The Effects of Sevelamer Carbonate on Diabetic Nephropathy

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gary Striker, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT01493050
First received: December 13, 2011
Last updated: April 8, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to see if taking a medication can lower the amount of oxidants from food that go into our body. Previous research shows that if the investigators lower the oxidants from food in people with diabetes, this simple change lowers different risks for heart disease and the worsening of kidney disease. The investigators focus on a specific type of oxidant, advanced glycation endproducts (AGEs). A previous, smaller study, conducted by our group showed that a drug, already approved by the FDA, will lower AGEs in the investigators compared Renvela® to Tums®. Both of these drugs have few side effects and have been used for a long time in patients with diabetes and kidney disease. While our previous study was interesting, it was just too small to be able to be sure that it will help all people with diabetes, or if the good effects the investigators found were simply due to chance. The investigators are doing this new study to confirm or deny the possibility that Renvela® can really help people with diabetes and kidney disease.


Condition Intervention Phase
Diabetic Nephropathy
Drug: Sevelamer Carbonate
Drug: calcium carbonate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multi-Center Study of the Effect of Sevelamer Carbonate (Renvela®) on Metabolic/Inflammatory/ROS in Diabetics With Nephropathy

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • glucose metabolism [ Time Frame: baseline ] [ Designated as safety issue: No ]
    HbA1C and serum AGE levels

  • glucose metabolism [ Time Frame: at 3 months ] [ Designated as safety issue: No ]
    HbA1C and serum AGE levels

  • glucose metabolism [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
    HbA1C and serum AGE levels


Secondary Outcome Measures:
  • markers of inflammation and oxidative stress [ Time Frame: baseline ] [ Designated as safety issue: No ]
  • markers of inflammation and oxidative stress [ Time Frame: at 3 months ] [ Designated as safety issue: No ]
  • markers of inflammation and oxidative stress [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
  • serum lipid levels [ Time Frame: baseline ] [ Designated as safety issue: No ]
  • serum lipid levels [ Time Frame: at 3 months ] [ Designated as safety issue: No ]
  • serum lipid levels [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
  • serum phosphate level [ Time Frame: at one week ] [ Designated as safety issue: No ]
    to check for hypophosphatemia

  • serum phosphate level [ Time Frame: at two weeks ] [ Designated as safety issue: No ]
    to check for hypophosphatemia


Enrollment: 117
Study Start Date: February 2012
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: 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
Active Comparator: calcium carbonate
1200 mg of calcium carbonate TID with meals for 26 weeks
Drug: calcium carbonate
1200 mg of calcium carbonate TID with meals for 26 weeks
Other Name: (Tums®)

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01493050

Locations
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
Beth Israel Medical Center
New York, New York, United States, 10003
Sponsors and Collaborators
Gary Striker
Investigators
Principal Investigator: Gary Striker, MD Mount Sinai School of Medicine
  More Information

No publications provided by Mount Sinai School of Medicine

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gary Striker, Principal Investigator, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT01493050     History of Changes
Other Study ID Numbers: GCO 11-0973
Study First Received: December 13, 2011
Last Updated: April 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mount Sinai School of Medicine:
Diabetic Nephropathy
Sevelamer Carbonate

Additional relevant MeSH terms:
Diabetic Nephropathies
Kidney Diseases
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Calcium, Dietary
Calcium Carbonate
Sevelamer
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antacids
Molecular Mechanisms of Pharmacological Action
Chelating Agents
Sequestering Agents

ClinicalTrials.gov processed this record on August 20, 2014