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Sponsored by: |
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00098020 |
Retinoids are analogues of vitamin A that regulate cellular differentiation, leading to therapeutic use in skin disease and malignancy. In animal models of kidney disease, retinoids restore podocyte phenotype toward normal and reduce proteinuria. The objective of this phase II trial is to evaluate safety and develop preliminary evidence of efficacy of retinoid treatment in patients with podocyte disease. The study is an open-label, randomized trial of two physiologic retinoids: tretinoin (all-trans retinoic acid) and isotretinoin (13-cis retinoic acid). The study will be performed under the auspices of an IND from the FDA. We will enroll 22 patients with biopsy-proven minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy (CG). Inclusion criteria will include a prior trial of immunosuppressive therapy and proteinuria greater than or equal to 3.5 g/d while on angiotensin antagonist therapy.
The duration of the trial will be 24 weeks. The primary clinical endpoint will be reduction in proteinuria as compared to the baseline value assessed by paired t test. The data from each group will be analyzed separately. The secondary clinical endpoints will be the fraction of patients who achieve complete remission (CR) or partial remission (PR) at 24 and 48 weeks, confirmed on urine collections four weeks apart. Retinoid therapy will be discontinued at the time a CR is confirmed. Follow-up will last 48 weeks after cessation of drug therapy. Patients who have had CR, who have had less than 12 weeks of retinoid therapy, and who experience a relapse with greater than 3.5 g/d proteinuria during follow-up will be eligible for a second 24 week course of the retinoid that induced remission. Patients who discontinue therapy within the first 8 weeks due to an adverse event may have the opportunity to cross-over to the other arm.
Research renal biopsy will be performed twice in most patients: 1) at baseline, unless renal biopsy has been done within 24 weeks of enrollment and 2) when the diagnosis of CR or increased proteinuria is confirmed or alternatively upon completing 24 weeks of therapy (patients who exit the trial before 24 weeks due to non-renal adverse events will not undergo renal biopsy). Histologic endpoints will include change in linear extent podocyte foot process effacement, extent of podocyte proliferation, and expression of podocyte genes at the RNA and protein levels. Laboratory endpoints will include serum and urine cytokine levels and urine levels of podocyte proteins, including nephrin. Toxicity screening will include serum and urine chemistries, psychological profiles, radiographic films of cervical, thoracic spines and calcanei, and bone mass assessment with dual photon excitation absorptiometry (DEXA) at spine and hip.
Condition | Intervention | Phase |
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Kidney Diseases Glomerulosclerosis, Focal |
Procedure: Kidney needle biopsy Procedure: DEXA Scan Procedure: X-rays Drug: Retinoids for Podocyte Disease |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment |
Official Title: | Retinoids for Podocyte Disease |
Estimated Enrollment: | 10 |
Study Start Date: | November 2004 |
Retinoids are analogues of vitamin A that regulate cellular differentiation, leading to therapeutic use in skin disease and malignancy. In animal models of kidney disease, retinoids restore podocyte phenotype toward normal and reduce proteinuria. The objective of this phase II trial is to evaluate safety and develop preliminary evidence of efficacy of retinoid treatment in patients with podocyte disease. The study is an open-label trial of isotretinoin (13-cis retinoic acid). The study will be performed under the auspices of an IND from the FDA. We will enroll 10 adult patients with biopsy-proven minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy (CG). Inclusion criteria will include a prior trial of immunosuppressive therapy and proteinuria greater than or equal to 3.5 g/d while on angiotensin antagonist therapy.
The duration of the trial will be 6 months with possible additional 6-month extension for patients who only develop partial response (PR) or limited response (LR). Those who have complete response (CR) will continue the treatment for one additional month, for no more than 7 months total. Non-responders will stop at the end of 6 months. The primary clinical endpoint will be reduction in proteinuria as compared to the baseline value assessed by paired t test. The secondary clinical endpoints will be the fraction of patients who achieve (CR) or (PR) at 6 months and at one year, confirmed on urine collections four weeks apart. Retinoid therapy will be discontinued at the time a CR is confirmed, one month after the first detection of CR. Follow-up will last one year after cessation of drug therapy. Patients who have had CR or PR, but experience a relapse with greater than 3.5 g/d proteinuria during follow-up will be eligible for further retinoid therapy.
Research renal biopsy will be performed twice in most patients: 1) at baseline, unless renal biopsy has been done within 24 weeks of enrollment and 2) when the diagnosis of CR or increased proteinuria is confirmed or alternatively upon completing 6 months of therapy (patients who exit the trial before 6 months due to non-renal adverse events will not undergo renal biopsy) or; 3) when one year of therapy is completed for those undergoing 6-month extension. Histologic endpoints will include change in linear extent podocyte foot process effacement, extent of podocyte proliferation, and expression of podocyte genes at the RNA and protein levels. Laboratory endpoints will include serum and urine cytokine levels and urine levels of podocyte proteins, including nephrin. Toxicity screening will include serum and urine chemistries, psychological profiles, radiographic films of cervical, thoracic spines and calcanei, and bone mass assessment with dual photon excitation absorptiometry (DEXA) at spine and hip.
Ages Eligible for Study: | 16 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
EXCLUSION CRITERIA:
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 | |
United States, New York | |
Mt. Sinai Medical Center | Recruiting |
New York, New York, United States, 10029-0574 |
Responsible Party: | National Institutes of Health ( Monique E. Cho, M.D./National Institute of Diabetes and Digestive and Kidney Diseases ) |
Study ID Numbers: | 050015, 05-DK-0015 |
Study First Received: | December 1, 2004 |
Last Updated: | October 6, 2008 |
ClinicalTrials.gov Identifier: | NCT00098020 |
Health Authority: | United States: Federal Government |
Glomerulosclerosis Proteinuria Fibrosis Chronic Kidney Disease |
Nephrotic Syndrome Glomerulosclerosis Chronic Kidney Disease Nephrotic Syndrome |
Glomerulosclerosis, Focal Segmental Glomerulonephritis Proteinuria Nephrosis, Lipoid Urologic Diseases Fibrosis |
Renal Insufficiency, Chronic Nephritis Kidney Failure, Chronic Kidney Diseases Focal segmental glomerulosclerosis Nephrotic Syndrome |