Hladunewich 2014.

Study characteristics
Methods	Study design: parallel, open‐label, dose‐finding RCT Study duration: recruitment period not reported; treatment for 12 weeks Duration of follow up: 1 year
Participants	Setting: multicentre (Mayo Clinic and University of Toronto) Country: US & Canada Inclusion criteria: IMN with diagnostic biopsy performed < 36 months from the time of dose randomisation and did not demonstrate in excess 30% glomerulosclerosis and/or interstitial fibrosis or tubular atrophy; > 18 years; at least 3 months of treatment with RAS blockade to lower BP to < 130/75 mm Hg in > 75% of the readings prior to the initiation of ACTH treatment; nephrotic range proteinuria as defined by UPCR ≥ 4.0 on a spot sample aliquot from a 24‐h urine collection without significant renal insufficiency as defined by an eGFR ≥ 40 mL/min/ 1.73 m² while taking blockade of the RAS Special cases that were included: partial response to other regimens or significant side effects were eligible. These study patients were required to be off glucocorticoid therapy, CNI or MMF for > 1 month, and alkylating agents for > 6 months Baseline characteristics Mean SBP/DBP ± SD (mm Hg): 121 ± 16 / 72 ± 824 Proteinuria (in gram/24h): 9.068 ± 3.384 Mean serum albumin ± SD (g/L): 2.72 ± 0.83 Mean eGFR ± SD (mL/min/1.73 m²): 77 ± 30 Mean triglyceride ± SD (mmol/L): 225 ± 190 Mean serum cholesterol ± SD (mmol/L): 306 ± 133 Disease‐course (time since diagnosis) at immunosuppressive treatment initiation: maximum 36 months Pathological classification: not reported Co‐morbidities: not reported Number: treatment group 1 (9); treatment group 2 (11) Mean age ± SD: 51 ± 15 years Sex (M/F): 13/7 Exclusion criteria: documented resistance to immunosuppressive routines used in IMN (e.g. CNI ± steroids or cytotoxic agents ± steroids); active infections; secondary causes of membranous nephropathy (e.g. hepatitis B, SLE, medications, malignancies); type 1 or 2 DM to exclude proteinuria secondary to diabetic nephropathy; pregnancy or nursing women; documented acute thrombosis, requiring anticoagulation therapy
Interventions	Treatment group 1 ACTH(SC): 40 IU for up to 12 weeks. If at day 91 no response has been shown the option to increase the dose of ACTH to 80 units for up to an additional 120 days (5/9 had their dose increased to 80 IU after the trial, and followed up to 1 year) Treatment group 2 ACTH (SC): 80 IU for up to 12 weeks Both groups The dose of ACTH was increased from one injection every other week to 2 injections/week. It was then continued at full dose, either 40 or 80 units twice/week, for 12 weeks. The injections were given on the following days One injection/week: days 0, 14, 21, 28 Two injections/week: days 31, 35, 38, 42, 45, 49, 52, 56, 59, 63, 66, 70, 73, 77,80, 84, 87 and 91 Co‐medications: antihypertensive therapy (most patients, ARB 1st choice, more medications added if needed to control BP) atorvastatin 10 mg (dose raised over time)
Outcomes	Changes in the measures of nephrotic syndrome, including: Change in proteinuria Change in serum albumin Change in LDL cholesterol, HDL cholesterol, and triglycerides Side effects/toxicity Complete or partial remission, and the effect of maximizing angiotensin II blockade on proteinuria complete remission: proteinuria < 0.3 g/day partial remission: reduction in proteinuria by > 50% with a final urine protein < 3.5 g/day, but > 0.3 g/day No response: reduction in proteinuria by < 50% or worsening of proteinuria
Notes	Funding source: Questor Pharmaceuticals Not reported as a trial, doses changed after 12 weeks and outcomes reported for whole group, not randomised group. Not enough patients left in 40 IU treatment‐arm for analysis Anti‐PLAR2‐Ab levels were measured
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation occurred in 1:1 ratio using a block randomisation technique
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome‐assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	High risk	Poor reporting of outcomes within the randomised groups. no intention‐to‐treat analysis. many patients switched treatment arms.
Selective reporting (reporting bias)	High risk	Outcomes not properly reported for randomised groups separately
Other bias	High risk	High number of patients that changed the treatment‐arm during the study. SCr not reported in outcome measures. Industry‐funded trial, however the pharmaceutical company had no role in the design and/or evaluation of the study, nor the writing of the manuscript