Cattran 2001.

Study characteristics
Methods	Study design: parallel RCT Study duration: before 2001 Duration of follow‐up: 18 months
Participants	Setting: multi‐centre (11 sites) Countries: Canada, USA Inclusion criteria: biopsy‐proven steroid‐resistant IMN and nephrotic‐range proteinuria; all patients must have failed to achieve remission of their proteinuria after a minimum of 8 weeks of prednisone treatment at ≥ 1 mg/kg/day Baseline characteristics Pathology stage (I‐IV): treatment group 1 (2.2, 1‐4); treatment group 2 (2.4, 1‐4) Mean proteinuria ± SD (g/24 hours): treatment group 1 (9.7 ± 5.3); treatment group 2 (8.8 ± 4.7) Mean serum albumin ± SD (g/L): treatment group 1 (28 ± 6); treatment group 2 (27 ± 6) Mean SCr ± SD (mg/dL): treatment group 1 (1.3 ± 0.5); treatment group 2 (1.1 ± 0.3) Mean GFR ± SD (mL/min/1.73 m²): treatment group 1 (95 ± 37); treatment group 2 (90 ± 27) Baseline declining kidney function: CrCl was ≥ 42 mL/min/1.73 m² in all included patients Use of ACEi or ARB during follow‐up: yes, no confounding effect Previous immunosuppressive status: no immunosuppressive agents, plasma exchange therapy, or antilymphocyte products were allowed in the 6 months prior to entry to the study Number: treatment group 1 (28); treatment group 2 (23) Mean age ± SD (years): treatment group 1 (47 ± 11); treatment group 2 (49 ± 14) Sex (M/F): treatment group 1 (26/2); treatment group 2 (16/7) Exclusion criteria: women unwilling to take effective birth control; comorbid conditions with an expected survival of < 2 years; any serious systemic infection, DM; malignancy; conditions associated with secondary MGN; SLE; infection
Interventions	Treatment group 1 CSA + prednisone CSA: started at a dose of 3.5 mg/kg/day in 2 equal doses at 12‐hour intervals. Adjustments in dosages were made to achieve a whole‐blood 12‐hour trough level measured by monoclonal assay between 125 and 225 mg/L. It was continued for 26 weeks and then tapered to zero over 4 weeks Prednisone: 0.15 mg/kg/day up to a maximum dose of 15 mg. This was reduced after 26 weeks by thirds at 4‐week intervals and was stopped after 8 weeks Early stop points included a confirmed ≥ 30% rise in baseline Cr. Confirmed meant that the Cr was not improved by two 25% reductions in the dose of the test medication spaced out over a four‐week period. Other premature stop points included a doubling of baseline liver enzymes and intolerable side effects. The test medication was also stopped if a complete remission of proteinuria was achieved and persisted for 1 month or more. The mean CSA dose was 3.7 ± 2.0 mg/kg. The mean trough level at 26 weeks was 148 ± 29 ng/L. All patients completed the 6 months of the test medications except 1 case of complete remission, where the CSA was stopped at week 20 after 4 weeks with no proteinuria Treatment group 2 Placebo + prednisone Placebo: started at a dose of 0.035 mL/kg/day. A comparable number of adjustments were made in the placebo patient's medication volume to ensure that masking was maintained. It was continued for 26 weeks and then tapered to zero over 4 weeks Prednisone: 0.15 mg/kg/day up to a maximum dose of 15 mg. This was reduced after 26 weeks by thirds at 4‐week intervals and was stopped after 8 weeks
Outcomes	Death ESKD 50% or 100% Cr increase Final SCr Partial or complete remission Final proteinuria Side effects leading to patient withdrawal or hospitalisation
Notes	Funding information: supported by the Kidney Foundation of Canada and Novartis Canada Baseline comparison: comparable Sample size calculation: the estimated total sample size was 50 patients. The number of finally included patients was similar to the estimate (51). Confounding factors: no. At randomisation, 53% (27) of the patients were hypertensive (CSA (16), placebo (11)). Nineteen were on ACEi (CSA (11), placebo (8)), and 8 were on other antihypertensive medications. During the CS period, there was an increase in the number of patients in both groups that required antihypertensive medication, but more in the CSA than in the placebo group (8 versus 5). Despite this, no significant differences in supine, sitting, or mean arterial pressure measurements were noted during the active medication period or during the post‐CSA period. Since ACEi could not be introduced in this period, these additional cases resulted in a decreased percentage of hypertensive patients within each group on this class of CSA. In the CSA group, this fell from 69% to 46% and in the placebo group from 73% to 50%. During the post‐test medication period, neither the percentage of patients with hypertension nor the use of ACEi changed significantly. There was no difference in the CSA group between those on ACEi compared with those not on an ACEi in either baseline proteinuria or in the amount of protein reduction by week 26. The number, as well as the severity of hypertension, was greater in the CSA compared with the placebo group in the active treatment period. A new antihypertensive agent (8) or an increase in the dose of the antihypertensive drugs (2) was required in the CSA group versus a new agent (5) in the placebo group The average per patient prednisone dose given prior to the 6‐month run‐in period was not different in the 2 groups. In the placebo group, the mean total dose was 92 mg/kg (range 65 to 120), and in the CSA group, it was 108 mg/kg (range 60 to 140). The mean duration of treatment was also similar at 12 weeks in the placebo patients (range 8 to 22) and 14 weeks in the CSA patients (range 8 to 28). In addition, in the prestudy period, 18 patients (placebo (10), CSA (8)) had failed a course of cytotoxic agents (CPA (9), chlorambucil (5), AZA (4)) for an average of 4 months (range 2 to 12)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed by the clinical coordinating centre from a table of random numbers and was stratified by centre in blocks of two to ensure a balance between groups
Allocation concealment (selection bias)	Low risk	Central randomisation method described could not allow investigators/participants to know or influence intervention group before eligible participant entered in the study
Blinding of participants and personnel (performance bias) All outcomes	High risk	The patients were masked in regard to CSA versus placebo assignment. Novartis Canada Ltd. (Whitby, Ontario, Canada) provided CSA in a drink solution (100 mg/mL) and an identical placebo made from the same carrier. The physicians were not masked in regard to CSA versus placebo assignment for safety reasons
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The end points were objective and measured centrally by a lab blinded to patient designation. No further information was provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients except 2 patients completed the study. The reasons were relocation outside of North America and noncompliance
Selective reporting (reporting bias)	Low risk	The study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were pre‐specified
Other bias	Low risk	The study appeared to be free of other sources of bias