ZEUS Study 2011.

Methods	Study design: parallel RCT Study duration: recruitment June 2005 to September 2007 Duration of follow‐up: 5 years
Participants	Setting: multicentre (32 centres) Country: Germany and Switzerland Patients who received de novo kidney transplant aged 18 to 65 years; at 4.5 months post‐transplant patients had to have no graft loss, dialysis dependency, or death; maintained on an immunosuppressive regimen with EC‐MPS (≥ 720 mg/d), CsA, and corticosteroids; SCr < 265·2 μmol/L; proteinuria of no more than 1 g/d; no previous changes to immunosuppressive regimen due to immunological reasons; no rejections of Banff grade 2 or greater, no recurrent or steroid‐resistant AR; counts of leucocytes of at least 2500/μL, neutrophils of at least 1500/μL, platelets of at least 75 000/μL, Hb of at least 60 g/L; no evidence of severe liver disease, intractable immunosuppressant side‐effects, or infections Number: treatment group (155); control group (145) Mean age ± SD (years): treatment group (46.9 ± 11.7); control group (46.7 ± 11.9) Sex (M/F): treatment group (102/53); control group (86/49) Exclusion criteria: 2nd transplant who previously had immunological graft loss within 1 year; recipients of multiple organ transplants or an organ donated after cardiac death; donors < 5 years or > 65 years; recipients of A‐B‐O‐incompatible transplants; a previous peak PRA > 25%; antibodies against the HLA of the donor organ
Interventions	Treatment group EVL: started at month 4.5 1.5 g/d; target trough level 3 to 7 ng/mL (step 1) and 6 to 10 ng/mL thereafter CsA withdrawal: stepwise over 4 weeks (50%, 25%, 0%) Control group CsA trough levels: 120 to 180 ng/mL (months 4.5 to 6), thereafter 100 to 150 ng/mL Both groups CsA trough levels (to month 4.5): 150 to 220 ng/mL PRED as per local protocol
Outcomes	GFR at 12 months BPAR Graft loss Death Evolution of between 4.5 to 12 months and safety
Notes	Funding source: "This study was funded by Novartis Pharma...Tim Mitchell and Caroline Barnett from Real Science Communications provided medical writing support on behalf of Novartis"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomly assigned in a 1:1 ratio by use of a central, validated system that automated the random assignment of treatment groups to randomisation numbers (stratified according to living‐donor or deceased donor status)
Allocation concealment (selection bias)	Low risk	Central automated random assignment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All outcomes reported and missing data accounted
Selective reporting (reporting bias)	Low risk	prespecified variables reported
Other bias	High risk	Funded by Novartis

ACEi ‐ angiotensin‐converting enzyme inhibitor; ACR ‐ albumin:creatinine ratio; ALG ‐ antilymphocyte globulin; ATG ‐ antithymocyte globulin; ATN ‐ acute tubular necrosis; AR ‐ acute rejection; ARB ‐ angiotensin II receptor blocker; AUC ‐ area under the curve; AZA ‐ azathioprine; BMI ‐ body mass index; BP blood pressure; BPAR ‐ biopsy‐proven acute rejection; BPM ‐ beats per minute; C2 ‐ drug concentration 2 hours post ingestion; CAN ‐ chronic allograft nephropathy; CMV ‐ cytomegalovirus; CNI ‐ calcineurin inhibitor; CrCl ‐ creatinine clearance; CsA ‐ cyclosporin A; CPA ‐ cyclophosphamide; DGF ‐ delayed graft function; ECG ‐ electrocardiogram; EC‐MPS ‐ encapsulated mycophenolate sodium; ESKD ‐ end‐stage kidney disease; EVL ‐ everolimus; FSGS ‐ focal segmental glomerulosclerosis; (e or m)GFR ‐ (estimated or measured) glomerular filtration rate; Hb ‐ haemoglobin; HBV ‐ hepatitis B virus; HCV ‐ hepatitis C virus; HIV ‐ human immunodeficiency virus; HLA ‐ human leukocyte antigen; IL2RA ‐ interleukin 2 receptor antagonist; ITT ‐ intention‐to‐treat; M/F ‐ male/female; MMF ‐ mycophenolate mofetil; MPS ‐ mycophenolate sodium; MMF ‐ mycophenolate mofetil; MPA ‐ mycophenolic acid; mTOR‐I ‐ mammalian target of rapamycin inhibitors; NODAT ‐ new‐onset diabetes after transplantation; PRA ‐ panel reactive antibodies; PRED ‐ prednisone/prednisolone; PTLD ‐ post‐transplant lymphoproliferative disease; RCT ‐ randomised controlled trial; SCr ‐ serum creatinine; SD ‐ standard deviation; SRL ‐ sirolimus; TAC ‐ tacrolimus; Treg ‐ regulatory T cells; WCC ‐ white cell count