Fibrosis, Focal Glomerulosclerosis, Kidney Failure, Nephrotic Syndrome, Proteinuria
Conditions
Keywords
Fibrosis, Nephrotic Syndrome, Proteinuria, Renal Failure, TGF-Beta, Focal Segmental Glomerulosclerosis, FSGS
Brief summary
This study will examine the effectiveness of the drug pirfenidone in treating focal segmental glomerulosclerosis (FSGS). Patients with this disease have kidney fibrosis (scarring) and proteinuria (excessive excretion of protein in the urine). About half of patients with FSGS eventually require kidney dialysis or transplant. Steroids, which are currently used to treat the disease, are effective in only a minority of patients. Other drugs, such as cyclosporin and cyclophosphamide, improve proteinuria in a very small percentage of patients and have serious side effects. Patients with FSGS who wish to participate in this study will undergo pre-study evaluation with blood and urine tests. Patients must be on a stable dose of an ACE inhibitor (a drug that lowers blood pressure and reduces proteinuria) for at list 6 months before starting pirfenidone therapy. (Patients who are not already taking an ACE inhibitor will be started on the drug; those who cannot tolerate ACE inhibitors will be given a different drug.) Patients with elevated cholesterol will take a cholesterol-lowering drug. A diet containing approximately 1 gram of protein per kilogram of body weight per day will be recommended. Patients will take pirfenidone by mouth 3 times a day for 12 months. Blood and urine will be tested once a month, either at NIH or by the patient's local kidney specialist. They will collect two 24-hour urine samples at the beginning of the treatment period, at 2-month intervals throughout the study, and at a 6-month follow-up. Patients will also be asked to give three to five tubes of blood and urine samples for analysis during the study. In animal studies, pirfenidone improved kidney function and proteinuria and reduced kidney scarring in rats with a disease similar to FSGS. In human studies, pirfenidone improved breathing and survival in patients with lung fibrosis.
Detailed description
The objective of this pilot phase II trial is to evaluate the ability of pirfenidone, a novel anti-fibrotic agent, to reduce the proteinuria and slow the rate of progression of renal insufficiency in patients with focal segmental glomerulosclerosis (FSGS). We will enroll 25 patients with renal biopsy proven FSGS and evidence of impaired renal function (glomerular filtration rate, GFR, of 10-80 ml/min; after 1/02 must have GFR greater than 25 ml/min) as assessed by the 4 variable Modification of Diet in Renal Disease equation. As standard of care therapy, all patients will also receive angiotensin converting enzyme inhibitor (ACEI) therapy, and will receive an HMG Co-A reductase inhibitor drug if hypercholesterolemic. Preliminary evaluation will assure that the patients meet the study requirements, and an evaluation period will be used to ensure that patients are on maximal conservative therapy prior to the baseline period. Patients will receive treatment with pirfenidone daily, with dose adjusted for body weight and level of kidney function. The primary end point will be the decrease glomerular filtration as a marker of glomerular injury; reduction in proteinuria will be a secondary end-point. If the pilot study suggests this drug delays progression of renal insufficiency or reduces proteinuria in patients with FSGS, we will proceed with a large scale randomized, placebo-controlled study.
Interventions
DRUGPirfenidone
During the study drug period of 12 months, patients will receive oral pirfenidone daily. For patients whose initial renal function is 50-80 ml/min as assessed by the MDRD equation, the initial pirfenidone dosage will be calculated at 40 mg/kg/d, with a maximum dose of 800 mg TID. For patients whose initial renal function is 30-50 ml/min, the initial dose will be 30 mg/kg/d. For patients whose initial renal function is between 15 and 30 ml/min, the initial dose will be 20 mg/kg/d.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: 1. Adults greater than or equal to 18 years of age. 2. Patients will provide informed consent. 3. Biopsy proven FSGS. 4. Glomerular filtration rate of at least 25 and no more than 80 ml/minute as assessed by the 4 variable Modification of diet in renal disease GFR equation. 5. At least 6 months of renal function data must be available prior to the patient's receiving pirfenidone, and renal function must show a rate of decline of greater than or equal to 0.4 ml/min/month during this baseline period. 6. Patients must have received no glucocorticoids, cyclophosphamide, mycophenolate or other immunosuppressive drugs for at least 2 months prior to the study period. 7. Patients must have received no cyclosporin for at least 6 months prior to the study period. 8. Patients must have been taking an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) at a stable dose for at least 6 months, unless intolerant of both classes of medication. 9. Patients who are HIV seropositive will receive standard care for HIV disease (patients receiving immune-modulating therapy will be excluded). 10. Women with child-bearing potential must maintain an effective birth control regimen (oral contraceptive, intrauterine device, barrier plus spermicide). 11. Men will be advised that although Ames testing has been negative for any evidence of mutagenicity, they should consider use of contraceptives during the study period as well.
Exclusion criteria
1. Inability to give informed consent or cooperate with study. 2. Known intolerance to pirfenidone. 3. Evidence of FSGS associated with an additional primary or secondary glomerular disease (e.g. diabetes, membranous nephropathy, IgA nephropathy). 4. Recent (within 6 months) history of myocardial infarction. 5. History of peptic ulcer within 6 months. 6. History of cerebrovascular disease manifested by transient ischemic attack or cerebrovascular accident within 6 months. 7. Pregnancy, breast feeding or inadequate birth control. 8. History of photosensitivity dermatitis. 9. Concurrent drug treatment with gemfibrozil, cyclosporin or erythromycin, potassium-sparing diuretics and other drugs which may potentiate hyperkalemia, or concurrent immunosuppresive medications. 10. Requirement for NSAID therapy. 11. Requirement for interleukin-2 therapy or other immune-modulating medication. 12. Existence of any other condition which would complicate the implementation or interpretation of the study. 13. Renal transplant. 14. Evidence of significant hepatic disease, as indicated by serum transaminases greater than 3 times upper limit of normal, protime greater than 2 seconds prolonged.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Decrease in GFR During Treatment Period | 12 months from baseline |
Secondary
| Measure | Time frame |
|---|---|
| Proteinuria After Treatment | 12 months from baseline |
| Proportion of Patients With Positive Change in GFR | 12 months from baseline |
Countries
United States
Participant flow
Recruitment details
21 adults patients were enrolled between 2000-2004 at the clinical center of NIH
Participants by arm
| Arm | Count |
|---|---|
| Pirfenidone During the study drug period of 12 months, patients will receive oral pirfenidone daily. For patients whose initial renal function is 50-80 ml/min as assessed by the MDRD equation, the initial pirfenidone dosage will be calculated at 40 mg/kg/d, with a maximum dose of 800 mg TID. For patients whose initial renal function is 30-50 ml/min, the initial dose will be 30 mg/kg/d. For patients whose initial renal function is between 15 and 30 ml/min, the initial dose will be 20 mg/kg/d. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | disabling sedation | 1 |
| Overall Study | newly diagnosed colon cancer | 1 |
| Overall Study | non-compliance | 1 |
Baseline characteristics
| Characteristic | Pirfenidone |
|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 10 |
| Baseline GFR | 26.0 ml/min/1.73 m^2 STANDARD_DEVIATION 9.4 |
| Baseline period proteinuria | 3.2 g/d |
| Decrease in GFR during baseline period | -0.61 ml/min/1.73 m^2 |
| Duration of angiotensin antagonist therapy before treatment | 15 month |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 21 |
| serious Total, serious adverse events | 3 / 21 |
Outcome results
Primary
Decrease in GFR During Treatment Period
Time frame: 12 months from baseline
Population: ITT
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pirfenidone | Decrease in GFR During Treatment Period | -0.45 ml/min/1.73 m2 |
Comparison: H0: GFR Decrease during baseline period and treatment period are samep-value: <0.01Wilcoxon (Mann-Whitney)
Secondary
Proportion of Patients With Positive Change in GFR
Time frame: 12 months from baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pirfenidone | Proportion of Patients With Positive Change in GFR | 13 participants |
Secondary
Proteinuria After Treatment
Time frame: 12 months from baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone | Proteinuria After Treatment | 4.3 g/d |
Comparison: H0: Proteinuria during baseline and treatment periods are samep-value: 0.16Kruskal-Wallis