APN 2008

Methods	Study design: parallel RCT Time frame: January 2001 to November 2004 Follow‐up period: 48 weeks for whole study
Participants	Setting: tertiary, multicentre study Countries: Germany, Austria; study by the Arbeitsgemeinschaft fur Pädiatrische Nephrologie SRNS: Initial non‐responder; absence of complete remission (proteinuria < 4 mg/m2/h) 14 days after ≥ 4 weeks of prednisone (60 mg/m2/d) and 3 methylprednisone pulses (500 mg/m2); FSGS (21), MCD (10) or MesPGN (1) on biopsy; normal C3; CrCl > 70 mL/min/1.73 m2 Number CSA group: 15 (MCD (6), FSGS (8), MesPGN (1)) CPA group: 17 (MCD (4), FSGS (13), MesPGN (0)) Age (mean ± SD) CSA group: 6.99 ± 5.48 years CPA group: 6.84 ± 3.90 years Sex (M/F) CSA group: 11/4 CPA group: 8/9 Exclusion criteria: hereditary, syndromic and secondary nephrotic syndrome; pre‐treatment with immunosuppressive therapy other than prednisone; prednisone regimen other than APN or ISKDC
Interventions	CSA group Oral CSA 150 mg/m2/d in 2 divided doses aiming for trough levels of 120 to 180 ng/mL for 24 weeks and then CSA to achieve trough level of 80 to 120 ng/mL for 24 weeks CPA group IV CPA starting at 500 mg/m2 over 4 hours every 4 weeks for 7 doses; dose increased or decreased by 250 mg/m2 according to WCC; maximum dose 1 g/m2 Co‐interventions Tapering dose of alternate day prednisone to week 48
Outcomes	Complete remission (proteinuria < 4 mg/m2/h) within 24 weeks but non‐responder treatment offered from 12 weeks so results only interpretable to 12 weeks Partial remission (resolution of oedema, albumin > 35 g/L, proteinuria 4 to 40 mg/m2/h at 24 weeks) at 12 weeks Adverse events
Notes	Exclusions post randomisation but pre‐intervention: none Stop or end points/s: study to be discontinued if number of patients achieving complete/partial remission by 12 weeks was significantly greater with one treatment; patients failing to respond were offered non‐responder protocol after 12 weeks therapy Additional data requested from authors: none Other: more patients with FSGS in cyclophosphamide group; 6 patients in CPA group had heterozygous mutations or sequence variations of NPHS2 gene Inclusion criteria allowed inclusion of patients with partial response to prednisone (proteinuria > 4mg/m2/h but < 40 mg/m2/h)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random lists, stratified by centre
Allocation concealment (selection bias)	Low risk	Central allocation by study coordinator
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding of participants or investigators; lack of blinding could influence management
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Laboratory measure of primary outcome unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Complete follow‐up to 12 weeks, then non‐responders could be withdrawn to enter non‐responder protocol 5/15 CSA group withdrawn from 12 weeks onwards (4 treated with non‐responder protocol of high dose CSA) 14/17 CPA group withdrawn from 12 weeks onwards (7 treated with non‐responder protocol of pulse methylprednisolone)
Selective reporting (reporting bias)	Low risk	Complete or partial remission, adverse effects reported at 12 weeks
Other bias	High risk	Funded in part by a grant from Novartis Pharma