Table 2:
Clinical trials of mTORi in renal transplantation
| Study | Type and duration of follow-up | n | Treatment groups | Outcomes |
|---|---|---|---|---|
| Groth et al (1999)24 | Multi-centre, open-label (1 year) | 83 | Steroid + AZA + CsA or SRL | Graft survival, patient survival and BPAR similar; serum creatinine lower in SRL group; higher pneumonia rates in SRL group |
| Kahan et al (1999)104 | Phase II trial (1 year) | 149 | Steroid + CsA + placebo or low- or high-dose SRL, steroid + low-dose CsA + low- or high-dose SRL | Addition of SRL reduced BPAR in standard dose CsA group; no difference in graft or patient survival; haematologic and lipid abnormalities in SRL group, HT and NODAT in CsA group |
| Kreis et al (2000)106 | Multi-centre, open-label (1 year) | 78 | Steroid + MMF + CsA or SRL | Graft survival, patient survival and BPAR similar; serum creatinine lower in SRL group |
| Rapamune US (2000)105 | (1 year) | 719 | Steroid + CsA + AZA or SRL | Reduced occurrence and severity of BPAR in SRL group at 6 months |
| Rapamune Global (2001)103 | Phase III (1 year) | 576 | Steroid + CsA + placebo, low- or- high-dose SRL | Addition of SRL reduced acute rejection rates |
| Johnson et al (2001)316 | Open-label (1 year) | 525 | Steroid + CsA + SRL, 3 month withdrawal CsA or CsA maintenance | Improved renal function and lower BP when CsA withdrawn; thrombocytopenia, hypokalemia and abnormal LFTS in SRL group |
| Gonwa et al (2001)317 | Phase II, open-label (1 year) | 246 | CsA + SRL or reduced-dose CsA (taper at 2 months)+ SRL | Renal function better in CsA elimination arm; graft and patient survival similar, BPAR similar |
| Rapamune Maintenance Study (2003318, 2005319) | Phase III (4 years) | 525 | Steroid + CsA + SRL, random assignment to CsA withdrawal at 3 months | 2 years: CsA withdrawal showed improved renal function and blood pressure, no change in graft loss or late acute rejection rates; 4 years: Non-significant increase in acute rejection rates with CsA withdrawal; higher incidence of adverse effects with triple therapy |
| Larson et al (2006)320 | (1 year) | 165 | Steroid + MMF + TAC or Steroid + MMF + SRL | Similar acute rejection, graft survival and renal function |
| SPIESSER Study (2007321, 2012322, 2016323) | (8 years) | 1 year: 145 5 years: 133 8 years: 119 |
Polyclonal antilymphocyte antibodies + steroid + MMF + CsA or SRL | 1 year: BPAR, graft survival and patient survival not different; SRL group had higher adverse events (bronchopneumonia, proteinuria) and discontinuation rates 5 years: eGFR higher in SRL group; graft and patient survival no different, adverse effects more common in SRL group 8 years: No difference in graft survival, eGFR greater in SRL group, no detrimental impact in patients in whom SRL was withdrawn. No difference in malignancy |
| Symphony (2007108, 2009324) | (3 years) | 1 year: 1,645 3 years: 958 |
Steroid + CsA + MMF or daclizumab + MMF + low-dose CsA/low-dose TAC or low-dose SRL |
1 year: GFR and allograft survival highest and BPAR lowest in low-dose TAC; adverse effects most common in low-dose SRL 3 years: highest GFR and graft survival in MMF+TAC group |
| CONCEPT Study (2009325, 2011326) | (4 years) | 1 year: 192 (237 enrolled) 4 years: 162 |
Steroid+MMF + CsA, ± converted to SRL at 3 months | 1 year: patient and graft survival similar, GFR better in SRL group, ACR rates not significantly higher in SRL group, more adverse events in SRL group 4 years: mean benefits in renal function maintained |
| Glotz et al (2010)121 | 1 year | 141 | Steroid + MMF + SRL or TAC | No difference in GFR or patient survival, graft loss, withdrawal and adverse events higher in SRL group |
| SMART trial (2010327, 2012328) | 3 years | 1 year: 141 2 & 3 years: 132 |
ATG induction, steroids + MMF + CsA, conversion to SRL at 10–24 days | 1 year: GFR better in SRL group, BPAR, patient and graft survival not different, lower incidence CMV infection, more adverse events in SRL group 2 & 3 years: SRL conversion associated with sustained improvement of renal function; discontinuation of SRL due to adverse events was common |
| ZEUS Study (2011329, 2015330) | 5 years | 1 year: 503 enrolled, 5 year follow- up: 245 |
Basiliximab induction, steroids + MMF + CsA, at 4–5 months conversion to EVL or stay on CsA | 1 year: GFR better in EVL group, higher BPAR, lipidaemia and proteinuria, lower haemoglobin and greater adverse events 5 years: EVL group: better GFR Higher BPAR (grade I), did not affect long-term graft function. No difference in graft loss, mortality, adverse events and neoplasm |
| ASCERTAIN study (2011)331 | Multi-centre, open-label, 2 years | n=394 | Randomization at >6 months to EVL with CNI elimination, EVL with CNI mimization or CNI unchanged | Conversion to EVL with CNI elimination or minimization had no renal benefit; more frequent adverse events and discontinuation |
| Heilman et al (2011)120 | (2 years) | 122 | MMF+TAC or MMF+SRL | 63% withdrawal from SRL group |
| STN Study (2011332, 2016333) | (8 years) | 2 years: 229 8 years: 128 |
MMF+CNI MMF+SRL | 2 years: Similar renal function between groups 8 years: Improved long-term renal function with SRL/MMF compared to CNI/MMF |
| Orion (2011)109 | Phase IV trial (2 years) | 443 | (1) SRL+TAC, TAC eliminated week 13; (2) SRL+MMF; (3) TAC+MMF All patients also received steroids and daclizumab | Group 2 had high BPAR (>30%), SRL assoc with hyperlipidemia and delayed wound healing, SRL assoc w greater proteinuria and discontinuation, TAC assoc with NODAT, SRL not associated with improved outcomes |
| Mjörnstedt et al (2012334, 2015)335 | (3 years) | 1 year: 202 3 years: 182 |
Steroid+MMF + CsA, at 6 weeks convert to EVL or stay on CsA | 1 year: GFR better in EVL group, but higher incidence of BPAR and adverse events leadng to discontinuation 3 years: EVL associated with significant benefit in renal function but drug discontinuation more common |
| APOLLO Study (2015)336 |
(1 year) | 93 | Remain on CsA or convert to EVL | Premature termination due to slow recruitment. Higher rate of discontinuation with EVL |
Abbreviations: ACR, acute cellular rejection; ATG, anti-thymocyte globulin; AZA, azathioprine; BPAR, biopsy proven acute rejection; CMV, choriomeningitis virus; CsA, cyclosporine; GFR, glomerular filtration rate; LFTS, liver function tests; MMF, mycophenolate mofetil; NODAT, new onset diabetes after transplantation; EVL, Everolimus; SRL, Sirolimus; TAC, Tacrolimus