[This post can also be found on MedPageToday]
The DreamRCT Initiative is a project by Dr. Jordan Weinstein (@drjjw) of UKidney and Dr. Joel Topf (@kidney_boy) of pbfluids.com and #NephJC.
The project points out that nephrology has the fewest randomized controlled clinical trials of any subspecialty in medicine, and hopes to bring interest to areas where gaps in knowledge are most lacking.
In the area where nephrology intersects with rheumatology, we have actually been quite fortunate. The two conditions in this area which carry the highest burden are ANCA-associated vasculitis and lupus nephritis. For ANCA-associated vasculitis, we have been fortunate to have recently well performed RCTs regarding the use of rituximab for induction of remission and maintenance as well as treatment of relapses.
We have also made recent advances in our understanding of therapies for induction of lupus nephritis, with studies looking at the role of tacrolimus as monotherapy or as part of a multitarget therapy regimen along with MMF.
Despite this, one of the biggest questions rheumatologists and nephrologists have regarding lupus nephritis is: why the heck doesn’t rituximab seem to work in bigger RCTs?
My entry for DreamRCT: RoRo-LuN (Role of Rituximab only in Lupus Nephritis):
Previous studies looking at the role of rituximab for the treatment of lupus nephritis have been highly criticized for poor design. Initial data from the RITUXILUP group (rituximab and IV methylprednisolone on days 1 and 15 with background MMF but no oral steroids) have been extremely promising, but many patients cannot tolerate MMF, and the role of rituximab as monotherapy given over 6 month intervals will remain uncertain. RoRo-LuN would randomize patients with biopsy proven class III or IV lupus nephritis to one of three arms to be followed over 2 years, with the primary endpoint to be renal remission defined as normal creatine or return to baseline creatinine, inactive urinary sediment, and urine protein/creatinine ≤0.5. Group 1: rituximab without oral steroids (rituximab 1 g on weeks 0 & 2, 26 & 28, 52 & 54, 78 & 80, IV methylprednisolone 1 g on weeks 0 and 2); group 2: same as group 1 but with the addition of tapering oral steroids over 6 months; group 3: standard therapy (initial pulse steroids, MMF, tapering oral prednisone).
Background:
Unfortunately, despite clinical experience by clinicians and promising reports in many smaller studies, larger RCTs have not shown effectiveness of rituximab against lupus and lupus nephritis. However, these studies have been extensively criticized for their trial design as the reason for failures.
The first of the larger RCTs evaluating the role of rituximab in lupus was the EXPLORER trial, which looked at patients that did not have renal involvement. This trial randomized 257 patients with moderate-severe SLE (on one background immunosuppresive [methotrexate, azathioprine, or MMF], with 57% of patients corticosteroid deponent) to rituximab infusions or placebo at a ratio of 2:1 on days 1, 15, 168, and 182. The primary endpoint was the effect of achieving and maintaining clinical response at week 52, assessed using BILAG, was not met. The EXPLORER trial was criticized for having a small number of participants, confounding background immunosuppressives, and for questions regarding the ability of BILAG to detect a meaningful clinical response.
Following this, the LUNAR trial looked at 144 patients with class III or IV lupus nephritis being treated with MMF and corticosteroids, and randomized them 1:1 to receive rituximab or placebo on days 1, 15, 168, and 182. The primary endpoint was a 20% superior renal response in the rituximab group at week 52. Again, the primary endpoint was not met, although overall response rates were 56.9% in the rituximab group compared to 45.8% in placebo. Failure to meet the primary endpoint was thought due to faulty design due to background immunosuppressives confounding any benefit of rituximab, as well as being underpowered.
Interestingly, 78-week follow up data to the LUNAR trial did suggest that rituximab had a longer term effect, with improved proportion of patients who had remission of proteinuria and fewer patients who required additional immunosuppression:
”In LUNAR, the exploratory data demonstrated that at week 52, the difference (10%) in the proportion of patients with 50% reduction in proteinuria favored rituximab treatment; the difference increased to 17% at week 78 (P = 0.04).”
”The other compelling suggestion of a benefit is the finding that significantly (P < 0.01) fewer patients in the rituximab group required cyclophosphamide for worsening disease, and more achieved a renal domain BILAG C score, and this was sustained up to 78 weeks.”
The currently ongoing RITUXILUP trial hopes to avoid oral steroids entirely in patients with class III/IV or V lupus nephritis while determining whether rituximab is an effective therapy when added to maintenance MMF. In this regimen, patients are given two doses of rituximab (1 g) and methylprednisolone (500 mg) on days 1 and 15, and maintenance treatment with MMF, compared to standard therapy using initial IV methylprednisolone, MMF, and tapering oral steroids. This trial is powered to show superiority non-inferiority of the Rituxilup regimen, with patients followed for at least 2 years, and should be completed in 2018.
Initial data from the first 50 patients treated with the Rituxilup regiment has been extremely promising, with 90% (45/50) patient achieving complete or partial remission by a median of 37 weeks, including 72% (36/50 achieving complete remission by a median of 36 weeks, low incidence of systemic lupus flares, and infrequent adverse events.