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Protocol Details

Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

09-DK-0223

Sponsoring Institute

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

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 100

Referral Letter Required

No

Population Exclusion(s)

Children

Special Instructions

Currently Not Provided

Keywords

Kidney Disease;
Nephrotic Syndrome;
Autoimmune Diseases;
Clinical Trial;
Proteinuria

Recruitment Keyword(s)

None

Condition(s)

Nephrotic Syndrome;
Proteinuria;
Autoimmune Disease;
Glomerular Disease;
Membranous Glomerulonephritis

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

Drug: Rituximab Infusion
Drug: Oral Cyclosporine

Supporting Site

National Institute of Diabetes and Digestive and Kidney Diseases

Background:

- Membranous nephropathy is associated with damage to the walls of the glomeruli, the small blood vessels in the kidneys that filter waste products from the blood. This damage causes leakage of blood proteins into the urine and is associated with low blood protein levels, high blood cholesterol values, and swelling of the legs. These problems can decrease or go away without treatment in about 25 percent of patients, but if they persist, some patients may experience impaired (or loss of) kidney function, blood vessel and heart disease, and a risk of forming blood clots in veins.

- Kidney biopsies that show that antibodies have been deposited along the glomeruli suggest that specialized cells of the immune system, called B and T cells, are causing damage to the kidneys through their increased activity. To suppress the action of B and T cells and to decrease the harmful deposits in the kidneys, drug treatments are required.

- Patients with membranous nephropathy are often treated with immunosuppressive drugs such as cyclosporine or cytoxan plus steroids that attempt to reduce or suppress the activity of the immune system, decrease antibody production, and reduce antibody deposits in the kidney. However, not everyone responds to these medications and the kidney disease can return in some patients when the drugs are stopped. Also, there are side effects associated with long term usage of these medications. Rituximab, a different immunosuppressant, has also been used for this purpose. Although cyclosporine and Rituximab have been used separately, they have not been tried in combination as a possible treatment for membranous nephropathy.

Objectives:

- To determine the safety and effectiveness of combining rituximab and cyclosporine to treat membranous nephropathy.

Eligibility:

- Individuals 18 years of age and older who have been diagnosed with membranous nephropathy based on a kidney biopsy done within the preceding 24 months, and who have had excess levels of protein in the urine for at least 6 months based on urine and blood tests.

Design:

- Potential participants will be screened with an initial clinic evaluation and full medical history.

- Before the treatment, there will be a run-in period that will last up to 2 months. During this time, participants will be placed on a blood pressure lowering medication and will not take any other immunosuppressant medications.

- Participants will visit the NIH clinical center for a baseline evaluation, four intravenous infusions of rituximab, and also at 1- to 6-month intervals throughout the study.

- Active treatment period will involve a 6-month course of cyclosporine and a total of four doses of rituximab. Participants will take cyclosporine tablets twice daily, and have two infusions of rituximab given 2 weeks apart, After 6 months, the cyclosporine dose will slowly be decreased over several weeks and then completely discontinued. Participants will then receive another course (two doses 2 weeks apart) of rituximab, depending on results of blood work.

- Participants will have frequent blood and urine tests performed to monitor the results of treatment and reduce the chance of side effects.

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Eligibility

INCLUSION CRITERIA:

1. Ability and willingness to provide informed consent (adults greater than or equal to 18 years).

2. Nephrotic range proteinuria that persists for at least 6 months greater than 3.5 grams /24 hours (based on 24 hour urine collection).

3. Nephrotic range proteinuria (>3.5 g/24 hours) that persists despite angiotensin antagonist therapy (ACE inhibitor or ARB) for at least 2 months unless intolerant.

4. Renal biopsy within the past 24 months must reveal typical changes of membranous nephropathy by light and electron microscopy.

5. There is no evidence to suggest secondary forms of membranous nephropathy. Diagnostic studies for the common causes of membranous nephropathy are listed under Baseline evaluation. Additional studies will be obtained as indicated.

EXCLUSION CRITERIA:

1. Age <18 years old

2. Estimated GFR<40 ml/min/1.73 m^2 (determined by the 4 variable version of the MDRD Study prediction equation) while on ACEI/ARB therapy . Lab values from the preceding 2 months prior to enrollment will be used to assess eligibility.

3. Immunosuppressive medications or experimental medications of any type during the three month period prior to initiating Rituximab and cyclosporine.

4. Prior exposure to cyclosporine or tacrolimus for more than 6 months and/or evidence of intolerance or toxicity associated with cyclosporine treatment of any duration including irreversible azotemia, liver dysfunction or hypertension.

5. Prior treatment with Rituximab.

6. Clinically significant medical conditions (i.e. severe heart failure NYHA class IV, uncontrolled coronary artery disease/unstable angina), which in the opinion of the investigator, could increase the subject s risk of participating in the study or could confound the interpretation of the results of the study. Patients with a history of arrhythmias will be evaluated by a cardiology consultant regarding recommendations as Rituximab has been reported to exacerbate arrhythmias (in patients with rheumatoid arthritis).

7. Active acute or chronic infection requiring antimicrobial therapy or serious viral infection (HIV, hepatitis B or C, herpes simplex, varicella zoster virus, parvovirus).

8. Live viral vaccines within one month prior to Rituximab.

9. Pregnant women, nursing mothers or individuals (men or women) not practicing birth control.

The rationale is that the safety of Rituximab during pregnancy, lactation, and infancy has not been determined. However, limited data indicate that rituximab is present in human milk and the effect on the breastfed child and no data on the effect on milk production. IgG molecules are known to cross the placenta and Rituximab has been detected in the serum of infants exposed in utero. Limited data indicate that B cell lymphocytopenia lasting less than six months can occur in infants exposed to Rituximab in utero. Pregnancy is not recommended until at least one year after Rituximab administration. Breastfeeding is not recommended during treatment with rituximab and for 6 months after the last dose. In humans, cyclosporine crosses the placenta and premature births and low birth weight are consistently observed. Cyclosporine enters breast milk and may lead to immune suppression in the infant as well as the unknown effects on growth or association with carcinogenesis.

10. Uncontrolled hypertension defined as BP >140/90 on >25% of measurements. Blood pressures will be measured 3 times at each clinic visit after the patient has sat quietly for at least 5 minutes.

11. Cancer diagnosis or cancer recurrence within the preceding 5 years, excluding basal cell carcinoma of the skin.

12. Clinical evidence of cirrhosis or chronic active liver disease sufficiently severe to impair cyclosporine metabolism; this would include a prolonged prothrombin time. Patients with abnormal liver function tests will be evaluated by the Hepatology Consult Service to determine whether protocol participation is appropriate.

13. Cytopenia (neutrophils <1500/mm^3 and/or thrombocytopenia <75,000) and/or CD4 T cell count <200/mm^3).

14. Diabetes mellitus.


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Citations:

Glassock RJ. Diagnosis and natural course of membranous nephropathy. Semin Nephrol. 2003 Jul;23(4):324-32.

Cattran D. Management of membranous nephropathy: when and what for treatment. J Am Soc Nephrol. 2005 May;1 (5):1188-94. Epub 2005 Mar 30.

Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis). J Am Soc Nephrol. 1996 Dec;7(12):2518-26.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Meryl A. Waldman, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10-CRC RM 5-5750
10 CENTER DR
BETHESDA MD 20814
(301) 451-6990
waldmanm@mail.nih.gov

Meryl A. Waldman, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
BG 10-CRC RM 5-5750
10 CENTER DR
BETHESDA MD 20814
(301) 451-6990
waldmanm@mail.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: 1-866-411-1010
PRPL@cc.nih.gov

Clinical Trials Number:

NCT00977977

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