MEmbranous Nephropathy Trial Of Rituximab



Status:Active, not recruiting
Conditions:Renal Impairment / Chronic Kidney Disease, Nephrology
Therapuetic Areas:Nephrology / Urology
Healthy:No
Age Range:18 - 80
Updated:1/11/2019
Start Date:November 2011
End Date:October 2019

Use our guide to learn which trials are right for you!

"A Randomized Controlled Trial of Rituximab Versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (IMN)"

The primary outcome of this study is to determine whether or not the B cell targeting with
Rituximab is non-inferior or more effective than Cyclosporine in inducing long term remission
of proteinuria.

In IMN, experimental data suggests that B cells are involved in the pathogenesis of the
disease. To date, the best proven therapy for patients with MN consists of the combined use
of corticosteroids and cyclophosphamide (CYC). Since the mechanism of action of CYC includes
suppression of various stages of the B cell cycle including B cell activation, proliferation,
and differentiation and inhibition of immunoglobulin secretion, it lends credence to the
hypothesis that B cells abnormalities are involved in the pathogenesis of MN. Given the key
role of IgG antibodies in MN, it is reasonable to postulate that suppression of antibody
production by depleting B cells may improve or even resolve the glomerular pathology and be
reflected by a reduction in proteinuria. Thus, a case could be made for using an agent
capable of selectively depleting B cells, and therefore halting the production of
immunoglobulins against antigens potentially present in the glomeruli. This approach could
stop the initiating sequence of pathogenic events and result in resolution of the. The P.I.
believes that the application of selective B cell targeting with Rituximab (RTX) will prove
at least equal, or even superior, both in the production of short term and long term control
of the NS and be safer than any current therapeutic regimen used to treat MN.

Based on this rationale, we conducted a pilot trial in 15 newly-biopsied patients (<3 years)
with IMN and proteinuria >5g/24h despite ACEi/ARB use for >3months and systolic BP <130mmHg.
Mean baseline creatinine was 1.4 mg/dl. Thirteen males and 2 females, median age 47 (range
33-63), were treated with RTX (1g) on days 1 and 15. At six months, patients who remained
with proteinuria >3g/24 received a second identical course of RTX. Baseline proteinuria of
13.0±5.7g/24h (range 8.4-23.5) decreased to 6.0±7.0 g/24h (range 0.2-20) at 12 months (mean ±
SD). In the fourteen patients who completed a 12 months follow-up complete remission
(proteinuria <0.3g/24h) was achieved in 2 patients and partial remission (<3g/24h) in 7
patients. In 5 of these 7 patients, proteinuria was <1.5g/24h and follow up at 18 months
showed that 3 of these 7 patients on PR achieved CR of proteinuria. Five patients did not
respond. The mean drop in proteinuria from baseline to 12 months was 6.2± 5.1g (p=.002,
paired t-test). There were a limited number of minor side-effects. Initial CD20+ B cell
depletion was seen in all patients. However, at 3 months, CD20+ B cells were starting to
recover with five patients >35 cells/µl (range 35-152).(50) These data contrasts with
previous work by Ruggenenti et al. using RTX given weekly (375 mg/m2) for 4 weeks.
Pharmacokinetic (PK) analysis showed that RTX levels in this 2-dose regimen were 50% lower
compared to non-proteinuric patients, which could potentially result in undertreatment.

Based on these results, we recently conducted a study postulating that in patients with MN, 4
weekly doses of RTX would result in more effective B cell depletion, a higher remission rate
and maintaining of the same safety profile compared to patients treated with RTX dosed at 1g
x 2. Twenty patients (11 failures to prior therapy) with MN and proteinuria >5g/24h received
RTX (375mg/m2 x 4), with retreatment at 6 months regardless of proteinuria response. A
detailed PK was conducted simultaneously along with immunological analyses of the adaptive
immune compartment (T and B cells) to ascertain the impact of RTX on lymphocyte
subpopulations. Baseline proteinuria of 11.9±4.9g/24h decreased to 4.2±3.8g/24h and
2.0±1.7g/24h at 12 and 24 months, respectively (p<0.001) while creatinine clearance increased
from 72.4±33 at baseline to 88.4 ±31.5 ml/min/1.73m2 at 24 months (p=0.02).

Of 18 patients who completed 24-months follow up, 4 are in complete remission, 12 are in
partial remission (CR + PR = 80%), 1 has a limited response (>50% drop in P but >3.5g/24h)
and 1 patient relapsed. When interpreting these results we should take into account that >50%
of these patients had failed previous immunosuppressive therapy. This study also emphasizes
that proteinuria is reduced gradually and may take several months to reach its nadir an
observation that is in agreement with previous reports in patients with MN treated with
prednisone in combination with a cytotoxic agent but without the short-term toxicity seen
with alkylating agents. Kidney function remained stable or improved in all patients.

Serum RTX levels were similar to those obtained with 2 doses of RTX. Four 4 doses of RTX did
result in more effective B cell depletion but proteinuria reduction was basically identical
to the results obtained using RTX 1000mg on days 1 and 15. Thus, we believe that this
particular dosing regimen with retreatment at 6 months should be used in a randomized-control
trial comparing RTX to Cyclosporine (the standard of care for IMN in the US). We believe that
RTX will prove equal or superior to Cyclosporine in the treatment of MN and could represent
the new standard of care for patients with this disease

Inclusion Criteria

- Idiopathic MN with diagnostic biopsy

- Female, must be post-menopausal, surgically sterile or practicing a medically approved
method of contraception(no birth-control pill)

- Must be off prednisone or mycophenolate mofetil for >1 month and alkylating agents for
>6 months.

- ACEi and/or ARB, for >3 months prior to randomization and adequate blood pressure
(target BP <130/80 mmHg in >75% of the readings, but subjects with BP <140/80 mmHg in
>75% of the readings will be eligible). Patients with documented evidence of >3 months
treatment with maximal angiotensin II blockade, on an HMG-CoA reductase inhibitor, and
BP control (BP <140/80 mmHg in >75% of the readings) who remain with proteinuria
>5g/24h may enter and be randomized to RTX/CSA without the need of the
run-in/conservative phase of the study.

- Proteinuria >5g/24h on two 24-hour urine collection collected within 14 days of each
other

- Estimated GFR ≥40 ml/min/1.73m2 while taking ACEi/ARB therapy OR quantified endogenous
creatinine clearance >40 ml/min/1.73m2 based on a 24-hour urine collection.

Exclusion Criteria

- Presence of active infection or a secondary cause of MN (e.g. hepatitis B, SLE,
medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred <2
years prior to enrollment into the study.

- Type 1 or 2 diabetes mellitus: to exclude proteinuria secondary to diabetic
nephropathy. Patients who have recent history of steroid induced diabetes but no
evidence on renal biopsy performed within 6 months of entry into the study are
eligible for enrollment.

- Pregnancy or breast feeding for safety reasons

- History of resistance to CSA (or other calcineurin inhibitors, e.g. tacrolimus), RTX
or alkylating agents (e.g. Cytoxan). Patients who previously responded to CSA/CNI, RTX
or alkylating agents with either a CR or PR but relapsed off CSA/CNI after 3 months or
relapsed off RTX or alkylating agent after 6 months are eligible.
We found this trial at
19
sites
?
mi
from
Milwaukee, WI
Click here to add this to my saved trials
1720 2nd Ave S
Birmingham, Alabama 35233
(205) 934-4011 
University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
?
mi
from
Birmingham, AL
Click here to add this to my saved trials
9500 Euclid Avenue
Cleveland, Ohio 44106
216.444.2200
Cleveland Clinic Cleveland Clinic is committed to principles as presented in the United Nations Global...
?
mi
from
Cleveland, OH
Click here to add this to my saved trials
2500 N State St
Jackson, Mississippi 39216
(601) 984-1000
University of Mississippi Medical Center The University of Mississippi Medical Center, located in Jackson, is...
?
mi
from
Jackson, MS
Click here to add this to my saved trials
500 S State St
Ann Arbor, Michigan 48109
(734) 764-1817
University of Michigan The University of Michigan was founded in 1817 as one of the...
?
mi
from
Ann Arbor, MI
Click here to add this to my saved trials
?
mi
from
Cleveland, OH
Click here to add this to my saved trials
281 W. Lane Ave
Columbus, Ohio 43210
(614) 292-6446
Ohio State University The Ohio State University’s main Columbus campus is one of America’s largest...
?
mi
from
Columbus, OH
Click here to add this to my saved trials
Jacksonville, Florida 32216
?
mi
from
Jacksonville, FL
Click here to add this to my saved trials
3901 Rainbow Blvd
Kansas City, Kansas 66160
(913) 588-5000
University of Kansas Medical Center The University of Kansas Medical Center serves Kansas through excellence...
?
mi
from
Kansas City, KS
Click here to add this to my saved trials
?
mi
from
Miami, FL
Click here to add this to my saved trials
630 W 168th St
New York, New York
212-305-2862
Columbia University Medical Center Situated on a 20-acre campus in Northern Manhattan and accounting for...
?
mi
from
New York, NY
Click here to add this to my saved trials
70 Washington Square S
New York, New York 10012
(212) 998-1212
New York University More than 175 years ago, Albert Gallatin, the distinguished statesman who served...
?
mi
from
New York, NY
Click here to add this to my saved trials
200 First Street SW
Rochester, Minnesota 55905
507-284-2511
Mayo Clinic Rochester Mayo Clinic is a nonprofit worldwide leader in medical care, research and...
?
mi
from
Rochester, MN
Click here to add this to my saved trials
660 S Euclid Ave
Saint Louis, Missouri 63110
(314) 362-5000
Washington University School of Medicine Washington University Physicians is the clinical practice of the School...
?
mi
from
Saint Louis, MO
Click here to add this to my saved trials
San Francisco, California 94304
?
mi
from
San Francisco, CA
Click here to add this to my saved trials
5777 E Mayo Blvd
Scottsdale, Arizona 85259
(480) 515-6296
Mayo Clinic Scottsdale Mayo Clinic Arizona was the second Mayo practice to be established outside...
?
mi
from
Scottsdale, AZ
Click here to add this to my saved trials
1959 NE Pacific St
Seattle, Washington 98195
(206) 598-3300
University of Washington Medical Center University of Washington Medical Center is one of the nation's...
?
mi
from
Seattle, WA
Click here to add this to my saved trials
Tucson, Arizona 85724
?
mi
from
Tucson, AZ
Click here to add this to my saved trials
Vancouver, British Columbia
?
mi
from
Vancouver,
Click here to add this to my saved trials