Primary Endpoint Failure in the Rituximab in ANCA-associated Vasculitis Trial

Background/Purpose:

The RAVE trial demonstrated that rituximab (RTX) is non-inferior to cyclophosphamide (CYC) for remission induction in severe ANCA-associated vasculitis.  The primary endpoint was a disease activity score (Birmingham Vasculitis Activity Score/Wegener’s granulomatosis; BVAS/WG) of 0 and a prednisone dose of 0 mg/d at month 6. We explored the reasons for primary endpoint failure (PEF) in RAVE. 

Methods:

PEFs were classified according to one of the following hierarchical reasons: early treatment failure (ETF) (advance of disease in one or more organs or failure to respond to treatment by BVAS/WG reduction in the first month); severe flare; limited flare; adverse event (AE); BVAS/WG > 0 at 6 months; prednisone > 0 mg/d at 6 months despite BVAS/WG of 0; or other.

Results:

Eighty-two of 197 pts (42%) were PEFs: 36 (36%) in the RTX group, 46 (47%) in CYC (P=0.09). Nine were ETFs (7 RTX, 2 CYC; P=0.17). Baseline characteristics of pts classified as ETFs did not differ from those of other pts in age, sex, ANCA type, disease, new diagnosis vs relapse, baseline BVAS/WG, or creatinine.  Most ETFs were due to progressive glomerulonephritis (5/9: 4 RTX, 1 CYC) or recurrent pulmonary hemorrhage (3/9). All ETFs were treated with CYC. One ETF (RTX) died from sepsis/respiratory failure.  All other ETFs improved, with resolution of pulmonary disease and improvement of renal function. 

Fifteen RTX pts were PEFs because of disease flares (4 severe, 11 limited), compared with 23 CYC pts (9 severe, 14 limited). Neither B cell detectability nor ANCA titer predicted disease flare well in the first 6 months, and the correlation was particularly poor among RTX-treated pts. B cells remained undetectable in 65% of flares (50% CYC, 92% RTX). Among disease flares, only 24% had rises in ANCA titers at the time of flare (36% CYC, 0% RTX).

Of the 13 severe flares, 11 were treated by blinded crossover.  Nine of 11 blinded crossovers achieved remission (BVAS of 0 and prednisone dose of 0mg) within 6 months after crossover.  Limited flares were typically controlled by an increase in prednisone dose.  Among pts with limited flares, the mean BVAS/WG at 6 months was 0.9 and the mean prednisone dose 9.3 mg/d. Six pts were PEFs because of BVAS/WG > 0 at 6 months (2 RTX, 4 CYC; mean 2.0), and 11 were PEFs because of failure to taper prednisone to 0 mg/d (7 RTX, 4 CYC; mean 9.3 mg/d).  Twelve pts (9 CYC, 3 RTX) discontinued because of AEs.

Conclusion:

There were multiple reasons for PEF but the distribution of causes was similar between groups. ETFs and pts who flared typically improved following a treatment intervention according to best medical judgment, blinded crossover, or increase in prednisone dose. B cell detectability and ANCA titers correlated poorly with flares in the first 6 months, particularly those in the RTX group.

Table 1 – Reasons for primary endpoint failure in RAVE