SEQUENTIAL THERAPY WITH TACROLIMUS AND RITUXIMAB IN PRIMARY MEMBRANOUS NEPHROPATHY

Cyclical treatment with corticosteroids and alkylating agents remains the first
therapeutic option in primary membranous nephropathy (MN), after showing in
several randomized controlled trials (RCT) a higher number of remissions and
improved long-term renal survival in comparison with supportive therapy.
However, serious concerns exist about the short and long-term side effects of
this treatment. Calcineurin inhibitors (CNI) have been recommended as an
alternative to cyclical treatments. CNI also induce a high number of
remissions, but relapses of nephrotic syndrome (NS) are common after CNI
discontinuation. Rituximab (RTX) has shown to induce remissions in primary MN,
although no prospective RCT have been performed. Recent observational studies
have shown that RTX administered after tacrolimus tapering can decrease the
incidence of NS relapse following tacrolimus withdrawal. This sequential
therapy tacrolimus-RTX showed a good safety profile, with only minor side
effects.
Since many nephrologists are still reluctant to use cyclical treatment with
steroids and alkylating agents in patients with primary MN due to the severity
of side effects, the use of CNI (particularly tacrolimus), RTX, and combined
sequential tacrolimus-RTX is increasing. However, no comparative RCT between
both therapies have been performed.
A formal, prospective and randomized trial in selected patients with primary MN
is needed to determine the efficacy of both therapies regarding NS remissions,
time to remissions, number and time of NS relapses, long-term renal survival
and side effects. This trial would also provide very important information with
better clinical evidence levels about the clinical use of tacrolimus followed
by RTX in the treatment of primary MN.

PRINCIPAL OBJECTIVE
To evaluate whether sequential therapy with tacrolimus for 9 months (6 months
of full therapy and 3 months of tapering doses) followed by a dose of RTX leads
to a greater increase in the proportion of primary MN patients with complete
remission (CR) defined as a reduction of proteinuria since baseline level to a
value equal or lower than 0.3 g/24 h proteinuria plus stable renal function
(eGFR >= 45 ml/min/1.73m2) and the proportion of patients with partial remission
(PR) defined as a reduction of proteinuria since baseline level to a value less
than 3.5 g/24 h and 50% lower than baseline proteinuria plus stable renal
function (eGFR >= 45 ml/min/1.73m2) when compared with patients receiving
cyclical treatment with corticosteroids and cyclophosphamide for 6 months.
This will be assessed after 24 months.

SUMMARY OF TRIAL DESIGN
1. Phase of the trial: and design: Phase III study, open label, randomized, and
active controlled trial.
This study will have 3 stages: screening and recruitment of patients for 12
months, treatment period for six months in corticosteroids plus
cyclophosphamide group and 9 months in Tacrolimus-RTX group, and finally
post-treatment follow-up period until to complete 24 months of follow-up since
initial treatment.
2. This will be an open-label, randomized and active controlled trial, with
parallel treatment design (two arms of treatment).
3. Expected duration of patient participation: Two years.
4. Number of visits: 13 within 24.

This study will compare the standard therapy for primary MN patients with
nephrotic range proteinuria (active control of steroids plus cyclophosphamide)
with a novel sequential therapy of tacrolimus and RTX, an approach of potential
high efficacy, low toxicity and more acceptable safety profile.

TRIAL INTERVENTION (STUDY TREATMENT IN DRUG CLINICAL TRIALS)
The arms of treatment will be the following:

First Arm: Cyclical Corticosteroids plus Cyclophosphamide (6 months)
Month 1: 1g IV methylprednisolone daily for three doses (days 1, 2,
and 3),
Oral prednisolone (0.5mg/kg/day) for 27 days (days 4 to 30).
Month 2: Oral Cyclophosphamide (2.0 mg/kg/day) for 30days
Months 3, 5: Repeat Month 1
Months 4, 6: Repeat Month 2


Second Arm: Sequential Tacrolimus-Rituximab
A) Oral Tacrolimus: Initial dose: 0.05 mg/Kg/day, adjusted to
achieve blood trough levels of 5-7 ng/ml) for six

months. Starting at the end of month 6, tacrolimus dosage will be reduced by
25% per month,

resulting in a complete withdrawal at the end of month 9.
B) Rituximab: A dose 1 g IV will be given during month 6
(at day 180), before the onset of tacrolimus dose

reduction.

In general, the extent of burden associated with participation is in line with
standard of care treatment, except for about 6 extra scheduled visits to the
hospital.

For patients in the active control arm (corticosteroids and cyclophosphamide
treamtent) the risks associated with participation are equal to those
associated with standard of care treatment, and mainly consist of the risk of
side effects to therpay. There are no direct benefits for these patients of
participating in the study, as in fact the receive the normal standard of care
therapy.


For patients in the arm of the study with sequential tacrolimus-rituximab, the
risks associated with participation, are also associated with the risk of side
effects of these particular drugs. In general side effects of
corticosteroids/cyclophosphamide are considered more severe. In theory,
patients in the second treatment arm have a risk of progression of their renal
disease if the studymedication appears to be less effective than standard of
care. To minimize this risk, subject withdrawal criteria include disease
progression.
The extra burden for the patients in the second arm is a treatment duration of
9 months instead of 6 months. On the other hand, they benefit from less
frequent IV medication ( only once instead of 9 times).
Another benefit of participating in his study for patients in this second group
may be that they theoretically may experience less, and less severe, adverse
events and side effects than patients treated with the standard of care
protocol.