Parameters
Yes
No
Comment
Validity
Is the randomization procedure well described?
+1
142 on cyclosporine + steroids
versus
149 best therapy at the time mostly azathioprine + steroids
Double blinded?
−2
Unblinded trial, thus raising potential of observer bias
Is the sample size calculation described/adequate?
+3
Power of 90 % to detect a 20 % difference, at a significance level of 0.05
Does it have a hard primary endpoint?
+1
Grafts and patients survival
Is the endpoint surrogate?
0
Is the follow-up appropriate?
+1
Average 3 years; up to 5 years follow-up
Was there a Bias?
−2
More second transplants, therefore higher risk, in the control group
Switching of patients between groups generates bias; 40 patients switched, after complications, from CyA to control group
Is the dropout >25 %?
+1
Is the analysis ITT?
+3
Also switching between groups confounds such analysis
Utility/usefulness
Can the findings be generalized?
+1
Was the NNT <100?
N/A
Comparative study between two treatment regimens
Score
46 %
Comments and Discussion
This pivotal trial comparing the impact of CyA versus azathioprine-based immunosuppressive regimens in renal cadaveric allograft recipients showed an advantage for those treated with CyA compared to controls in terms of graft and patient survival.
There was no difference in the incidence of graft rejection although the severity of allograft rejection episodes seemed more severe in the control group than in those treated with CyA. Renal function was lower in the CyA group.
This study has some limitations including:
1.
Its unblinded nature, claimed by the investigators to be due in part to the necessity to monitor CyA blood levels and adjust treatment accordingly, is liable to generate an element of observer bias.
2.
A bias in favor of the CyA arm may have been generated by having more recipients with second renal allografts, thus at a higher risk, in the control group. Also, patients who suffered CyA-induced side effects, mostly renal dysfunction, were allowed to switch to the control group, thus biasing the control group in a negative fashion. This may be compounded by the fact that the study was not blinded, thus raising concern over investigators’ bias and decision-making.
3.
Patients assumed to have acute rejection (AR) were not biopsied; this can create a diagnostic bias by unblinded investigators.
4.
The severity of the graft rejection was based on changes in serum creatinine rather than confirmed by a renal biopsy in all cases.
Conclusion
The Canadian multicenter study confirmed earlier and shorter follow-up studies [9, 10] showing the superiority of CyA-steroids combination treatment over the conventional immunosuppressive regimen of azathioprine plus steroids in recipients of cadaveric renal allograft recipients. From the mid-1980s onward, calcineurin inhibitor (CNI)-based induction immunosuppression has become the cornerstone of renal transplantation.
Tacrolimus Versus Cyclosporine in Renal Transplantation
If the advent of cyclosporine in the area of transplantation had marked a revolution in terms of 1-year survival, then the arrival of tacrolimus represented a further step in the evolution of immunosuppression [11]. Registry data had suggested that tacrolimus was a more potent immunosuppressive agent and furthermore head-to-head studies had demonstrated that tacrolimus was associated with significantly reduced rates of acute cellular rejection (ACR) and also more severe rejection episodes requiring antibody therapy. However, tacrolimus was associated with increased rates of neurotoxicity and new-onset diabetes after transplantation in these studies.
Lancet. 2002 Mar 2;359(9308):741–6.
Efficacy and safety of tacrolimus compared with cyclosporine microemulsion in renal transplantation: a randomized multicenter study.
Margreiter R; European tacrolimus vs Cyclosporine Microemulsion Renal Transplantation Study Group.
Abstract
Background: In previous comparative studies, tacrolimus was superior to the standard formulation of cyclosporine in preventing acute rejection after renal transplantation. We have compared the microemulsion formulation of cyclosporine with tacrolimus in a multicenter randomized trial.
Methods: The 6-month open study involved 560 patients in 50 European centers. Two hundred and eighty-seven patients were randomly assigned tacrolimus and 273 cyclosporine microemulsion plus azathioprine and corticosteroids. The initial oral daily doses were 0.30 mg/kg for tacrolimus and 8–10 mg/kg for cyclosporine. The primary endpoint was the proportion of patients with biopsy-proven acute rejection and the time to this event.
Findings: The two study groups were similar in terms of baseline characteristics. Three patients did not receive study treatment or did not undergo transplantation (one tacrolimus, two cyclosporine). The rate of biopsy-confirmed acute rejection was significantly lower with tacrolimus than with cyclosporine microemulsion (56 patients [19.6 %] vs 101 [37.3 %]; 17.7 % difference [95 % CI 10.3–25.1]; p < 0.0001). Biopsy-confirmed corticosteroid-resistant rejection was also significantly lower with tacrolimus (27 [9.4 %] vs 57 [21.0 %]; 11.6 % difference [5.7–17.5]; p < 0.0001). Crossover between therapies because of biopsy-proven rejection was judged necessary in one of 286 (0.3 %) tacrolimus-group patients and 27 of 271 (10.0 %) cyclosporine-group patients (p < 0.0001). There were no significant differences in survival of patients or grafts or in renal function. The overall frequency of adverse events was similar in the two groups, though hypertension and hypercholesterolemia were more common in the cyclosporine group and tremor and hypomagnesemia were more frequent in the tacrolimus group.
Interpretation: Tacrolimus was significantly more effective than cyclosporine microemulsion in preventing acute rejection after renal transplantation and had a superior cardiovascular risk profile.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | All eligible participants from each study center were randomized centrally in a one-to-one ratio to receive immunosuppressive therapy with tacrolimus (Prograf, Fujisawa GmbH, Munich, Germany) or cyclosporine microemulsion (Neoral, Novartis, Basel, Switzerland), with adjunctive azathioprine (Imuran, Glaxo Wellcome, Middlesex, UK) and corticosteroids | |
Double blinded? | −2 | Open label, thus subject to investigator bias | |
Is the sample size calculation described/adequate? | +3 | The sample size estimate was based on the assumption that the rate of acute rejection in tacrolimus-treated patients during the first 6 months after transplantation would be 25 %. It was estimated that 450 patients would be required to give a statistical test on a 0.05 significance level (two-sided) the power of 80 % to detect a difference of 13 % in the rate of acute rejection | |
Does it have a hard primary endpoint? | −1 | The primary endpoint of the study was the proportion of patients with a first biopsy-proven acute rejection (BPAR) within 6 months of transplantation and the time to onset of such a rejection episode | |
Is the endpoint surrogate? | −2 | No | |
Is the follow-up appropriate? | −1 | 6 months | |
Was there a Bias? | +2 | ||
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | ||
Was the NNT <100? | N/A | Comparative study between two treatment regimens | |
Score | 33 % | ||
Comments and Discussion
After a number of smaller studies implied superiority of tacrolimus (FK506) over cyclosporine (CyA) [12, 13], this European multicenter study showed that tacrolimus was more effective in preventing acute cadaveric allograft rejection. This larger European study was well powered to confirm previous observations. There was no difference in the secondary endpoints of graft and patients survival or renal function.
This study was confirmed by the US FK506 multicenter study that had a longer 12–18 months follow-up but smaller power and sample size [13]. The 5-year follow-up of the US multicenter study showed a favorable impact of tacrolimus on graft survival [14]. Of note, a meta-analysis performed in 2005 suggested that for every 100 patients treated with tacrolimus as opposed to cyclosporine, 12 patients would avoid an episode of rejection and 2 patients would keep their grafts 12 months after transplantation. However, five additional patients would have developed new-onset diabetes [15].
This study is not without limitations including:
1.
Its open-label nature thus raising concern over potential observer bias.
2.
Its soft primary endpoint of biopsy-proven acute rejection (BPAR) has become apparent since there is no strong correlation between BPAR and longer-term functional and graft-survival outcomes. There was no comment on the severity of the BPAR, but comments were made on a lower incidence of steroid-resistant AR episodes in patients treated with tacrolimus.
3.
It is unclear whether the biopsy and histology evaluation of BPAR was blinded to the investigators.
4.
The study follow-up of 6 months was too short as acute-rejection episodes continue to occur during the first 12 months after transplantation.
Conclusion
This study had a major impact on immunosuppression practice and induction therapy in recipients of cadaveric renal allograft recipients. Tacrolimus has since replaced CyA as the standard and preferred immunosuppressive agent.
Mycophenolate Mofetil in Renal Transplantation
Lancet. 1995 May 27;345(8961):1321–5.
Placebo–controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group.
[No authors listed]
Abstract
Preliminary studies suggested that mycophenolate mofetil (MMF), which inhibits proliferation of T and B cells, may reduce the frequency of acute rejection after renal transplantation. Our randomized, double-blind, multicenter, placebo-controlled study compared the efficacy and safety of MMF with placebo for prevention of acute-rejection episodes after first or second cadaveric renal allograft transplantation. Four hundred and ninety-one patients were enrolled; 166 were assigned placebo, 165 MMF 2 g, and 160 MMF 3 g. Patients also received cyclosporine and corticosteroids. Significantly fewer (p < or = 0.001) patients had biopsy-proven rejection or withdrew early from the trial (for any reason) during the first 6 months after transplantation with MMF 2 g (30.3 %) or 3 g (38.8 %) than with placebo (56.0 %). The corresponding percentages for biopsy-proven rejection were 17.0, 13.8, and 46.4 %. 28.5 % of MMF 2 g and 24.4 % of MMF 3 g patients needed full courses of corticosteroids or antilymphocyte agents for treatment of rejection episodes in the first 6 months, compared with 51.8 % of placebo recipients. By 6 months, 10.2, 6.7, and 8.8 % of the patients in the placebo, MMF 2 g and MMF 3 g groups, respectively, had died or lost the graft. Overall, the frequency of adverse events was similar in all treatment groups, although gastrointestinal problems, leukopenia, and opportunistic infections were more common in the MMF groups and there was a trend for more events in the 3 g than the 2 g group. MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated. The 3 g dose was somewhat less well tolerated.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | ||
Double blinded? | +2 | ||
Is the sample size calculation described/adequate? | +3 | Comparative analysis between CyA + steroids + placebo (166 patients) versus CyA + steroids + MMF 2 g/day (165) versus CyA + steroids + MMF 3 g/day (160) | |
Does it have a hard primary endpoint? | −1 | Biopsy-proven acute rejection (BPAR) | |
Also time to BPAR and treatment failure | |||
Is the endpoint surrogate? | −2 | Graft and patient survival were not primary endpoints | |
Is the follow-up appropriate? | −1 | 6 months | |
Was there a Bias? | −2 | Absence of azathioprine as comparator | |
Is the dropout >25 %? | +1 | Large withdrawal from the study ranging from 22 to 35 % | |
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | −1 | Not in the absence of an adequate comparator group | |
Was the NNT <100? | N/A | ||
Score | 20 % | ||
Comments and Discussion
The European Mycophenolate Mofetil (MMF) Cooperative Study showed the superiority of MMF over cyclosporine and steroid alone, in terms of biopsy-proven acute rejection (BPAR) for a regimen, in cadaveric renal transplantation. This was achieved by adding MMF to CyA and steroids compared to CyA and steroids alone. The percentage of those with BPAR on the CyA + steroids group was 46 %, compared to 17 % and 13.8 % in the MMF 2 and 3 g/day, respectively. The two MMF groups had comparable results up to 10 weeks; thereafter, the MMF 3 g/day had the higher cumulative rate of BPAR and treatment failure.
Of note, the dose of CyA and the blood levels achieved were not given and seemed to vary according to the clinical practice in the different European centers included in the study.
This study has the main limitation of not including a valid comparator to MMF using another antimetabolite such as azathioprine (Imuran), thus precluding any possible comparison with best practice at the time in cadaveric renal transplantation including CyA, azathioprine, and steroids. This was subsequently addressed by the US Renal Transplant Mycophenolate Mofetil Study Group that showed the superiority of MMF over azathioprine in terms of BPAR as well as graft loss at 6 months [16]. A systematic review undertaken in 2009, including 19 studies and 3,143 patients, confirmed the superiority of MMF-containing regimen over azathioprine [17]. This systematic review showed MMF used with a CNI conferred a benefit over azathioprine containing regimen as far as acute rejection, and “possibly” graft loss was concerned. Of interest, no difference was noted in terms of renal function [17].
Conclusion
A body of evidence has shown the superiority of MMF over azathioprine containing immunosuppressive regimen in cadaveric renal transplantation.
ELITE-Symphony Trial
N Engl J Med. 2007 Dec 20;357(25):2562–75.
Reduced exposure to calcineurin inhibitors in renal transplantation.
Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, Margreiter R, Hugo C, Grinyó JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study.
Abstract
Background: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.
Methods: We randomly assigned 1,645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary endpoint was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary endpoints included acute rejection and allograft survival.
Results: The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 mL/min) than in the other three groups (range, 56.7–59.4 mL/min). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3 %) than in those receiving standard-dose cyclosporine (25.8 %), low-dose cyclosporine (24.0 %), or low-dose sirolimus (37.2 %). Allograft survival differed significantly among the four groups (P = 0.02) and was highest in the low-dose tacrolimus group (94.2 %), followed by the low-dose cyclosporine group (93.1 %), the standard-dose cyclosporine group (89.3 %), and the low-dose sirolimus group (89.3 %). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2 % vs. a range of 43.4–44.3 %), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3–90.5 %).
Conclusions: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute-rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].)
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure described well? | +1 | Patients were randomly assigned in a 1:1:1:1 ratio to receive one of four treatments | |
Was the study double blinded? | −2 | Not investigators blinded | |
Was the sample–size calculation described/adequate? | +3 | The initial protocol called for the enrolment of 1,300 patients. In an amendment to the protocol, the number was increased to 1,760 patients (440 per group) to provide a power of 80 % to detect a difference of 6.5 mL/min in GFR in one group with respect to the others in a global test, a value that was considered to be clinically relevant. To calculate GFR, a last-observation-carried-forward method was used for serum creatinine and weight, and 10 mL/min was imputed for missing values | |
Did the study have a hard primary endpoint? | −1 | Estimated GFR by the Cockcroft-Gault method was used to evaluate renal function. True GFR was not measured | |
Was the endpoint surrogate? | −2 | Same as above and somewhat unrelated to hard endpoints such as allograft and patient’s survival | |
Was the follow-up appropriate? | +1 | Yes for the surrogate endpoint, but not for the harder secondary endpoints | |
Was there any Bias? | −2 | The low-cyclosporine and the low-sirolimus groups received subtherapeutic doses of immunosuppressants. | |
Blood levels of cyclosporine, tacrolimus, and sirolimus were measured using locally available assays. Hence, in this protocol, because immunosuppressants were used at very low doses, this heterogeneity gives a huge bias because, for a given target, the result can be very different depending on the test used to measure it | |||
Was the dropout rate >25 %? | −1 | Withdrawal from an assigned treatment ranged from 20 % in the low-dose tacrolimus to 48.9 % in the low-sirolimus group. In all groups, treatment failure was the main reason for withdrawal | |
Was the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | ||
Was the NNT <100? | N/A | As comparative study between different drug regimens | |
Score | 6.5 % | ||
Comments and Discussion
This important study defined our current immunosuppression-preferred induction regimen, with emphasis on short-term renal functional preservation.
However, the study is not without its limitations:
1.
Not double blinded, thus subject to investigator bias.
2.
There was no comparison made between low and high tacrolimus dose but instead comparison between tacrolimus and CyA, with the former having a potential therapeutic advantage over the latter as discussed above [18].
3.
The low-cyclosporine and the low-sirolimus groups received subtherapeutic doses of immunosuppressants.
4.
In the absence of calcineurin inhibitors (i.e., cyclosporine or tacrolimus) and because of the half-life of sirolimus (~60 h, implying that its steady state is not achieved in less than 8 days), it could be anticipated that, in the low-sirolimus group, there would be more treatment failures. Thus, the low-cyclosporine as well as the low-sirolimus groups started the study with a handicap and an inherent bias.
5.
eGFR is a soft endpoint as graft and patient survival are considered hard endpoints in renal transplantation.
6.
eGFR was relied upon and true GFR was not measured (mGFR); patients with more frequent rejection episodes and higher cumulative dose of steroids may be confounded by weight loss/sarcopenia and/or the impact of steroid therapy on muscle/creatinine metabolism. eGFR has also not been validated for the evaluation of renal function trajectories in renal transplantation.
7.
Blood levels of cyclosporine, tacrolimus, and sirolimus were measured using locally available assays. Of the 83 participating sites, the reference tests were used in 33.3 % of sites for cyclosporine, in 61.7 % of site for sirolimus, and in 65 % of sites for tacrolimus. Hence, in this protocol, because immunosuppressants were used at very low doses, this heterogeneity gives a huge bias because, for a given target, the result can be very different depending on the test used to measure it.
8.
Also, with issues with drug blood level measurements and the related bias, optimization of treatment in different groups is doubtful.
Conclusion
Major and pivotal study in renal transplantation that defined the current, preferred, immunosuppression/induction regimen.
However, the study is not without its serious limitations described above including potential observer bias, patient allocation bias, and issues related to drug blood level measurements as well as estimation of kidney function.
Monoclonal Antibodies in Renal Transplantation
Basiliximab (anti-IL-2 Receptor) in Renal Transplantation
Lancet. 1997 Oct 25;350(9086):1193–8.
Randomized trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group.
Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP.
Abstract
Background: Currently available immunosuppressive regimens for cadaver kidney recipients are far from ideal because acute-rejection episodes occur in about 30–50 % of these patients. In the phase III study described here, we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients.
Methods: Three hundred and eighty adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4–6 weeks (n = 193), or to receive placebo (n = 187). Both groups received baseline dual immunosuppressive therapy with cyclosporine and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study.
Findings: Three hundred and seventy-six patients were eligible for intention-to-treat analysis (basiliximab, n = 190; placebo, n = 186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8 %) of 171 in the basiliximab group compared with 73 (44.0 %) of 166 in the placebo group (32 % reduction; 14.2 % difference [95 % Kaplan-Meier CIs 3–24 %], p = 0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10 % vs 23.1 %, 13.1 % difference [5.4–20.8 %], p < 0.001). At weeks 2 and 4 posttransplantation, the mean daily dose of steroids was significantly higher in the placebo group (p < 0.001 with one-way analysis of variance). The incidence of graft loss at 12 months posttransplantation was 23 (12.1 %) of 190 in the basiliximab group and 25 (13.4 %) of 186 in the placebo group (1.3 % difference [−5 to 9 %], p = 0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. Fourteen deaths (basiliximab n = 9; placebo n = 5; −2.0 % difference [−6 to 2 %], p = 0.293) occurred during the 12-month study and a further three deaths (basiliximab n = 1; placebo n = 2) occurred within the 380-day cutoff period. One posttransplantation lymphoproliferative disorder was recorded in each group.
Interpretation: Prophylaxis with 40 mg basiliximab reduces the incidence of acute-rejection episodes significantly, with no clinically relevant safety or tolerability concerns.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | 376 patients were eligible for intention-to-treat analysis (basiliximab, n = 190; placebo, n = 186). | |
Basiliximab or placebo on a background of CyA + steroids-only therapy | |||
Double blinded? | +2 | ||
Is the sample size calculation described/adequate? | +3 | ||
Does it have a hard primary endpoint? | −1 | The primary-efficacy assessment was a comparison of the proportion of patients in each group who experienced at least one acute-rejection episode during the first 6 months after transplantation, with follow-up data to 12 months. | |
Biopsy-confirmed acute rejection was a secondary endpoint | |||
Is the endpoint surrogate? | −2 | ||
Is the follow-up appropriate? | −1 | 6 months, too short | |
Was there a Bias? | +2 | ||
Is the dropout >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | European transplantation centers. As US practice often includes the addition of an ATG/ALG during induction | |
Was the NNT <100? | +1 | ||
Score | 62 % | ||
Comments and Discussion
The study showed clearly that the addition of basiliximab to baseline dual immunosuppression including CyA and steroids significantly decreased the number of rejection episodes and the number of BPAR including those that were steroids resistant. However, there was no difference in the severity of the AR episodes between the groups.
Graft and patient survival were comparable between the groups. Basiliximab was not associated with more side effects in the study’s short observation period.
This study has some limitations:
1.
Basiliximab was added to a dual therapy of CyA and steroids without the added benefit of an antimetabolite such as azathioprine, available at the time of the trial and considered a useful adjunct to dual therapy.
2.
Basiliximab-enhanced induction was not compared to common practice in the USA of inclusion of an antilymphocyte or an antithymocyte globulin (ALG/ATG). In that respect, further studies (reviewed in [19]) and a systematic review showed no advantage of IL-2R monoclonal antibodies over ATG in terms of graft and patient survival [20].
3.
The use of the soft endpoint of acute rejection while showing a benefit does not always translate to improved graft function or survival at 12 months. Of relevance here is that basiliximab did not reduce the histological severity of BPAR, as severe AR may impact longer-term outcomes.
Conclusion
Compared with ATG (antithymocyte globulin), basiliximab, as with daclizumab, is generally associated with similar efficacy in standard/low-risk patients, but reduced efficacy in high-risk patients. It also appears to be less effective than alemtuzumab in low immunological risk patients [21]. Compared to other induction regimen, basiliximab has not demonstrated improved graft or patient survival over the long term. An advantage of basiliximab induction in low-risk patients is that it allows for reduced dosage of corticosteroids or calcineurin inhibitors, while maintaining adequate immunosuppression.
Alemtuzumab (Anti-CD52 Antibody) Induction in Renal Transplantation
Alemtuzumab was originally discovered by virtue of its ability to cause profound lymphodepletion, initially in rodents but later in humans. It is a humanized monoclonal IgG1 antibody derived from rat antihuman CD52. It was originally used in renal transplantation by the Cambridge group who showed that in combination with cyclosporine monotherapy, it provided effective medium-term immunosuppression.
Interest intensified following the demonstration in animal models that profound lymphocyte depletion permitted the induction of tolerance and this prompted a number of trials in humans using alemtuzumab induction and then minimal single agent immunosuppression. However, these latter trials were blighted by unacceptably high acute-rejection rates in immunologically low-risk transplants (reviewed in [22]). However, a number of groups have demonstrated that alemtuzumab can be an effective induction agent if used as part of a more conventional multidrug regimen. Unfortunately, many of these studies were short term, underpowered, and very short term [22].
The INTAC Trial
N Engl J Med. 2011 May 19;364(20):1909–19. doi:10.1056/NEJMoa1009546.
Alemtuzumab induction in renal transplantation.
Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J; INTAC Study Group.
Collaborators (28)
Abstract
Background: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunological risk or low immunological risk.
Methods: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute-rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20 % or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary endpoint was biopsy-confirmed acute rejection at 6 and 12 months. Patients were followed for 3 years for safety and efficacy endpoints.
Results: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3 % vs. 15 %, P < 0.001) and 12 months (5 % vs. 17 %, P < 0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10 % vs. 22 %, P = 0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18 % vs. 15 %, P = 0.63). Adverse-event rates were similar among all four treatment groups.
Conclusions: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.)
