Tacrolimus Versus Cyclophosphamide as Treatment for Lupus Nephritis
Information source: Zhejiang University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: SLE; Lupus Nephritis; Renal Insufficiency; End-stage Renal Disease
Intervention: Tacrolimus (Drug); cyclophosphamide (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Zhejiang University Official(s) and/or principal investigator(s): Jianghua Chen, MD, Principal Investigator, Affiliation: The First Affiliated Hospital, College of Medicine, Zhejiang University
Summary
In this comparative open-label cohort study, the investigators compared the efficacy and
safety of tacrolimus (TAC)and cyclophosphamide (CYC) in the treatment of diffuse
proliferative and membranous lupus nephritis with severe renal disease. Treatment of lupus
nephritis (LN) with cyclophosphamide is effective, but retain a certain proportion of renal
function exacerbations. Tacrolimus may be a suitable substitute treatment for CYC.
Methods: Forty patients with diffuse proliferative or membranous were recruited for this
trial, 45% of them had lower Ccr (<60mL/min/1. 73m2), 10% had increased serum creatinine
(>180µmol/L) and 67. 5% had nephritic proteinuria (>3. 5g/day). The investigators compared the
efficacy and adverse effects of TAC (0. 04-0. 08 mg/kg/d) and prednisone for 12 months (TAC
group) with pulse cyclophosphamide (750mg/m2 per month for six months) and prednisone
followed by azathioprine (50mg/day)for 6 months (CYC group).
Clinical Details
Official title: Tacrolimus Versus Cyclophosphamide as Treatment for Diffuse Proliferative or Membranous Lupus Nephritis: Prospective Cohort Study
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis
Secondary outcome: Evaluating the effective and safety of TAC for severe lupus nephritis compared CYC protocol.
Detailed description:
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. About 60% of SLE
patients have renal disease, and patients with rapidly progressive destruction of renal
parenchyma have significantly poorer prognosis. Drug therapies that employ corticosteroids,
cyclophosphamide, and/or mycophenolate mofetil have improved patient outcomes, but a
significant number of patients have refractory disease or cannot tolerate these drugs.
Moreover, SLE patients who are partially responsive or resistant to treatment have
significant morbidity,mortality, and exacerbations of renal function. Thus, in patients with
lupus nephritis (LN), the two main causes of morbidity and mortality are treatment-related
or patient-related. It has been suggested that new therapies be developed for SLE that more
specifically target the relevant immunopathogenetic pathways, so as to achieve greater
efficacy and reduce therapy-related toxicities ,and to save or protect renal function.
Tacrolimus (TAC) is an immunosuppressive macrolide of the calcineurin inhibitor (CNI) group
that is widely administered following organ transplantation. In 1989, Takabayashi K. et al.
studied the effect of TAC on a murine model of SLE, and showed that it prolonged lifespan,
reduced proteinuria, and prevented the progression of nephropathy, although it had no
appreciable effect on the levels of anti-dsDNA antibodies. More recent small-scale studies
have shown that TAC may be an effective treatment for nephritic syndrome and LN8-11.
However, there is little clinical experience in the use of TAC for treatment of LN,
especially for LN with severe renal disease, and limited knowledge of the comparative
efficacy of TAC and other therapies.
In this comparative open-label cohort study, we compared the efficacy and safety of TAC and
CYC in the treatment of diffuse proliferative and membranous lupus nephritis with severe
renal disease.
LN is characterized by autoantibody-mediated vasculitis that may lead to rapid progression
of multi-system and organ damage. The kidneys are often involved due to excretion of
excessive urinary protein and/or rapidly progressive kidney injury, and end-stage renal
disease may result. Treatment-related differences in the rates of renal failure may not be
discernible early in the course of treatment, but there are definite advantages of rapid
remission, effective prophylaxis against relapse, and prevention of renal failure.
An intravenous pulse CYC regime has been the "gold standard" immunosuppressive regime for
the treatment of LN. The activation of lymphocytes, production of autoantibody, and high
expression of IFN-γ in the circulation and renal tissue are important indicators of renal
injury in SLE. Previous clinical and animal studies have shown that TAC therapy inhibits
T-lymphocyte activation, suppresses cytokine production in lymphocytes, suppresses
antigen-induced monokine (TNF-α) production in macrophages, reduces interleukin-2 mRNA
expression, decreases serum levels of IFN-γ and IFN-γ mRNA expression in the kidney and
spleen, and decreases serum levels of IgG-class anti-DNA antibodies. A recent study also
showed that TAC treatment affects B-cell antibody responses indirectly by interfering with
T-helper cells.
The risk of end-stage renal failure is particularly high in patients with diffuse
proliferative glomerulonephritis. Despite the diverse and complex interplay of various
causative factors in individual patients, two previous studies suggested that SLE patients
who experience glomerulonephritis that does not diminish following treatment with
conventional immunosuppressive therapies have increased risk for subsequent deterioration of
renal function and poor long-term outcome. This suggests that there is an urgent need for
alternative immunosuppressive therapies for treatment of SLE, and motivated our
investigation of TAC. On the other hand, it is well know that calcineurin inhibitors (such
as TAC) are associated with chronic nephrotoxicity. For example, Tse et al. showed that one
of six patients developed chronic nephrotoxicity after 10 months of TAC therapy. As a
calcineurin inhibitor, TAC has a lower potential for nephrotoxicity than cyclosporine.
Opportunistic infection is a severe complication that can result from treatment of LN with
immunosuppressive drugs.
Eligibility
Minimum age: 15 Years.
Maximum age: 64 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- SLE patients: diagnosis based on American Rheumatism Association criteria;
- renal biopsy-proven active LN (diffuse proliferative and membranous lupus nephritis,
class IV, V, V+IV and/or V+III, according to the ISN/RPS 2003 classification13)
- urinary protein excretion of at least 2. 0 g per 24 h
- serum creatinine less than 221 µmol/dL (2. 5mg/dL)
- creatinine clearance more than 30 mL/min/1. 73m2
Exclusion Criteria:
- pregnant or lactating
- previous treatment with cyclosporine, mycophenolate mofetil treatment for at least
two weeks in the previous three months
- known allergies to calcineurin inhibitors
- severe infection or illness
- symptoms of a central nervous system disorder
- alanine aminotransferase more than 100U/L
- evidence of active hepatitis
- fasting blood glucose more than 6. 2 mmol/L
- 2 h post-meal blood glucose more than 11. 1mmol/L
Locations and Contacts
Additional Information
Starting date: March 2003
Last updated: August 22, 2011
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