Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy

• ClinicalTrials.gov Identifier: NCT00977977
• Recruitment Status: Recruiting
• First Posted: September 16, 2009
• Last Update Posted: July 1, 2022
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Nephrotic Syndrome; Proteinuria; Autoimmune Disease; Glomerular Disease; Membranous Glomerulonephritis	Drug: Rituximab Infusion; Drug: Oral Cyclosporine	Phase 2

Detailed Description:

This is a pilot intervention study to evaluate preliminary evidence of the safety and effectiveness of a novel combination immunosuppressive regimen, Rituximab plus cyclosporine, in the treatment of idiopathic membranous nephropathy. Membranous nephropathy is a condition that affects the kidney and involves damage to the walls of tiny blood vessels filters in the kidneys called glomeruli. This damage allows blood proteins to leak into the urine (proteinuria). As a result, patients have low protein levels in the blood, high blood cholesterol levels and often develop leg swelling. This combination of symptoms and signs is called the nephrotic syndrome. Some patients with membranous nephropathy develop impaired kidney function and a proportion of these patients may develop kidney failure. The immunosuppressive drugs that are most often used to treat membranous nephropathy include cyclophosphamide plus steroids or cyclosporine. These vary in their effectiveness among patients and there are side effects with each treatment. Rituximab alone has been used experimentally to treat membranous nephropathy in small clinical trials. It has been associated with decreased proteinuria of variable degrees in some patients. The purpose of this pilot study is to evaluate whether the combination of Rituximab plus cyclosporine, two drugs with different effects on the immune system, results in a greater number of remissions of the nephrotic syndrome and more sustained remissions than is expected with cyclosporine alone. Although each of these medications has been used separately in membranous nephropathy, the potential benefits and risks of this combination have not yet been formally explored. Patients age 18 years and older with idiopathic membranous nephropathy will be eligible to participate in this study. Pregnant and nursing women may not participate. Candidates must have persistent nephrotic syndrome despite a 6 month observation period and treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blocker. Candidates will be screened with a medical history, physical examination, blood and urine tests, review of the medical records and kidney biopsy results. Participants will come to NIH in Bethesda, Maryland for evaluation and to receive intravenous infusions of Rituximab. Two doses of Rituximab will be given (2 weeks apart). Participants will also take cyclosporine pills twice a day. After 6 months, the dose of cyclosporine will be tapered over several weeks and then discontinued. Patients will be re-treated with a second course of Rituximab (two infusions given two weeks apart) after a minimum of 6 months has passed since completing the first course of Rituximab. The exact timing of the second course of Rituximab will depend on the results of blood tests. All patients will be followed for a minimum of 24 months from the time that therapy is initiated.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
• Actual Study Start Date: December 2, 2010
• Estimated Primary Completion Date: January 31, 2023
• Estimated Study Completion Date: January 31, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combination of Rituximab plus cyclosporine; 2 infusions (each 1000 mg) separated by 2 weeks; repeated after 6 months. Daily therapy for 6 months (3-5 mg/kg), then tapered and discontinued.	Drug: Rituximab Infusion; Drug Rituximab Infusion 2 infusions (each 1000 mg) separated by 2 weeks; repeated after 6 months; Drug: Oral Cyclosporine; Daily therapy for 6 months (3-5 mg/kg), then tapered and discontinued

Outcome Measures

Primary Outcome Measures :

1. Safety [ Time Frame: 24 months ]
   Safety 24 months We will assess using the National Cancer Institute common Terminology Criteria for Adverse Events (CTCAE)
2. Percentage of complete and partial remissions (CR and PR) [ Time Frame: 6 months ]
   Proteinuria; complete remission (CR) defined as less than 300 mg/24 proteinuria and partial remission (PR) <3.5 grams/day and >=50%reduction of proteinuria
3. Percentage of complete and partial remissions (CR and PR) [ Time Frame: 24 months ]
   Proteinuria; complete remission (CR) defined as less than 300 mg/24 proteinuria and partial remission (PR) <3.5 grams/day and >=50%reduction of proteinuria
4. Percentage of complete and partial remissions (CR and PR) [ Time Frame: 18 months ]
   Proteinuria; complete remission (CR) defined as less than 300 mg/24 proteinuria and partial remission (PR) <3.5 grams/day and >=50%reduction of proteinuria
5. Percentage of complete and partial remissions (CR and PR) [ Time Frame: 12 months ]
   Proteinuria; complete remission (CR) defined as less than 300 mg/24 proteinuria and partial remission (PR) <3.5 grams/day and >=50%reduction of proteinuria

Secondary Outcome Measures :

1. Time to remission Baseline to 24 months [ Time Frame: Baseline to 24 months ]
2. Time to relapse (in those who achieved a remission) [ Time Frame: Baseline to 24 months ]
3. Change in proteinuria from baseline to 12 months [ Time Frame: Baseline to 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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.

Contacts and Locations

Contacts

Contact: Meryl A Waldman, M.D.; (301) 451-6990; waldmanm@mail.nih.gov

Locations

United States, Maryland

National Naval Medical Center; Recruiting

Bethesda, Maryland, United States, 20889

National Institutes of Health Clinical Center, 9000 Rockville Pike; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Meryl A Waldman, M.D.; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

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

Cattran D. Management of membranous nephropathy: when and what for treatment. J Am Soc Nephrol. 2005 May;16(5):1188-94. Epub 2005 Mar 30. Review.

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. Review.

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00977977
• Other Study ID Numbers: 090223; 09-DK-0223
• First Posted: September 16, 2009
• Last Update Posted: July 1, 2022
• Last Verified: December 17, 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):

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

Additional relevant MeSH terms:

Proteinuria; Nephrotic Syndrome; Nephrosis; Glomerulonephritis; Glomerulonephritis, Membranous; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Immune System Diseases; Urination Disorders; Urological Manifestations; Nephritis; Cyclosporine; Rituximab; Cyclosporins; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Calcineurin Inhibitors