This study will determine whether the experimental drug pirfenidone can slow kidney disease in patients with diabetes. Diabetes can cause accumulation of proteins in the kidneys, leading to scar formation and eventual kidney failure. Pirfenidone has been beneficial in other diseases involving scar formation, such as pulmonary fibrosis and focal segmental glomerulosclerosis. The drug may be able to slow scar formation in diabetic kidney disease as well, possibly prolonging kidney function.

Patients 18 years of age and older with type 1 or 2 diabetes who have increased protein leakage in their urine, whose blood pressure and blood sugar are well controlled, and who are taking ACE inhibitors or angiotensin receptor blockers may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests.

This study is conducted at the NIH Clinical Center in Bethesda, Maryland, and at Thomas Jefferson University in Philadelphia, Pennsylvania. Participants are randomly assigned to take either 1200 mg of Pirfenidone, 2400 mg of Pirfenidone, or a placebo (look-alike pill with no active ingredients) by mouth three times a day for 1 year. They return to the clinic 2 weeks after the initial screening visit and then every 3 months throughout the study for fasting blood and urine tests, blood pressure measurement and reviews of any health-related issues. Additional blood samples may be drawn to see if pirfenidone is affecting the level of certain proteins or other related molecules that are thought to be related to kidney disease progression in diabetes.

Patients are asked to check their blood pressure at home at least 3 times a week and record it in a log. A patient whose blood pressure is greater than 130/80 must call the doctor to adjust his or her medications. Patients may also need to monitor their blood sugar more frequently than usual (up to 4 times a day) and possibly give more frequent insulin injections to achieve good control of their diabetes.

Patients are asked to collect 24-hour urine five times during the study: at baseline, 2 weeks, 6 months, 12 months, and 54 weeks (end of study). In addition, they are seen by an eye doctor at baseline and at the end of the study to evaluate if pirfenidone may be beneficial for eye problems related to diabetes.

Treatment or Intervention	Phase
Drug: Pirfenidone	Phase II

Further Study Details: 

Expected Total Enrollment:  30

Pirfenidone, initially developed as an anti-helminthic agent, has been shown to reduce fibrosis in multiple experimental models, including pulmonary fibrosis, sclerosing cholangitis, multiple sclerosis, and renal disease. In animal models of renal diseases, pirfenidone reduces glomerulosclerosis and interstitial fibrosis. The objective of this phase II trial is to evaluate safety and efficacy of pirfenidone therapy in patients with diabetic nephropathy. The study is a randomized, double-blind, dose ranging, three-arm study. All subjects will be randomized to one of the following: a daily dose of pirfenidone at 1200 mg, 2400mg, or placebo. Patients will be maintained on the current standard of care for diabetic nephropathy, including an angiotensin converting enzyme (ACE) inhibitor and/or angiotensin receptor blocker (ARB), antihypertensive therapy with blood pressure target of less than 130/80, and aggressive glycemic control with target hemoglobin A1C of less than 7%. We will enroll 30 adult patients with type 1 or 2 diabetes with glomerular filtration rate (GFR) between 20-75 ml/min/1.73m2, greater than 300 mg/d of proteinuria, and blood pressure less than or equal to 140/90 on an ACE inhibitor or an ARB.

The duration of therapy will be 54 weeks. The primary endpoint will be the change in renal function from baseline to the end of the study period. Renal function will be assessed by the GFR calculated by the 4-variable Levy equation. The GFR will be calculated based on two serum creatinine measurements obtained two weeks apart at baseline and two measurements at the end of the study period. The secondary endpoints will include the percent change in urine albumin excretion and the levels of urine and plasma TGF-beta from baseline to the end of the study period. All patients enrolled at the NIH will also have assays to measure oxidative damage at baseline and at the end of the study. In addition, NIH patients will undergo ophthalmologic examination at baseline and at the end of the study to assess if pirfenidone has a beneficial or adverse effect on diabetic retinopathy.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA :
Type 1 or type 2 diabetes. Ages greater than or equal to 18.
GFR between 20-75 ml/min/1.73m(2).
History of overt proteinuria (greater than 300 mg/24h or albumin positive by dipstick).
Blood pressure controlled to less than or equal to 140/90 including treatment with ACE-I and/or ARB.
Able to understand and sign consent to participate.
Able to understand and accept the guidlines of the study and comply with medication and follow up schedules.
Willing to refrain from becoming pregnant for the duration of the study.
EXCLUSION CRITERIA :
Inability to give informed consent or cooperate with the study.
Known intolerance to pirfenidone.
Presently pregnant or planning to become pregnant during the study period.
Males and females unwilling to use appropriate contraceptive measures.
Breast feeding or lactating.
Hematologic disease.
Malignancy.
Liver disease, screen for Hep B, Hep C, and HIV +.
On immunosuppressive medication.
Other known renal disease besides diabetic nephropathy by history.
Congestive heart failure (NYHA class III or worse).
History of recent myocardial infarction or unstable angina within the past 6 months.
History of peptic ulcer within 6 months.
History of cerebrovascular disease manifested by transient ischemic attack or cerebrovascular accident within 6 months.
Uncontrolled blood pressure (consistently above 140/90 despite maximal medical therapy).
Uncontrolled diabetes (hemoglobin A(1)C greater than 10%).
History of photosensitivity dermatitis, as this is a described potential risk of pirfenidone.
Expected to undergo renal transplantation or dialysis within 1 year time of enrollment.

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050113; 05-DK-0113
Record last reviewed:  February 23, 2005
Last Updated:  April 6, 2005
Record first received:  March 11, 2005
ClinicalTrials.gov Identifier:  NCT00105391
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08