Parameters
Yes
No
Comment
Validity
Is the randomization procedure well described?
+1
Random from masked card sequence
Double blinded?
−2
Open label
Is the sample size calculation described/adequate?
−3
No power calculation
Does it have a hard primary endpoint?
+1
Probability of renal failure (ESRD) censored for death
Is the endpoint surrogate?
+2
Is the follow-up appropriate?
+1
Followed for more than 65 months
Was there a Bias?
−1
Ancestry not stated; unequal distribution of pathological classes
Is the dropout >25 %?
+1
Is the analysis ITT?
−3
Kaplan-Meier; censored
Utility/usefulness
Can the findings be generalized?
0
Not applicable to A-A
Was the NNT <100?
+1
Score
0 %
Summary and Discussion
This is the “granddaddy” of RCT in LN and it had a profound impact on clinical practice despite its several flaws. The studies were carried out over many years (1969–1981) and incorporated several randomized protocols. One of the comparator groups (oral prednisone only) was a historical rather than concurrent control. The number of subjects randomized to each regimen was small (prednisone only = 28; oral azathioprine (AZA) = 19; oral cyclophosphamide (CYC) = 18; oral AZA + oral CYC = 22; IV CYC = 20). The distribution of glomerular lesion among the groups was not equal. 5/20 (25 %) assigned to IV CYC had membranous LN, 5/29 (17 %) assigned to the oral prednisone group had membranous LN, and 1/18 (6 %) assigned to the oral CYC group had membranous LN. Altogether 78/107 (73 %) subjects had proliferative LN and 16/107 (15 %) had membranous LN. Over the course of follow-up (varying from 65 to 126 months for those developing ESRD), a total of 23/107 (21 %) developed ESRD and only 4 subjects were lost to follow up. In the prednisone only category, 10/28 developed ESRD (36 %) whereas only 1/20 (5 %) of those assigned to IV CYC developed ESRD—a significant difference. On the other hand, 6/40 (15 %) of patients assigned to oral CYC or AZA + CYC developed ESRD, a value which was not significant. An outcome of ESRD or doubling of baseline serum creatinine occurred in 24/38 (63 %) of the prednisone only treated group compared with 13/ 46 (28 %) in the oral CYC or oral AZA + CYC group and 5/21 (24 %) in the IV CYC group. The difference in outcomes between the assigned treatment groups did not become apparent until at least 5–7 years had elapsed, at which time only 78/107 randomized patients had been followed. Among the 72 subjects deemed to be at high risk of ESRD at randomization (chronic lesions in renal biopsy), the only comparison that achieved statistical significance was the IV CYC group versus the oral prednisone group, but the study was underpowered to examine similar comparisons with the other treatment groups. Adverse events were common in all groups but of differing character—major infections were seen in 25 % of the oral prednisone only group but only in 10 % of the IV CYC group. But premature ovarian failure was seen in 71 % of the oral CYC group and in 45 % of the IV CYC group, and hemorrhagic cystitis was seen in about 15 % of those who received oral CYC but none of the IV CYC-treated patient group. Deaths (n = 13) were equally divided between the groups.
Conclusions
This seminal study, although quite seriously flawed by contemporary standards, did support the view that high-dose prednisone alone strategies were inadequate and unsafe for management of severe proliferative LN. At best, this study was hypothesis generating that a regimen of intermittent IV CYC (in high dosage) was superior (in efficacy or safety) to other immunosuppressive regimens, including oral CYC + prednisone. Subsequent randomized, controlled trials, conducted by the NIH group, showed that intermittent IV CYC is superior to intermittent IV methylprednisolone in treatment of severe LN [4] and that IV methylprednisolone added to IV cyclophosphamide has greater short- and long-term efficacy at no increase toxicity compared with high-dose IV CYC plus oral steroids [5, 6]. In addition, longer-term treatment with IV CYC (monthly for 6 months and then quarterly for an additional 2 years) reduced relapse rates but had no beneficial effect on renal function decline compared with shorter courses of IV CYC (monthly for 6 months) in severe LN (4). These additional studies, published between 1992 and 2001 and generally of moderate quality, tended to solidify the opinion that intermittent IV CYC plus intermittent IV methyl prednisolone was the “standard of care” in severe lupus nephritis, despite the lack of any comparisons to other regimens, such as oral CYC. In fact, there has never been an adequately powered RCT directly comparing a daily oral CYC + prednisone regimen to an intermittent IV CYC + prednisone regimen in severe LN for efficacy (hard endpoint of ESRD) and safety.
Trial #2
Chan TM, LI FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS, Wong AK, Tong MK, Chan KW, Lai KN. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis: Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343:1156–62
Abstract
Background: The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Whether mycophenolate mofetil can be substituted for cyclophosphamide is not known.
Methods: In 42 patients with diffuse proliferative lupus nephritis, we compared the efficacy and side effects of a regimen of prednisolone and mycophenolate mofetil given for 12 months with those of a regimen of prednisolone and cyclophosphamide given for 6 months, followed by prednisolone and azathioprine for 6 months. Complete remission was defined as a value for urinary protein excretion that was less than 0.3 g per 24 h, with normal urinary sediment, a normal serum albumin concentration, and values for serum creatinine and creatinine clearance that were no more than 15 % above the baseline values. Partial remission was defined as a value for urinary protein excretion that was between 0.3 and 2.9 g per 24 h, with a serum albumin concentration of at least 30 g per liter.
Results: Eighty-one percent of the 21 patients treated with mycophenolate mofetil and prednisolone (group 1) had a complete remission, and 14 % had a partial remission, as compared with 76 and 14 %, respectively, of the 21 patients treated with cyclophosphamide and prednisolone followed by azathioprine and prednisolone (group 2). The improvements in the degree of proteinuria and the serum albumin and creatinine concentrations were similar in the two groups. One patient in each group discontinued treatment because of side effects. Infections were noted in 19 % of the patients in group 1 and in 33 % of those in group 2 (P = 0.29). Other adverse effects occurred only in group 2; they included amenorrhea (in 23 % of the patients), hair loss (19 %), leukopenia (10 %), and death (10 %). The rates of relapse were 15 and 11 %, respectively.
Conclusions: For the treatment of diffuse proliferative lupus nephritis, the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prednisolone followed by azathioprine and prednisolone but is less toxic.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | −1 | Not well described | |
Double blinded? | −2 | Open label | |
Is the sample size calculation described/adequate? | −3 | No power calculation | |
Does it have a hard primary endpoint? | −1 | Complete remission (urine protein <300 mg/day) with normal serum albumin concentration, normal urinary sediment, and stable renal function as the endpoints. Not possible to have a hard endpoint due to infrequency of events | |
Is the endpoint surrogate? | −1 | ||
Is the follow-up appropriate? | 0 | 12 months only | |
Was there a Bias? | +1 | Chinese subjects only | |
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | −3 | ||
Utility/usefulness | |||
Can the findings be generalized? | 0 | Not to Caucasians or A-A | |
Was the NNT <100? | +1 | ||
Score | 0 % |
Summary and Discussion
This was a very influential trial, despite its several weaknesses. The number of randomized subjects is small (n = 42) and the follow-up short (12 months). Randomized patients had class IV or class V plus IV LN, and baseline renal function was normal or only slightly reduced. Most patients had nephrotic syndrome, with serological as well as histological activity of disease, but only moderate evidence of chronicity. The dose of MMF was 2.0 g/day for 6 months and then 1.0 g/day for the remaining 6 months. The comparator arm received 2.5 mg/kg/day of oral CYC for 6 months and then 1.5 mg/kg/day of oral azathioprine (AZA). After 12 months, AZA was replaced with MMF, and AZA dosage was reduced to 1 mg/kg/day in the comparator arm. The primary endpoint at 12 months was a complete remission of abnormal urinary findings plus stable renal function, as assessed by serum creatinine alone (not by measured GFR). Possible effects of steroids on creatinine generation were not considered, but both arms of the trial received similar doses of prednisone (about 0.8 mg/kg initially and then tapering doses over 6 months). Complete remission developed in 81 % of the MMF group and in 76 % of the oral CYC group at 12 months, and treatment failure and relapse rates were similar in the two arms (about 10–20 %), but the study is likely to be underpowered to show a difference. Adverse events were common (19–33 %), slightly more in the CYC group, but not significant (again underpowered to examine safety).
Conclusions
This study is primarily hypothesis generating and does not establish efficacy or safety of MMF, in the dosage described, compared with a sequential oral CYC + AZA regimen. The lowering of the dosage of MMF at 6 months may have contributed to the findings suggestive of equivalence of oral MMF to a sequential oral CYC + AZA regimen for LN. The study cannot be generalized to Caucasians or African-American with severe LN. A follow-up study at 5 years with a “hard endpoint” of doubling of serum creatinine showed similar results (6.3 % in MMF and 10.0 % in the CYC + AZA groups), but hospitalizations for serious infections were lower in the MMF group [7]. The study was underpowered to examine ESRD rates.
Trial #3
Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido EER, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gul A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46:2121–31
Abstract
Objective: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment.
Methods: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed.
Results: Follow-up continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20 % of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, and 24-h urinary protein and the disease activity scores significantly improved in both groups during the first year of follow-up. Renal remission was achieved in 71 % of the low-dose group and 54 % of the high-dose group (not statistically significant). Renal flares were noted in 27 % of the low-dose group and 29 % of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant.
Conclusion: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 g) followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | −1 | Not well described | |
Double blinded? | −2 | Open label | |
Is the sample size calculation described/adequate? | −3 | No power calculation | |
Does it have a hard primary endpoint? | +1 | Treatment failure including relapse and serum creatinine—GFR not measured | |
Is the endpoint surrogate? | +1 | ||
Is the follow-up appropriate? | +1 | Followed for more than 40 months | |
Was there a Bias? | +1 | No African-Americans | |
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | 0 | Except for A-A | |
Was the NNT <100? | +1 | ||
Score | 19 % |
Summary and Discussion
This study introduced a new “twist” on the use of IV CYC regimens in proliferative LN—that of a lower-dose shorter duration treatment, with consolidation of remission with AZA rather than continued quarterly IV CYC dosing, now known as the “Euro-Lupus regimen” (6 IV CYC pulses at 500 mg each every 2 weeks and then 2 mg/kg/day of AZA starting 2 weeks after the last IV CYC dose). The sample size (n = 90) was reasonable, but the study may have been underpowered to show a true difference between the two treatment groups. Renal remission was high in both groups (54 % in the high-dose group, equivalent to the NIH protocol group (see Trial #1), and 71 % in the Euro-Lupus protocol group). Rates of treatment failures and adverse events were equivalent in both groups, but the study was underpowered to examine safety in both groups. Steroid dosage did not differ, blunting arguments that a serum creatinine-based endpoint might be biased by muscle loss due to steroids.
Conclusions
Although plausibly underpowered to examine the main endpoints, this study did promote a conversion from the then commonly used high-dose, prolonged CYC regimen of the NIH to one involving lower IV CYC dosage over shorter intervals combined with AZA consolidation (maintenance). A 10-year follow-up cohort analysis of 84 patients from the original study showed equivalent “hard” outcomes for the two groups (doubling of serum creatinine), 14 % in the Euro-Lupus protocol group and 11 % in the NIH protocol group [8]. Due to the ancestry of the randomized patients, this protocol cannot be assumed to be effective in African-Americans, Asians, or Hispanics or in membranous LN.
Trial #4
Contreras G, Pardo V, Leclrecq B, Lenz O, Tozman E, ONan P, Roth D. Sequential therapies for proliferative lupus nephritis. N Engl J Med. 2004;350:971–80
Abstract
Background: Long-term therapy with cyclophosphamide enhances renal survival in patients with proliferative lupus nephritis; however, the beneficial effect of cyclophosphamide must be weighed against its considerable toxic effects.
Methods: Fifty-nine patients with lupus nephritis (12 in World Health Organization class III, 46 in class IV, and 1 in class Vb) received induction therapy consisting of a maximum of 7 monthly boluses of intravenous cyclophosphamide (0.5–1.0 g per square meter of body surface area) plus corticosteroids. Subsequently, the patients were randomly assigned to one of three maintenance therapies: quarterly intravenous injections of cyclophosphamide, oral azathioprine (1–3 mg per kilogram of body weight per day), or oral mycophenolate mofetil (500–3,000 mg per day) for 1–3 years. The baseline characteristics of the three groups were similar, with the exception that the chronicity index was 1.9 points lower in the cyclophosphamide group than in the mycophenolate mofetil group (P = 0.009).
Results: During maintenance therapy, five patients died (four in the cyclophosphamide group and one in the mycophenolate mofetil group), and chronic renal failure developed in five (three in the cyclophosphamide group and one each in the azathioprine and mycophenolate mofetil groups). The 72-month event-free survival rate for the composite endpoint of death or chronic renal failure was higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group (P = 0.05 and P = 0.009, respectively). The rate of relapse-free survival was higher in the mycophenolate mofetil group than in the cyclophosphamide group (P = 0.02). The incidence of hospitalization, amenorrhea, infections, nausea, and vomiting was significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group.
Conclusions: For patients with proliferative lupus nephritis, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | Sealed enveloped—stratified by ancestry | |
Double blinded? | 0 | Open label; masking not attempted | |
Is the sample size calculation described/adequate? | +3 | ||
Does it have a hard primary endpoint? | +1 | Composite—patient and renal survival | |
Is the endpoint surrogate? | +2 | ||
Is the follow-up appropriate? | +1 | 72 months for composite endpoint | |
Was there a Bias? | +1 | Low chronicity score at baseline in the CYC group | |
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | −3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | ||
Was the NNT <100? | +1 | ||
Score | 50 % |
Summary and Discussion
This study is one of the first to examine the issue of maintenance regimens for the avoidance of relapse and renal failure after “induction” therapy—in this case with the NIH IV CYC regimen. The randomization step, after induction therapy, minimized the risk of bias. Remission status and intensity of induction therapy were equivalent in the three maintenance arms at the time of randomization. About 80 % of the subjects were in complete or partial remission at the time they were randomized to the maintenance regimens (continued IV CYC, MMF, or AZA for 1–3 years). Renal function was normal or near normal in all groups at randomization. Steroid dosage was approximately equal in the three groups post randomization.
The results were striking. Maintenance therapy with IV CYC performed poorly by all criteria with event-free survival (composite endpoint) at <50 % in 5 years of follow-up, versus 85–90 % in the AZA and MMF groups. This was driven mainly by patient survival, as the cumulative rate of renal survival was comparable in the three groups—74 % for IV CYC group, 80 % in the AZA group, and 95 % in the MMF group. Relapse-free interval was highest for the MMF group and lowest for the IV CYC group and intermediate for the AZA group. Hospitalization rates were higher for IV CYC. 55 of the 59 randomized subjects were African-Americans or Hispanics, which precluded any comparison of the results between Caucasian and non-Caucasian subjects.
Conclusions
This well-done trial provided a “death knell” for maintenance therapy with IV CYC (or oral CYC for that matter as well) in proliferative LN after completion of “induction” therapy, at least in African-Americans and Hispanics. From then on, it was a contest between MMF and AZA (see below).
Trial #5
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, Petri M, Gilkeson GS, Wallace DJ, Weisman MH, Appel GB. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353:2219–28
Abstract
Background: Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.
Methods: We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1,000 mg per day, increased to 3,000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary endpoint was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary endpoint was partial remission at 24 weeks.
Results: Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 %) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 %) had complete remission, for an absolute difference of 16.7 percentage points (95 % confidence interval, 5.6–27.9 percentage points; P = 0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 %) and 17 of the 69 patients (24.6 %), respectively (P = 0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea cases occurred among those receiving mycophenolate.
Conclusions: In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.
Critical Analysis
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | ||
Double blinded? | −1 | Open label—but an oral vs. IV comparison | |
Is the sample size calculation described/adequate? | +3 | No power calculation | |
Does it have a hard primary endpoint? | −1 | Complete remission at 6 months. Not possible to have a hard endpoint due to infrequency of events | |
Is the endpoint surrogate? | −1 | See above | |
Is the follow-up appropriate? | +1 | Followed to relapse | |
Was there a Bias? | +1 < div class='tao-gold-member'>
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