Treatment of Diabetic Nephropathy

COX-2 is an enzyme that is found in several different tissues in the body. COX-2 appears to produce a substance called prostaglandins, mainly at sites of inflammation. Several drugs have been approved by the FDA that inhibit COX-2 such as celecoxib, or brand name Celebrex®. These drugs are primarily used in patients with osteoarthritis and rheumatoid arthritis to decrease inflammation and pain. COX-2 inhibitors have been developed because they are more selective in treatment of inflammation and pain and tend to have fewer gastrointestinal side effects than NSAIDs (nonsteroidal anti-inflammatory drugs) such as aspirin, ibuprofen, naproxen, etc.

The normal adult kidney expresses COX-2 in various regions. Prostaglandins, which are produced in the kidney by COX-2, may contribute to glomerular and tubulointerstitial inflammatory diseases (types of kidney diseases due to inflammation). In some animal studies, COX-2 inhibitors have been shown to be potentially beneficial in reducing the amount of protein spilled in the urine and preserving kidney function with these inflammatory kidney diseases. This study will compare the effects of COX-2 inhibitor to placebo (an inactive substance) in patients with diabetic nephropathy (kidney disease due to diabetes) and proteinuria (spilling protein in the urine) on 24-hour urinary protein excretion.

This study is designed to see whether COX-2 inhibitors are useful in treating diabetic patients with kidney disease. The purpose of this study is a short-term pilot study that will allow the gathering of important data such as the ability to carry out the study and carry it out safely. Subjects with proteinuria and diabetic kidney disease already on ACE (Angiotensin-Converting Enzyme) inhibitor or ARB (Angiotensin Receptor Blocker) therapy (types of blood pressure medicines) will be randomized to a type of study in which each subject will serve as their own control. The study is set up so that each subject will receive either the COX-2 inhibitor or placebo for a period followed by a period of no drug and then followed by a period of receiving either the COX-2 inhibitor or placebo (whichever they did not receive the first period).

Study Overview

• Status: Terminated
• Conditions: Diabetic Nephropathy
• Intervention / Treatment: Drug: celecoxib

Detailed Description

The study is designed with a screening period, a baseline period and a treatment period. The purpose of screening is to identify eligible subjects and to exclude ineligible subjects. A careful history and physical examination will be conducted to ensure that the subject meets all the inclusion criteria and does not meet any of the exclusion criteria. The screening period lasts from 2 days to 2 months in duration.

The baseline period is from 2 - 3 months in duration. During the first baseline visit, there is withdrawal of previously used angiotensin converting enzyme inhibitors or angiotensin receptor antagonists (if any) and the initiation of quinapril 20 mg daily therapy (or irbesartan --150 - 300 mg daily). The subject will then be seen as frequently as determined by the investigator for subject's safety. The purpose of the second baseline visit is to determine safety after the initiation of therapy quinapril 20 mg po per day (or irbesartan 150 - 300 mg per day). The purpose of third baseline visit is to insure that the subject meets all the inclusion and none of the exclusion criteria prior to randomization. In addition, it will be assured that the subject's blood pressure is at a safe level to proceed with randomization and the laboratory and urinary collections will be made.

Only those subjects who fulfill all inclusion and none of the exclusion criteria will proceed to randomization. Also, in order to proceed to the randomization phase of the study, the subject must have a blood pressure of less than or equal to 135/85mmHg.

The treatment phase will consist of 18 weeks. During the treatment phase, the subject will be followed for safety and efficacy. The subjects will be randomly assigned to COX-2 inhibitor for 6 weeks (1st 6 week cycle), washout 3 weeks, placebo 6 weeks (2nd 6 week cycle), washout 3 weeks or to placebo 6 weeks (1st 6 week cycle), washout 3 weeks, COX-2 inhibitor 6 weeks (2nd 6 week cycle), washout 3 weeks.

During baseline and treatment periods, interim visits will be held in order to address blood pressure control or other problems that the patient or the PI deems necessary for protocol adherence.

• Study Type: Interventional
• Enrollment: 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush Presbyterian St. Luke's Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 years or greater
• Men or non-pregnant, non-lactating women with Type 1 or Type II diabetes and renal disease
• 24-hour urinary protein excretion greater than or equal to 500 mg
• Serum creatinine less than or equal to 3 mg/dl
• Willingness and ability to give informed consent and to cooperate with the protocol including discontinuing current antihypertensive medications if necessary

Exclusion Criteria:

• Pregnant or lactating women
• Renal disease other than diabetic nephropathy
• Renal Transplant or on dialysis
• Immunosuppressive agents for greater than 2 weeks in the 3 months prior to randomization (inhaled steroids are permissible)
• Renal vascular disease (uncorrected and hemodynamically significant)
• Obstructive uropathy (uncorrected and hemodynamically significant)
• History or evidence of acute renal failure within 6 months prior to randomization visit
• Serum potassium greater than 5.2 mEq/L
• Known human immunodeficiency virus disease (HIV)
• Any major disorder which in the opinion of the investigator would reduce life expectancy during the course of this study or could preclude participation in this or could adversely effect the interpretation of the data.
• Anticipated inability to cooperate with or any condition of sufficient severity to impair participation in the study.
• Any of the following cardiovascular conditions within 1 month of the screening visit: myocardial infarction, coronary angioplasty, coronary artery bypass graft, other revascularization procedure, severe or unstable angina, stroke, transient ischemic attack or hemodynamically important vascular disease.
• Need for chronic (greater than 2 weeks) immunosuppressive therapy including oral or IV corticosteroids. (Inhaled steroids are permissible.)
• History of drug sensitivity or adverse reaction to both ACE I and ARB.
• History of drug sensitivity, allergy, or adverse reaction to COX-2 inhibitor, aspirin, or sulfonamides.
• Evidence or suspicion of drug abuse or excessive alcohol consumption within 12 months prior to screening visit 1.
• Receipt of any investigational drug within 30 days or 5 half-lives of the investigational drug (the longer period will apply) before screening visit 1.
• Active psychiatric disorder.
• History of peptic ulcer disease and/or gastrointestinal bleeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Sinsakul M, Sika M, Rodby R, Middleton J, Shyr Y, Chen H, Han E, Lehrich R, Clyne S, Schulman G, Harris R, Lewis J. A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease. Am J Kidney Dis. 2007 Dec;50(6):946-51. doi: 10.1053/j.ajkd.2007.09.005.

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Study Completion: December 1, 2004

Study Registration Dates

• First Submitted: July 28, 2003
• First Submitted That Met QC Criteria: July 30, 2003
• First Posted (Estimate): July 31, 2003

Study Record Updates

• Last Update Posted (Estimate): January 14, 2010
• Last Update Submitted That Met QC Criteria: January 12, 2010
• Last Verified: January 1, 2010

More Information

Terms related to this study

• 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; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Cyclooxygenase 2 Inhibitors; Celecoxib
• Other Study ID Numbers: TRMTDN (terminated)