metabolic acidosis. The development of Sevelamer Carbonate provides an opportunity to study patients with earlier stages of CKD, and to determine if it prevents or slows the progression of CKD. We propose a study designed to compare the effects of calcium carbonate and of Sevelamer Carbonate on serum AGE levels and OS in patients with stage II-IV diabetic nephropathy.

Hypothesis:

Sevelamer Carbonate administration in persons with stage II-IV CKD, compared with calcium carbonate administration, will result in at least a:

1. 20% decrease in serum levels of AGE's;

2. 10% decease in inflammatory markers of CRP and VCAM-1, or of OS (AGER1/RAGE) in circulating mononuclear cells.

Conditions

Diabetic Nephropathy

Keywords

Diabetic nephropathy; CKD progression; AGEs; oxidative stress; dietary AGEs

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sevelamer Carbonate crossover

Participants will be patients with stage II-IV CKD due to diabetic nephropathy randomized to start either with sevelamer carbonate or calcium carbonate

Group Type: OTHER

Sevelamer Carbonate

Intervention Type: DRUG

This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.

Calcium Carbonate crossover

Participants will be patients with stage II-IV CKD due to diabetic nephropathy randomized to start either with sevelamer carbonate or calcium carbonate

Group Type: OTHER

Calcium Carbonate

Intervention Type: DRUG

This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.

Interventions

Sevelamer Carbonate

This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.

Intervention Type: DRUG

Calcium Carbonate

This is a 4 month, prospective, comparative, crossover study. The study will be conducted in 20 patients with stage II, III or stage IV diabetic nephropathy. Patients will be randomized 1:1 to receive either 1,250 mg of calcium carbonate TID with meals (control arm) or Sevelamer Carbonate 1,600 mg (two 800 mg tablets) with meals. Each group of 10 subjects will take the assigned drug for 8 weeks. Following the 8 week treatment period, subjects will discontinue the assigned drug for a one week washout period. Following the washout period, those who were taking calcium carbonate will be crossed over to Sevelamer Carbonate therapy and those who were receiving Sevelamer Carbonate will be crossed over to calcium carbonate for a final 8 week treatment phase.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years old

2. Evidence of CKD II, III or IV Stage II CKD: eGFR 60-89 cc/min Stage III CKD: eGFR 30-59 cc/min Stage IV CKD: eGFR 15-20 cc/min

3. Proteinuria on urinalysis on two occasions within 18 months of recruitment

4. Diagnosis of diabetes and receiving at least one medication for diabetes mellitus.

Exclusion Criteria

1. Age < 18 years old

2. Stage I and V CKD

3. Patients receiving active treatment for hyperphosphatemia.

4. Biopsy proven renal disease other than diabetic nephropathy

5. Hypophosphatemia

6. Hypercalcemia

7. any history of significant gastrointestinal disorders

8. any history of significant gastrointestinal surgery such as ileostomy, colostomy and colectomy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Icahn School of Medicine at Mount Sinai

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Helen Vlassara, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Locations

Mount Sinai School of Medicine

New York, New York, United States

Countries

United States

References

Uribarri J, Peppa M, Cai W, Goldberg T, Lu M, He C, Vlassara H. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J Am Soc Nephrol. 2003 Mar;14(3):728-31. doi: 10.1097/01.asn.0000051593.41395.b9.

Reference Type: BACKGROUND

PMID: 12595509 (View on PubMed)

Peppa M, Uribarri J, Cai W, Lu M, Vlassara H. Glycoxidation and inflammation in renal failure patients. Am J Kidney Dis. 2004 Apr;43(4):690-5. doi: 10.1053/j.ajkd.2003.11.022.

Reference Type: BACKGROUND

PMID: 15042546 (View on PubMed)

Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, Vlassara H. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc. 2004 Aug;104(8):1287-91. doi: 10.1016/j.jada.2004.05.214.

Reference Type: BACKGROUND

PMID: 15281050 (View on PubMed)

Uribarri J, Cai W, Peppa M, Goodman S, Ferrucci L, Striker G, Vlassara H. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci. 2007 Apr;62(4):427-33. doi: 10.1093/gerona/62.4.427.

Reference Type: BACKGROUND

PMID: 17452738 (View on PubMed)

Other Identifiers

GCO 08-0976

Identifier Type: -

Identifier Source: org_study_id