Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This interesting multicenter open-label study investigated the interaction between low- and high-dose tacrolimus and use of ACE inhibitors on the development of IF/TA following renal transplantation. The investigators used a 2x2 randomised design to compare low- versus high-dose prolonged release tacrolimus and ACEi/ARB versus other antihypertensive use. Protocol biopsies were taken at baseline, 6 months and 24 months. The largest reduction in 24-month IF/TA came from the use of low-dose tacrolimus, although there was some interaction between the two treatments with the lowest rate of IF/TA seen in the ACEi and low-dose Tac group. Use of ACEi/ARB in conjunction with low-dose tacrolimus also appears to reduce the rejection risk associated with low-dose tac use. Interestingly, post-hoc analysis also demonstrated a significant reduction in the risk of IF/TA with inflammatory infiltrate associated with ACEi/ARB use. Taken together, these results suggest that addition of ACEi/ARB to low-dose tacrolimus early after transplantation is safe and may confer some benefit in the progression of IF/TA and risk of T-cell mediated rejection. It is not clear whether the histopathologists involved in this study were blinded to treatment assignment, raising the risk of measurement bias. Longer-term follow-up will determine whether the early benefits seen translate to differences in graft function and survival.
Expert Review
Reviewer:
Robert M. Langer M.D., Ph.D. Professor of Surgery and Nephrology Ordensklinikum Linz, Austria, Krankenhaus der Elisabethinen
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
Usually in daily practice one can see the negative side effects of combined treatments. In this Canadian multicenter study we can observe a positive, beneficial example of RAS blockade combined with low dose tacrolimus. It may have a practice-changing effect, similar to the power of the Symphony study regarding the minimization of immunosuppression, specifically the effects of CNI. The Symphony study could show that low dose tacrolimus in combination with full dose mycophenolate provides the best results with the available immunosuppressant combinations in means of kidney function. By taking another step forward Cockfield et al. show that ACE inhibitory (ACEi) treatment for hypertension in combination with low-dose tacrolimus can lower the T-cell mediated rejection rate and can mitigate the IF/TA histopathologically, so by blocking the chronic inflammation process it may allow for better long-term function. Today’s efforts to lengthen the half-life of allografts is one of the most challenging questions of transplantation, however quite hard to measure which is the major contributing factor. The above study may be a first step in this direction.
Aims:
To assess the effects of IF/TA prevalence using a reduced tacrolimus dosing strategy and RAS-blocking AHTs.
Interventions:
At randomization, patients were assigned to one of four possible treatments; standard-dose, prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=69), or low- dose prolonged-release tacrolimus, plus, either an ACE inhibitor or angiotensin II receptor blocker (n=71), or other antihypretensive therapy (n=68), corresponding to two tacrolimus interventions (low vs standard) and two AHT interventions (ACEi/ARB vs OAHT).
Participants:
281 adult renal transplant recepients. Of these, 235 completed the study.
Outcomes:
This study had two co-primary outcomes: the prevalence of IF/TA at Month 6 and at Month 24. Secondary endpoints included the progression of IF/TA post-transplant, and assessment of renal function, blood pressure and use of antihypertensive agents throughout the study period.
Follow Up:
Up to 24 months
Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This manuscript reports the 5-year follow-up of the TUMORAPA study, where kidney transplant recipients with a previous diagnosis of squamous-cell skin cancer were randomised to either continue CNI-based immunosuppression or convert to sirolimus. In patients remaining on randomised therapy, survival free of recurrent SCC was longer and the number of new cancers was lower in the sirolimus group, with equivalent graft and patient survival. These findings were largely limited to patients switched after diagnosis of a single SCC – those with multiple previous SCCs appear to gain less benefit. Whilst these data suggest that sirolimus may be beneficial in this patient group, it should be noted that this was an on-protocol analysis. Given the poor tolerance of mTOR inhibitors, it is perhaps more useful to look to an intent-to-treat analysis to examine the likely overall benefit in a population. Also, the proportion of patients reaching 5-year follow-up was low at less than 50%.
Expert Review
Reviewer:
Mehmet Haberal, MD, FACS (Hon), FICS (Hon), FASA (Hon), FIMSA (Hon); President, The Transplantation Society; Founder and Founder President, Baskent University; President of the Executive Supreme Board, Baskent University; Chair, Baskent University Division of Transplantation.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
This study showed that cutaneous squamous cell carcinoma free survival was significantly longer in kidney transplant recipients receiving sirolimus compared to those receiving calcineurin inhibitors. In those patients who previously had cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years and tolerance to sirolimus was acceptable. The results of this study indicate that conversion to mTOR inhibitors should be recommended for kidney transplant patients taking calcineurin inhibitors after the occurrence of the first cutaneous squamous cell carcinoma. In addition, it may be appropriate to consider sirolimus as the first choice in immunosuppressive therapy in areas where skin cancer rates are particularly high.
Aims:
To determine whether sirolimus-based immunosuppressive regimen reduces the occurrence of secondary skin cancers in a five year extension of the TUMORAPA randomised controlled trial*.
Interventions:
Participants were randomised to either continue with calcineurin inhibitor–based therapy or convert to sirolimus.
Participants:
120 calcineurin inhibitor–treated adult kidney transplant recipients with stable kidney function who had developed at least one invasive post-transplant cutaneous squamous cell carcinoma.
Outcomes:
The primary outcome measured was survival, free of new cutaneous squamous cell carcinomas at 5 years. Secondary measured outcomes included the time of onset of new cutaneous squamous cell carcinomas, occurrence of other skin and nonskin malignancies, graft function, patient and graft survival, and the effect of the minimisation strategies on recurrence.
Follow Up:
5 years
Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.
Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This is a well-conducted study of an adherence intervention in young (11 to 24 years) kidney transplant recipients. The study was adequately randomised and a good description of withdrawals and dropouts is given. Participants in the intervention arm had a significantly greater odds of taking prescribed medications and taking medications at or near the prescribed time. One of our key criticisms is the exclusion of participants who are unable to communicate comfortably in English (or French at the Montreal site), who may be at greater risk of non-adherence. There was also a large number of eligible patients (95/277) who refused consent because they were either not interested, were too busy or didn’t like the pillbox. This would seem to be the group at greatest risk of non-adherence and there is therefore a selection bias. The differences in electronically-monitored adherence may represent a more modified use or the pillbox in the intervention group, either taking medications without opening the box, or opening the box without taking medications every time. Lastly, patients who withdrew or stopped using the pillbox may represent patients who were less likely to adhere than those who continued. There was no significant difference in the standard deviation of tacrolimus trough levels, graft failures or acute rejection rates.
Expert Review
Reviewer:
Professor Nizam Mamode, Professor of Transplant Surgery, Guys and StThomas NHS Trust and Great Ormond Street Hospital, London, UK.
Conflicts of Interest:
None
Clinical Impact Rating
4
Review:
This is a very well-written manuscript describing a well-designed, randomized controlled trial of an intervention to promote adherence in teenagers and adults after kidney transplantation. The study tackles an important issue, as the main cause of graft loss (which is relatively high) in this age group is thought to be non-adherence, and this arises from a variety of factors, such as a desire for autonomy, belief structures concerning health and chaotic lifestyles. As the authors note, there are almost no trials in this area, and they are to be commended for conducting such a large study with an appropriate design. The trial intervention included the use of a 'coach' to conduct regular education sessions, feedback on non-adherence and development of strategies through an 'action-focussed problem solving' approach, which concentrated on developing solutions to barriers to adherence. This was collectively termed the TAKE-IT intervention, and continued for 12 months. Adherence was largely measured using an electronic pillbox. The trial included 169 participants at 8 transplant centres in North America, which is a large number for any pediatric transplant study. The study found that adherence, whether defined as taking the appropriate number of tablets (OR 1.66, 95% CI. 1.15-2.39) or taking medication within 2 hours of the recommended time (OR 1.74, 95% CI. 1.21-2.50), was significantly better in the intervention group. Interestingly, there was no difference in secondary endpoints such as tacrolimus levels, GFR, or other clinical outcomes. However, there are some issues with the study. Firstly, it is not quite clear how the primary outcome measure was calculated, as the absolute values from which the odds ratios were derived are not given. Secondly, there were some differences between the control and intervention groups (such as the proportion of living donors, and the length of time on dialysis) but it is unclear whether these are statistically significant. Finally, a significant proportion (over 15%) of each group did not use the electronic pillbox, which meant calculation of adherence was problematic. Nevertheless, the study has shown that an active, and relatively simple intervention can improve adherence in this age group. Further larger and longer studies are needed to determine whether such interventions lead to a sustained benefit, are worth the time and investment, and ultimately lead to an improvement in clinical outcomes. The authors are already embarking on this.
Aims:
To assess the efficacy of a clinic-based intervention in improving medication adherence among adolescent and young adult kidney transplant recipients.
Interventions:
Participants were randomised to receive either a clinic-based adherence promoting intervention which included standardised education with a coach and reminders via text message, e-mail or visual cues (intervention group), versus active listening and nonspecific support (control group).
Participants:
169 kidney only transplant recipients aged 11-24 years who were ≥ 3 months post-transplantation with a functioning graft.
Outcomes:
The primary measured outcomes were the proportion of prescribed doses taken (taking adherence) and proportion of prescribed doses taken within 1 hour before, to 2 hours after the prescribed dosing time (timing adherence). Secondary measured outcomes included the standard deviation of tacrolimus concentrations and self-reported adherence. Estimated glomerular filtration rate, adverse-event rates were also measured.
Follow Up:
15 months
BACKGROUND:
Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated.
STUDY DESIGN:
Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention.
SETTING & PARTICIPANTS:
Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included.
INTERVENTION:
Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data.
OUTCOMES:
The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure.
RESULTS:
81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls.
LIMITATIONS:
Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes.
CONCLUSIONS:
The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies.
TRIAL REGISTRATION:
Registered at ClinicalTrials.gov with study number NCT01356277.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This interesting multicentre study investigated the role of conversion from tacrolimus to cyclosporine-based immunosuppression in renal transplant recipients with post-transplant diabetes (PTDM). Patients were randomised to either switch to cyclosporine, or to continue tacrolimus, alongside MMF and/or steroids. Conversion to cyclosporine resulted in a significant reduction in the proportion of patients free from diabetes (34% vs. 10%), a reduction in the requirement for diabetic treatment and a reduction in HbA1C at 12 months. No difference in acute rejection or renal function between the groups was seen at 12 months. These results suggest that conversion to cyclosporine in patients with PTDM is safe and may reverse diabetes in a significant proportion of recipients. It should be noted that conversion to cyclosporine increased lipid levels, which may offset some of the cardiovascular benefit. Furthermore, trough tacrolimus levels in the control group were higher than contemporary practice in most units for stable patients (>8ng/ml), and it is unclear whether similar benefits could be achieved by reduction in tacrolimus exposure and/or withdrawal of corticosteroids.
Expert Review
Reviewer:
Professor Christophe Legendre, Hôpital Necker & Université Paris Descartes, France.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
This is a 12-months, multi-center, investigator-driven, prospective, randomized study, designed to assess whether conversion from tacrolimus to cyclosporine A can reverse PTDM after renal transplantation. Twelve months after conversion, patients had a significantly improved glucose tolerance in the cyclosporine group: more patients free of diabetes, more patients without glucose lowering medications, and lower HbA1c. Importantly this conversion was safe with regard to the risk of rejection.
Aims:
To assess whether conversion from Tacrolimus (TAC) to cyclosporine A (CYC) can reverse posttransplant diabetes (PTDM) after renal transplantation.
Interventions:
Participants were randomized to conversion to CYC or maintenance of TAC.
Participants:
87 recipients of a first or second renal graft ≥ 6 months before inclusion, treated with tacrolimus and persisting on minimal or no steroids in the three months prior to inclusion, aged ≥18 years with PTDM defined according to the 2005 criteria of the American Diabetes Association.
Outcomes:
The primary outcome measured was remission of diabetes one year after inclusion. Secondary measured outcomes included overall glycemic control, the dose of insulin and different oral glucose lowering agents, and the proportion of patients who stopped these treatments. Safety and clinical outcomes were also measured.
Follow Up:
12 months
Tacrolimus (TAC) increases the risk of posttransplant diabetes (PTDM) compared with cyclosporine A (CYC). The present 12-month, multicenter, investigator-driven, prospective, randomized study was designed to assess whether conversion from tacrolimus to CYC can reverse PTDM after renal transplantation. Predominantly white patients with PTDM according to the 2005 American Diabetes Association criteria were randomized to either replacement of TAC with CYC or continuation of their TAC-based regimen after stratification for type of glucose-lowering therapy, steroid therapy, and hepatitis C status. At 12 months, 14 of 41 patients with complete data in the CYC arm (34%; 95%CI 19%-49%) were free of diabetes, whereas this was the case in only 4 of 39 patients (10%; 95%CI 3%-20%) in the TAC arm (P = .01). At 12 months, 39% of patients in the CYC arm were off glucose-lowering medication vs 13% of patients in the TAC arm (P = .01). The CYC group decreased glycated hemoglobin level during the 12-month follow-up, resulting in significantly lower levels compared with the TAC group (6.0 ± 0.9% vs 7.1 ± 1.7% at 12 months; P = .002). In conclusion, replacement of TAC with CYC significantly improves glucose metabolism and has the potential to reverse diabetes during the first year after conversion. (EU Clinical Trials Register No. 2006-001765-42).
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This small but interesting RCT investigates the use of immune monitoring using NFAT-regulated gene expression (NFAT-RE) in stable kidney transplant recipients. All patients received cyclosporine and MMF with/without steroids, and control patients were monitored using standard trough cyclosporine levels. The authors demonstrate a significant improvement in pulse-wave velocity and GFR with NFAT-RE monitoring, with no obvious excess in adverse events or rejection. The small size of this study means that further evidence would be required to demonstrate safety in terms of rejection and graft survival. It appears, however, that NFAT-RE monitoring may allow minimisation of cyclosporine dose safely in these stable, low risk recipients. It is worth noting that trough cyclosporine levels in the standard monitoring arm increased over the 12-month study period, with a corresponding fall in GFR, which does raise the risk of treatment bias in a non-blinded study such as this.
Expert Review
Reviewer:
Professor Ron Shapiro, Kidney/Pancreas Transplantation, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mt. Sinai, USA.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
This is an extremely interesting trial of utilizing immunologic monitoring to manage immunosuppression in stable renal transplant recipients. Patients were randomized either to routine PK monitoring (i.e. peak and trough levels) or NFAT-regulated gene expression. Patients randomized to NFAT-regulated gene expression had reduced cardiovascular risk, as assessed by pulse wave velocity, fewer infections, and better renal function than the control group. This is a very important trial. Most immunosuppression is, at some level, an educated guess about what patients should be receiving, based on a composite of clinical and laboratory factors, but without any real immunologic monitoring data. This trial utilized immunologic monitoring to titrate immunosuppressive drug dosing. Even with a very small number of patients, the authors were able to demonstrate a benefit of immunologic monitoring. The study utilized an immunosuppressive agent, cyclosporine that is used in a very small minority of transplant recipients. This work should be repeated by other centers, with larger numbers of patients, utilizing tacrolimus-based immunosuppression. If the findings from this initial experience are replicated, this could lead to a sea change in how patients are managed after transplantation.
Aims:
To compare the monitoring of cyclosporine A (CsA) using nuclear factor of activiated T-cells -regulated gene expression (NFAT-RE), versus standard CsA trough level (C0) monitoring.
Interventions:
Participants were randomly assigned to either standard monitoring (CsA dose adjusted to target a C0 of 80–150 μg/L), or NFAT-RE (CsA adjusted to target a residual NFAT-RE of 15–30%).
Participants:
55 renal allograft recipients from a deceased or living donor ≥6 months prior to study entry, aged ≥18 years with stable renal allograft function, and receiving CsA microemulsion, mycophenolic acid with or without low-dose steroids.
Outcomes:
The primary outcome measured was the change in arterial stiffness, assessed by pulse wave velocity. Secondary outcomes included peripheral and central blood pressure, cardiac augmentation index, biopsy-proven acute rejection, graft loss or death, renal function, safety and tolerability.
Follow Up:
12 months
BACKGROUND:
A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE).
METHODS:
Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months.
RESULTS:
In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P < 0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009).
CONCLUSIONS:
NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.
Dr Ben Sprangers, University Hospitals Leuven, Leuven, Belgium.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
In this study, Alloway et al. address the question whether innovator tacrolimus is bioequivalent to generic tacrolimus, and whether generics of tacrolimus are bioequivalent to each other. This is an important issue as it has been argued in the past that for drugs with a narrow therapeutic index such as tacrolimus, clinicians should be cautious switching from innovator tacrolimus to generic tacrolimus. In this well-designed 8-week study, 35 kidney transplant recipients and 36 liver transplant recipients received treatment with innovator tacrolimus and two generic formulations of tacrolimus (tacrolimus Sandoz and tacrolimus Dr Reddy), and pharmacokinetic evaluation was performed. The authors demonstrated that the different tacrolimus formulations were bioequivalent according to the FDA average bioequivalence acceptance criteria, and within-subject variability was similar for AUC and Cmax for all products. In addition, the more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax. There are several limitations of this study: 1. Only a limited number of patients were included and the study was of short duration, 2. No evaluation of specific subgroups were performed (CYP3A5 genotype, ABCB1 genotype), 3. Selection of generic high and generic low tacrolimus formulations based abbreviated new drug applicants data from healthy individuals, 4. It is not an evaluation of all available generic tacrolimus formulations. In conclusion, this study demonstrates that innovator tacrolimus and generic tacrolimus formulations are bioequivalent and can be used interchangeably in clinical practice.
BACKGROUND:
Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, "brand") product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant.
METHODS AND FINDINGS:
From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (Cmax) (range 17.96-24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study.
CONCLUSIONS:
Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other.
Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:
This interesting single-centre RCT randomised 40 renal transplant recipients to belatacept or tacrolimus for one year after transplantation. Despite relatively robust baseline immunosuppression (basiliximab, 1g MMF bd and prednisolone) and low risk recipients (live donors, PRA <30%), a worryingly high risk of biopsy proven acute rejection was seen in the belatacept arm (55%) compared to the tacrolimus arm (10%). 3 grafts were lost in the belatacept arm due to acute rejection. Of interest, the authors also investigated a number of potential biomarkers that may predict the risk of rejection with belatacept. None of the investigated biomarkers demonstrated a relationship with post-transplant rejection. The study can only really be regarded as exploratory in nature, as the numbers are small and no power calculation was performed. Drug levels for tacrolimus and MPA are not reported. Nonetheless, the results are concerning and suggest that belatacept should probably only be used with depleting antibody induction. Also of concern is that of the 88 screened patients eligible for the study, 48 refused to take part due to concerns about rejection and the inconvenience of monthly infusions. This may further limit the utility of belatacept as a routine immunosuppressant.
Expert Review
Reviewer:
Emeritus Professor Ahmed Adel Hassan, Nephrology and Transplantation Department-Zagazig University, Egypt.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
This Single Centre RCT included forty live kidney transplant recipients who have been divided into two equal parallel groups, receiving Belatacept or tacrolimus for 1 year after transplantation. Despite the fact that all patients were immunologically low risk being pre-emptive with almost no ischemia time, negative current and historical cross-matches, and a strong immunosuppression protocol (consisting of basiliximab, 1gm MMF bd and prednisolone), the BPAR was significantly high (55%) in belatacept group compared to 10% in Tacrolimus group. The limitations of the study was the small number of patients, however the results are very worrying because of the high rejection rate. This can be used as a message to avoid such treatment as a basic immunosuppressive treatment or to combine it with a T-cell depleting drug. Also the need for a monthly infusion, which is inconvenient for many patients.
Aims:
To compare the acute rejection (AR) rate between belatacept and tacrolimus treated patients, and to investigate predictive immunological biomarkers for AR.
Interventions:
Participants were randomly assigned to receive either tacrolimus or belatacept.
Participants:
40 adult patients aged ≥18 years scheduled to receive a single-organ, blood group AB0-compatible kidney from a living donor at the Erasmus MC in the Netherlands.
Outcomes:
The primary outcome measured was the incidence of biopsy-proven AR within the first year after transplantation. Pretransplant circulating frequencies of CD8+CD28-, CD4+CD57+PD1- and end-stage terminally differentiated memory CD8+CD28++ T cells, as well as their intracellular expression of a Granzyme B were also measured.
Follow Up:
1 year
BACKGROUND:
Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated.
METHODS:
Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes.
RESULTS:
The rejection incidence was higher in belatacept-treated than tacrolimus-treated patients: 55% versus 10% (P = 0.006). All 3 graft losses, due to rejection, occurred in the belatacept group. Although 4 of 5 belatacept-treated patients with greater than 35 cells CD8CD28 end-stage terminally differentiated memory T cells/μL rejected, median pretransplant values of the biomarkers did not differ between belatacept-treated rejectors and nonrejectors. In univariable Cox regressions, the studied cell subsets were not associated with rejection-risk. CD86 molecules on circulating monocytes in belatacept-treated patients were saturated at all timepoints.
CONCLUSIONS:
Belatacept-based immunosuppressive therapy resulted in higher and more severe acute rejection compared with tacrolimus-based therapy. This trial did not identify cellular biomarkers predictive of rejection. In addition, the CD28-CD80/86 costimulatory pathway appeared to be sufficiently blocked by belatacept and did not predict rejection.
Dr Wilson Wong, King's College London, United Kingdom.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
Modarresi and colleagues describe their study in which N-acetylcysteine was given to kidney transplant recipients post-operatively. They found a significant difference in glutathione peroxidase activity but not the other parameters relating to oxidation status. Most importantly, there was an impressive improvement in eGFR at 7 and 14 days after transplantation. While the biochemical data on the oxidative stress is not entirely clear, this improvement of eGFR would be of interest to the kidney transplant community as N-acetylcysteine is already a licensed drug and is relatively inexpensive. There are a number of aspects concerning this study that can be improved. There is no mention about delayed graft function or primary non-function. I would be interested to know whether there is a difference between the 2 groups. The number of patients in the study is not small, but if this technique is to be used widely, it should be repeated on a larger population and preferably in a multi-centre trial.
N-acetylcysteine (NAC) is a potent antioxidant that acts through regenerating glutathione stores and scavenging oxygen-free radicals. This study assesses the short-term effects of NAC in cadaveric kidney transplant (KT) recipients. A double blind, randomized, placebo controlled trial was designed and patients were randomly assigned to receive either NAC or placebo. Glutathione peroxidase (GPX) activity in erythrocytes and serum malondialdehyde (MDA) levels were measured and serum creatinine levels and estimated glomerular filtration rate (eGFR) determined in the early phase after transplantation, were also compared between two study groups. Thirty-seven males and 20 females, with mean ± SD age of 44.6 ± 12.4 years completed the study. Significant difference (P = 0.02) was seen between GPX activity reduction in the placebo group, and that of the NAC group and on the levels of MDA there was no significant difference between two study groups (P = 0.53). Significant improvement in immediate graft function (IGF), (68% versus 40%, P = 0.05) and the first week eGFR were observed in the NAC group compared to the placebo group (52.46 ± 2.77 versus 38.75 ± 19.67 mL/min/1.73 m2, P = 0.02). It seems that the protective mechanisms of NAC, other than its antioxidant properties, can be favorable in KT patients.
This manuscript reports the 36-month extension from a phase 2 study randomising stable kidney transplant recipients (6-36 months post-transplant) to either continue CNI or switch to Belatacept. The renal function benefit seen at earlier time-points appears to be maintained, with an acceptable safety profile in both arms. Hazard for acute rejection is increased with Belatacept (HR 2.50), but this does not reach significance due to the small size of the study. In all, these data suggest that a switch to belatacept is safe and may result in small improvements in renal function compared to CNI-based therapy. The results are made difficult to interpret as patients/investigators were given the option to switch to belatacept at month 24. 16 patients (around 18%) in the CNI arm chose to switch, which may lead to an underestimation of any efficacy benefit or additional risk posed by the use of belatacept.
Expert Review
Reviewer:
Dr Claudio Ponticelli, Humanitas Clinical and Research Center, Rozzano, Milano, Italy.
Conflicts of Interest:
No
Clinical Impact Rating
5
Review:
In this multicenter controlled trial, 173 CNI-treated adult kidney transplant recipients with stable graft function were randomly assigned to continue therapy with CNI (89 patients) or to be converted to belatacept (84 patients) at 6-36 months after transplantation. Belatacept-treated patients showed a significantly greater increase in GFR compared to CNI (+1.9 vs 0.07 ml/min). No difference between the two arms was seen in death, graft loss, acute rejection, serious adverse events, serious infection or malignancy. However, viral infection occurred more frequently in belatacept-treated patients. This study confirms that switching patients with stable renal graft function from CNI to belatacept is safe. The fact that the mean GFR at 36 months is better in belatacept-treated patients may represent an important result. However, it is also comforting to note that no attrition of renal function was seen in patients who continued CNI up to 3 years. Of note, the concern that belatacept might increase the risk of posttransplant lymphoproliferative disorder (PTLD) seems to be limited to EBV negative patients. Indeed, no case of PTLD was observed in this trial. In conclusion, the results of this study reinforce the idea that different but equally effective treatments are now available for kidney transplant recipients and that switching from a treatment to another one seems to be feasible and relatively safe, at least in patients with stable renal graft function.
Aims:
To summarise outcomes, specifically the safety and tolerability of belatacept at 36 months post randomization of kidney transplant recipients with low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept.
Interventions:
Participants were randomized to either switch to a belatacept-based immunosuppression (5 mg/kg of belatacept intravenous on days 1, 15, 29, 43, and 57 and every 28 days thereafter) or continue with CNI-based therapy.
Participants:
173 adult stable kidney transplant recipients who were receiving CNI based maintenance immunosuppression.
Outcomes:
The primary outcome measured was safety, specifically adverse events (AEs) and serious AEs. Secondary outcomes measured were estimated glomerular filtration rate, acute rejection, transplant loss, and death.
Follow Up:
36 months
BACKGROUND:
In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.
STUDY DESIGN:
36-month follow-up of the intention-to-treat population.
SETTING & PARTICIPANTS:
CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2).
INTERVENTIONS:
At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).
OUTCOMES:
Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.
MEASUREMENTS:
Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.
RESULTS:
Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9).
LIMITATIONS:
Exploratory post hoc analysis with a small sample size.
CONCLUSIONS:
Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.
This is an interesting study of long-term (7 year) follow up assessing risk of skin and other cancers with two different immune suppression regimens in kidney transplantation. The original study was the A2309 study. Patients were randomized to everolimus plus reduced exposure cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine. The ANZDATA database was used to get these long-term outcomes. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with significantly reduced, unadjusted hazard ratios of 0.28, 0.39 and 0.41, respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Hazard ratios adjusted for non-cancer related deaths and other risk factors were also very favourable towards everolimus (0.34, 0.35 and 0.32 respectively). However, compliance with therapy was inferior for those randomized to everolimus, and more than 50% of participants discontinued everolimus by 2 years after transplantation. The small sample size is a concern, as is the use of a database in which under-reporting or misclassification may have occurred.
Expert Review
Reviewer:
Professor Hans J. Schlitt, Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany.
Conflicts of Interest:
No
Clinical Impact Rating
4
Review:
The paper by Lim, W.H. et al presents 7-year follow-up data obtained from a nation-wide registry for Australia and New Zealand on kidney-transplant patients that had been part of a 2-year prospective randomized trial (Novartis, A2309), comparing “standard” cyclosporine/ mycophenolate-based immunosuppression with reduced cyclosporine + everolimus. The impressive difference in de-novo cancers, particularly in non-melanoma skin cancers, is remarkable since: a) the number of patients in this (sub-)study was only 95; b) cyclosporine had not been withdrawn, but only reduced in the everolimus arms; and c) only slightly more than half of the patients in the everolimus arms were actually on assigned treatment. Performing an on-treatment analysis, the hazard ratio for developing de-novo tumors was less than 0.4 for everolimus patients and less than 0.2 for those on high-dose everolimus. This study, gives strong evidence that reducing cyclosporine and adding everolimus in kidney transplant patients leads to an impressive reduction in de-novo cancers (and to improved renal function) in the absence of negative effects on immunologic safety and graft and patient survival. Thus, physicians as well as patients should be aware of these potential benefits of everolimus when they consider stopping the drug because of its specific side effects: in clinical practice, this occurs rather frequently, especially if the treating physician is less experienced with this drug.
Aims:
To compare the risk of cancer incidence among kidney transplant recipients receiving everolimus plus reduced exposure cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine.
Interventions:
Participants were randomised to receive everolimus (1.5mg or 3mg) with reduced cyclosporine, versus mycophenolate sodium and standard exposure cyclosporine. Using data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) and adjusted Cox proportional hazard models, the seven year risk of cancer incidence and other graft outcomes were assessed.
Participants:
95 living and deceased donor kidney transplant recipients who participated in the A2309 study*.
Outcomes:
The primary outcome measured was the first non-melanoma skin cancer or any non-skin cancers diagnosed after transplantation. Other measured outcomes included delayed graft function, acute rejection, overall graft loss, death, estimated glomerular filtration rate, discontinuation rate, adverse events and a composite endpoint of graft loss and death.
Follow Up:
7 years
Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.
CET Conclusion