Podocyte Retinoids

NCT00098020 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 05001505-DK-0015
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This is a pilot study of retinoids for patients with unsatisfactory response to conventional treatment of nephrotic syndrome due to focal segmental glomerulosclerosis or minimal change disease, two renal disorders associated with putatively pathogenic malfunctioning of glomerular podocytes. The hypothesis that retinoids may have reparative effects on these cells is based on previous research showing that retinoids promote the differentiation or redifferentiation of aberrant epithelial cells. Results obtained by 6 months of treatment with retinoids (that have been approved for non-renal indications) will be used as preliminary information upon which to base further testing of these agents in formal clinical trials in refractory cases of these nephrotic syndromes.

Conditions

Collapsing Glomerulopathy; Glomerulosclerosis, Focal Segmental

Keywords

Glomerulosclerosis; Proteinuria; Fibrosis; Chronic Kidney Disease; Nephrotic Syndrome

Outcome Measures

Primary Outcomes (1)

• Change in Proteinuria at Week 24 From Baseline

  Change of proteinuria at Week 24 compared to the baseline using protein/creatinine ratio (PCR)

  Baseline and Week 24

Secondary Outcomes (1)

• Number of Patients Who Are in Complete Remission (CR) or Partial Remission (PR) at 6 Months or at the End of One Year.

  End of one year from baseline

Study Arms (1)

Isotretinoin

EXPERIMENTAL

Subjects will be treated with Isotretinoin.

Drug: Isotretinoin

Interventions

Isotretinoin DRUG

Isotretinoin

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with podocyte diseases, MCD, FSGS (including primary, secondary, and adaptive variants), and CG (including HIV-associated variant), who meet the following criteria:
• An adequate renal biopsy, defined as having minimum 10 glomeruli for light microscopy and minimum 3 glomeruli for electron microscopy, unless the podocyte disease is diagnostic on fewer glomeruli. Patients who have non-diagnostic or technically inadequate biopsies will be offered the opportunity to undergo a research biopsy to determine eligibility. For some patients who have had a non-diagnostic or technically inadequate biopsy, a repeat renal biopsy may be clinically indicated in an effort to diagnose and treat a potentially serious kidney disease.
• Greater than or equal to 16 years of age. The rationale for excluding younger children is that retinoids may carry greater toxicity in children, as there are reports of premature epiphyseal closure, development of slender long bones, and periostal thickening.
• Prior treatment with at least two immunosuppressive agents that have been shown to induce remission in MCD and FSGS: glucocorticoids, cyclosporine, tacrolimus, cyclophosphamide, chlorambucil, and mycophenolate mofetil. Therapy with each agent must last at least 8 weeks. Exemptions will be made for those with contraindications to these medications or those who cannot tolerate these medications. The rationale is to recruit patients who have failed conventional therapy. All patients will be off immunosuppression for at least 4 weeks before starting retinoids in order to avoid a confounding effect.
• Three first void urine protein/creatinine ratios \> 2 g/g obtained within one month prior to enrolling in the study. These urine collections will be obtained after the patient has been on a stable dose of angiotensin converting enzyme(ACE) inhibitor or angiotensin receptor blocker (ARB) for at least 4 weeks (the maximal antiproteinuric effect of these medications occurs after 4 weeks). The rationale is that patients with nephrotic-range proteinuria are at high risk for progressive renal disease, justifying participation in a clinical trial with novel agents. Patients with steroid-sensitive frequently relapsing MCD will not be required to have used ACE inhibitor or ARB, as steroids alone are typically sufficient therapy to induce remission.
• If hypertensive: blood pressure of less than or equal to 140/90 on a stable dose of ACE inhibitor or ARB for at least 1 month or greater than or equal to 75 percent of measurements before the entry of the study. The rationale is that uncontrolled hypertension can exacerbate proteinuria.

You may not qualify if:

• Pregnancy, breastfeeding, or unwillingness to use at least two contraceptive methods (at least one of which must be primary, including tubal ligation, partner vasectomy, oral contraceptives, implanted contraceptives, and intrauterine device). The rationale is that retinoids are teratogenic and are excreted in breast milk.
• Abnormal liver function test, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, or protime. The rationale is that retinoids can be hepatotoxic. The only exception will be the following: if the cause of abnormality of liver function tests (LFT) is felt to be due to a specific hepatotoxic drug such as a statin and the levels are less than 2 times the upper limit of the normal AND normalize upon holding the offending drug, patients may be considered for study participation after consultation with hepatology service.
• Hypertriglyceridemia greater than 500 mg/dL despite statin/fibrate therapy. The rationale is that retinoids can increase lipids, particularly triglyceride as this can lead to pancreatitis.
• Any medical conditions requiring concurrent immunosuppression, as this pilot study is designed to evaluate the effect of retinoids as a monotherapy.
• Any medical conditions requiring concurrent use of tetracycline, minocycline, or doxycycline, due to enhanced risk of increased intracranial pressure.
• Hypersensitivity to retinoids.
• Presence of any unstable cardiovascular disease, uncontrolled diabetes with hemoglobin A1c greater than 8 percent, chronic inflammatory or infectious conditions except HIV-1 infection. Retinoids have been associated with chest pain of unclear etiology, increased serum glucose, myelosuppression and increased risk of infection. The etiology of infection is not clear but may be related to myelosuppression.
• Those with HIV-1 infection must not have any evidence for opportunistic infectious complications and have cluster of differentiation 4 (CD4) count greater than or equal to 200. Both tretinoin and isotretinoin have been safely studied in HIV-infected patients for other indications.
• glomerular filtration rate (GFR) less than 40 ml/min/1.73m(2) estimated by 5-variable Modification of Diet in Renal Disease (MDRD) equation, as the metabolites of retinoids are excreted in part in urine, and there is a concern for increased toxicity. In participants less than 18 years of age, we will use Schwartz equation.
• Expansion of glomerulus or interstitial formation on the biopsy.
• Untreated depression, as retinoids have been associated with depression, suicidal ideation, and aggressive behavior. If patients manifest significant depressive symptoms, they will be included in the study only if assessed and agreed by a psychiatrist (either at NIH or other) and if they have regular follow-up visits with a psychiatrist.
• Factors that increase the risk of renal biopsy. These include the following: unwillingness to accept blood transfusion, bleeding diathesis, single kidney, small kidneys (less than 9.5 cm).

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• WILSON JG, ROTH CB, WARKANY J. An analysis of the syndrome of malformations induced by maternal vitamin A deficiency. Effects of restoration of vitamin A at various times during gestation. Am J Anat. 1953 Mar;92(2):189-217. doi: 10.1002/aja.1000920202. No abstract available.

  PMID: 13030424 BACKGROUND

• Lelievre-Pegorier M, Vilar J, Ferrier ML, Moreau E, Freund N, Gilbert T, Merlet-Benichou C. Mild vitamin A deficiency leads to inborn nephron deficit in the rat. Kidney Int. 1998 Nov;54(5):1455-62. doi: 10.1046/j.1523-1755.1998.00151.x.

  PMID: 9844121 BACKGROUND

• Kriz W, Elger M, Nagata M, Kretzler M, Uiker S, Koeppen-Hageman I, Tenschert S, Lemley KV. The role of podocytes in the development of glomerular sclerosis. Kidney Int Suppl. 1994 Feb;45:S64-72. No abstract available.

  PMID: 8158902 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Glomerulosclerosis, Focal Segmental; Proteinuria; Fibrosis; Renal Insufficiency, Chronic; Nephrotic Syndrome

Interventions

Isotretinoin

Condition Hierarchy (Ancestors)

Glomerulonephritis; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urination Disorders; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Renal Insufficiency; Chronic Disease; Disease Attributes; Nephrosis

Intervention Hierarchy (Ancestors)

Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors

Results Point of Contact

• Title: Dr. Jeffery Kopp
• Organization: National Institutes of Diabetes, Digestive, and Kidney Disorders

koppj@mail.nih.gov

301-594-3403

Study Officials

• Jeffrey B Kopp, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: Phase II, open-label pilot study

Study Record Dates

• First Submitted: December 1, 2004
• First Posted: December 2, 2004
• Study Start: November 26, 2004
• Primary Completion: June 27, 2016
• Study Completion: June 27, 2016
• Last Updated: December 13, 2017
• Results First Posted: December 13, 2017

Record last verified: 2017-10-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: Until study closure.
• Access Criteria: Collaborating investigators

Locations

US (1)