A randomized, controlled trial of everolimus‐based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Abstract

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model

“…The method of concealment of allocation was clearly reported in 12 trials (two induction studies, 97,128 nine maintenance studies, 58,114,129,130,133,140,147,150,152 and one study 136 of both induction and maintenance treatment). Fifty-four trials 51,[72][73][74][76][77][78][79][81][82][83][84][85][87][88][89][91][92][93]95,96,[98][99][100][102][103][104][105][106][108][109][110][111][112][113][115][116][117][118][119][120]124,…”

“…The majority of trials (52 maintenance studies, 51,[75][76][77][79][80][81][82][83][84]86,89,[91][92][93][94][99][100][101][102][104][105][106]108,109,[111][112][113][114][116][117][118][119][120][121][122]130,131,133,138,140,141,[144][145][146][147][148][149][151][152][153]155 nine induction studies, [71][72][73]…”

“…The remaining trials (four induction studies, 71,95,96,98 26 maintenance studies 59,[75][76][77][78][79][80][83][84][85]93,94,103,107,114,115,118,126,127,129,131,132,142,150,152,153 and one study 123 of both induction and maintenance) did not provide sufficient information for a judgement to be made about baseline similarity of groups, either by omitting to report sufficient statistical information, by reporting on a very limited range of patient baseline characteristics or by not reporting any patient baseline characteristics.…”

“…Five induction studies, 87,96,98,128,137 47 maintenance studies 51,59,76,[78][79][80][82][83][84]86,88,[92][93][94]103,[105][106][107][108]111,113,116,118,125,126,[129][130][131][132][133][134][135][138][139][140][141][142][144][145][146][147][148][149][151][152][153]155 and both of the studies of induction and maintenance treatment 123,148 did not blind participants to treatment allocation.…”

“…Fifty-seven trials (48 maintenance studies, 51,58,77,[80][81][82]84,86,94,99,100,102,[104][105][106][107][108][109][113][114][115][116][117][119][120][121][124][125][126][127]131,132,134,138,139,[141][142][143][144][145][146][147]149,150,152,154,156,157 eight induction studies 71,72,74,87,97,128,137 and one study …”