Table 2.
An overview of landmark randomized controlled trials of lupus nephritis treatments published since 2000
| Reference | Study design | Number of patients | Follow-up, months | Intervention | Steroids | Endpoint | Conclusion |
|---|---|---|---|---|---|---|---|
| Induction | |||||||
| Chan et al. [24] (2000) | Randomized, single-center study | 42 | 12 | MMF (1 g BID) versus CYC (2.5 mg/kg) | Prednisolone 0.8 mg/kg followed by taper, maintenance dose 10 mg/day | • Complete remission = Upr <0.3 g/day, with normal sediment, normal albumin, and SCr and CrCl ≤15% above baseline | Rate of remission similar between groups |
| • Partial remission = Upr ≥0.3 and <2.9 g/day, albumin ≥3.0 g/dL, and stable kidney function | |||||||
| • Treatment failure = Upr ≥3.0 g/day, or Upr <3.0 with serum albumin <3.0 g/dL, SCr that has increased >0.6 mg/dL, or CrCl >15% above baseline | |||||||
| Houssiau et al. [48] (2002) | Randomized non-inferiority, multicenter | 90 | 41 | High CYC (monthly pulses, dose adjusted based on WBC) versus low-dose CYC (500 mg every 2 weeks) | Methylpred three times followed by prednisolone taper, maintenance dose 5 to 7.5 mg/day | • Treatment failure = one of the following: | Similar treatment failure rates between groups |
| ○ Absence of a primary response after 6 months | |||||||
| ○ Occurrence of glucocorticoid resistant flare | |||||||
| ○ Doubling of serum creatinine | |||||||
| ○ Lack of improvement in kidney function if dysfunction present at baseline | |||||||
| Ginzler et al. [27] (2005) | Randomized, open-label, non-inferiority | 140 | 6 | Oral MMF daily (up to 3 g/day) versus monthly CYC (up to 1.0 g/m2) | Glucocorticoids 1 mg/kg per day followed by taper at clinician’s discretion | • Complete remission: return to within 10% of normal values for creatinine, proteinuria, and urine sediment | MMF was superior to CYC for induction |
| Appel et al. [25] (2009) | Randomized controlled, superiority trial | 370 | 6 | MMF (3 g/day) versus IV CYC (0.5 to 1.0 g/m2) | Glucocorticoids 60 mg followed by taper | • Response defined as: | Overall response rate the same in MMF and CYC groups |
| ○ Decrease in UPCR to <3 from a 24-hour collection in patients with baseline UPCR >3 | |||||||
| ○ Decrease in UPCR of >50% if sub-nephrotic at baseline | |||||||
| ○ Stabilization (±25%) or improvement in serum creatinine | |||||||
| Rovin et al. [28] (2012) | Randomized, placebo-controlled, multicenter | 144 | 12 | Addition of ritxumab versus placebo to MMF and steroids | Methylpred 1 g two times peri-study drug doses | • Complete renal response = normal SCr (if abnormal at baseline), inactive sediment, or UPCR <0.5 | Response rates similar among groups |
| • Partial renal response = SCr ≤115% of baseline, RBCs/hpf ≤50% above baseline, no RBC casts, and at least 50% decrease in UPCR or to <1.0 (if baseline was ≤3.0) or to ≤3.0 (if baseline was >3.0) | |||||||
| • No response = did not meet criteria for complete or partial response, terminated study early, or missing data limited ability to assess | |||||||
| Furie et al. [26] (2014) | Randomized, phase II/III multicenter, double-blind study | 298 | 12 | Standard dose abatacept, high-dose abatacept, or placebo | Protocol defined steroid (and MMF) dosing | • Complete response = eGFR ≥90% of screening or pre-flare value, UPCR <0.26, inactive urinary sediment | Time to achievement of complete response was similar in all arms. |
| ACCESS trial group, 2014 [33] | Randomized double blind, double-blind, placebo-controlled | 134 | 6 and 12 weeks | Euro-Lupus CYC with abatacept versus placebo | Methyl pred x3 followed by taper | Proportion of subjects achieving complete response at 24 weeks defined as: | No difference with abatacept |
| • Kidney function: stable or improved eGFR | |||||||
| • Proteinuria: UPCR <0.5 | |||||||
| • Urine sediment: not included | |||||||
| • Corticosteroid dose: tapered to ≤10 mg daily | |||||||
| Maintenance | |||||||
| Contreras et al. [29] (2004) | Single-center, randomized open-label trial | 60 | 72 | IV CYC (0.5 to 1.0 g/m2 every 3 months) or AZA 1 to 3 mg/kg per day or MMF (500 to 3,000 mg/day) | Glucocorticoids up to 0.5 mg/kg per day | • Patient survival | Patient survival was significantly better in AZA compared with CYC, and renal survival was similar in all groups. |
| • Renal survival, defined as sustained increase in SCr to at least two times the lowest level achieved during induction, need for RRT or transplant | |||||||
| Houssiau et al. [49] (2010) | Randomized trial | 105 | 48 | AZA (target 2 mg/kg per day) or MMF (target 2 g/day) | Methylpred three times followed by taper | • Time to renal flare = nephrotic syndrome, ≥33% increase in serum creatinine within 1 month, threefold increase in 24-hour proteinuria with hematuria, ≥ 33% reduction in C3 within 3 months | Fewer flares with AZA but failed to show superiority |
| Dooley et al. [30] (2011) | Randomized double-blind, double-dummy, multicenter | 227 | 36 | MMF (1 g BID) versus AZA (2 mg/kg daily) | Glucocorticoids 10 mg/day | • Time to treatment failure = time until the first event (death, ESKD, doubling of SCr, renal flare, or need for rescue therapy) | MMF superior to AZA |
ACCESS, Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study; AZA, azathioprine; BID, twice a day; CrCl, creatinine clearance; CYC, cystatin C; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; hpf, high-power field; IV, intravenous; Methylpred, methylprednisolone; MMF, mycophenolate mofetil; RBC, red blood cell; RRT, renal replacement therapy; SCr, serum creatinine; UPCR, urinary protein-to-creatinine ratio; Upr, urinary protein excretion; WBC, white blood cell.