Transplant Trial Watch

Transplant Trial Watch

Keeping the transplantation community informed with a monthly overview of 10 new Randomised Controlled Trials

The Transplant Trial Watch (TTW) lists 10 recently published randomized controlled trials (RCTs) in organ transplantation. The TTW includes a brief description of each RCT, an assessment of the reporting of some methodological quality features and the main conclusions of the report written by the Peter Morris Centre for Evidence in Transplantation (CET). RCTs are selected by the CET on the basis of quality or interest. Electronic publications ahead of print are listed as [record in progress]. For more information on the assessment of the methodological quality, click here.

For all published RCTs in organ transplantation go to the Transplant Library upon logging onto the ESOT member area.

To view the previous issues of the Transplant Trial Watch go to the CET website or download the free Transplant Trial Watch app.

Transplant Trial Watch January 2019 – Kidney Transplantation

Demey B, Tinez C, et al. Risk factors for BK virus viremia and nephropathy after kidney transplantation: A systematic review. J Clin Virol. 2018; 109:6-12.
Aim:
To carry out a systematic review of risk factors for BKPyV viremia and nephropathy in kidney transplant patients on the basis of multivariate analyses.
Interventions:
The PubMed database was searched for prospective or prospectively-based observational studies on risk factors for BKPyV viremia and/or nephropathy. A risk factor for BKPyV infection was defined as a preoperative, pre- or post-transplantation patient-related factor that is thought to increase the risk of onset of BKPyV viremia and/or nephropathy. The qualitative assessment of risk factors was based on the ORs and HRs calculated in multivariate regression analyses.
Participants:
34 prospective cohort studies and studies based on prospectively recorded databases were reviewed. 13135 patients were evaluated, and 1923 of these (14.6%) presented BKPyV viremia. Six studies featured a multivariate analysis of risk factors for BKPyVN neuropathy; a total of 2821 patients had been evaluated, and 149 of these presented BKPyVN neuropathy (5.3%).
Outcomes:
144 distinct factors had been analyzed statistically for BKPyV viremia and 19 distinct factors for BKPyV nephropathy.
Follow Up:
PubMed database was searched on September 30th, 2017; there was no restriction on publication date.
CETs Conclusions:
The systematic review aimed to identify preoperative, pre-transplantation and post-transplantation risk factors for BK polyomavirus viremia and nephropathy in kidney transplant recipients. PubMed was searched, limited to the English literature. Study eligibility was determined by two reviewers. The methodological quality of articles was not assessed and there was no description of how the data extraction was done. Risk factors for BK polyomavirus viremia were defined as those tested in at least two multivariate analyses and found statistically significant in at least one multivariate analysis. Risk factors for BK polyomavirus nephropathy were those found significant in one multivariate analysis. Thirty-four prospective cohort studies and studies based on prospectively recorded databases were included, analysing a total of 144 risk factors for BK polyomavirus viremia and 19 risk factors for BK polyomavirus nephropathy. The authors highlighted eight risk factors considered to be most relevant for BK polyomavirus viremia and two risk factors for BK polyomavirus nephropathy.
Reporting Quality:
Quality Notes 
Systematic review ‒ QA assessment not appropriate.
Trial Registration:
Not reported
Funding Source:
No funding
Menezes FG, Corrêa L, et al. A Randomized Clinical Trial Comparing Nitrofurazone-coated and Uncoated Urinary Catheters in Kidney Transplant Recipients: Results from a Pilot Study. Transpl Infect Dis. 2018; [record in progress].
Aim:
To compare the efficacy of Nitrofurazone-coated silicone urinary catheters with non-impregnated silicone urinary catheters in reducing bacteriuria and urinary tract infections in kidney transplant recipients (KTR).
Interventions:
Patients were randomized (1:1) to a Nitrofurazone-coated silicone urinary catheter or a non-impregnated silicone urinary catheter.
Participants:
214 living donor KTRs were randomized and 176 completed the study.
Outcomes:
The primary outcome was the incidence of asymptomatic bacteriuria and symptomatic urinary tract infection during the first 30 days after renal transplantation. Each patient was included only once as a case of urinary tract infection or asymptomatic bacteriuria. Urinalysis and urine cultures were scheduled for the transplant day (baseline), 7, 14 and 30 days after transplantation. Patients were questioned daily about discomfort with the device. After discharge, the evaluation schedule was: weekly for the first month, biweekly for the second month, and monthly at 3 months post-surgery.
Follow Up:
>30 days post transplantation
CETs Conclusions:
This pilot, single-centre, open-label, randomised controlled trial (RCT) tested whether Nitrofurazone-coated silicone urinary catheters reduced asymptomatic bacteriuria and urinary tract infections in adult living donor kidney transplant recipients. A computer-generated sequence randomised patients to Nitrofurazone-coated silicone urinary catheters or non-impregnated silicone urinary catheters. There was no description of allocation concealment. A sample size calculation showed that 836 patients were needed to achieve 80% power for an absolute reduction of 7.7% in asymptomatic bacteriuria. Because of costs and the uncertainty of clinical benefits, it was decided to conduct a small pilot study to obtain preliminary results. 214 patients were randomised of whom 176 completed the study. There were no differences between groups in the reduction of bacteriuria and urinary tract infections. Patients reported higher levels of discomfort with the use of Nitrofurazone-coated catheter (46.6% versus 38.9%). The results of this preliminary analysis do not justify the design of a larger RCT comparing the efficacy of the two catheters.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
No
Trial Registration:
ISRCTN - 57888785
Funding Source:
Non-Industry funded
Reischig T, Kacer M, et al. Less renal allograft fibrosis with valganciclovir prophylaxis for cytomegalovirus compared to high-dose valacyclovir: a parallel group, open-label, randomized controlled trial. BMC Infect Dis. 2018; 18(1):573.
Aim:
To compare the efficacy of valganciclovir and valacyclovir prophylaxis for CMV after renal transplantation, with the focus on chronic histologic damage within the graft.
Interventions:
Patients were randomized (1:1) to valganciclovir or valacyclovir prophylaxis for 3 months in the 2VAL Study.
Participants:
119 patients were enrolled (valganciclovir, n=60; valacyclovir, n=59). Protocol biopsy at 3 years with sufficient material was available from 101 patients (valganciclovir, n=51; valacyclovir, n=50).
Outcomes:
The primary endpoint was moderate-to-severe interstitial fibrosis and tubular atrophy assessed by protocol biopsy at 3 years evaluated by a single pathologist blinded to the study group. Data analysis was in an ITT population. Secondary endpoints included intrarenal mRNA expression of profibrotic genes, chronic rejection, CMV DNAemia, CMV disease, biopsy-proven acute rejection, renal function, patient and graft survival (not censored for death), and other infections. Patient and graft survival was assessed at 4 years, with other variables at 3 years.
Follow Up:
≥4 years after transplantation or until death.
CETs Conclusions:
In univariate analysis, this study showed that valganciclovir and valaciclovir for CMV prophylaxis in renal transplantation were associated with similar rates of IFTA on 3-year protocol biopsy. Despite randomisation, there was an imbalance in “high risk” donor distribution between the study arms. The authors subsequently carried out a multivariate analysis to reflect the higher proportion of “high risk” donors in the valganciclovir arm, and then did show a significant reduction in moderate-severe IFTA (OR=0.31, P=0.03). There was no significant difference in CMV disease or viraemia between the two groups, which was uniformly low. The study was not blinded, and the rate of IFTA in the control arm was possibly overestimated for the power calculation, explaining why the expected number of withdrawals could not be tolerated without risking an inconclusive result in the univariate analysis.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified intention to treat
Quality Notes 
Previously assessed as Reischig, T et al. Clinical Journal of The American Society of Nephrology; 10: 294-304, 2015.
Trial Registration:
Australian New Zealand Clinical Trials Registry - ACTRN12610000016033
Funding Source:
Non-Industry funded
Tonshoff B, Ettenger R, et al. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial. Am J Transplant. 2018; [record in progress].
Aim:
A 12-month study to evaluate the efficacy of early conversion to everolimus with reduced tacrolimus and steroid elimination in pediatric kidney transplant patients.
Interventions:
Patients randomized at 4 to 6 weeks posttransplant to continue a regimen of standard‐dose tacrolimus therapy with mycophenolate mofetil (sTAC/MMF) and steroids or switch to everolimus with reduced dose tacrolimus (EVR/rTAC) and steroid elimination, with steroid tapering planned to start at Month 5 post transplant.
Participants:
106 patients were randomized and formed the ITT and safety populations (EVR/rTAC, n = 52; sTAC/MMF, n = 54). In total, 103 of 106 patients (97.2%) completed the 12‐month study.
Outcomes:
Co‐primary efficacy end points were composite efficacy failure end point (BPAR, graft loss, or death) from randomization to Month 12 and renal function as assessed by eGFR at Month 12. Secondary efficacy end points included the incidence, timing and severity of BPAR; the incidence of steroid‐resistant BPAR and antibody‐mediated BPAR, graft loss, and death.
Follow Up:
12 months
CETs Conclusions:
This multicentre, open-label study investigated a switch to everolimus, low dose tacrolimus and steroid withdrawal in paediatric renal transplant recipients at 4-6 weeks post-op. At 12-month follow-up, outcomes were equivalent to a control group continuing a standard-dose tacrolimus, MMF and steroid regimen. The only significant difference was the rate of adverse events, with 35% those randomized to everolimus discontinuing this by Month 12. These results suggest that this regimen offers a safe and viable alternative to standard immunosuppression in a low-risk paediatric population. It should be noted that recipients with a PRA >20%, and those receiving a kidney from a donor over 60 years of age were excluded, so higher-risk transplants may not demonstrate the same outcomes. It is possible with longer-term follow-up that steroid avoidance may improve development and growth, although no difference was seen during the short follow-up period in the present study.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01544491
Funding Source:
Industry funded
Weiner DE, Park M, et al. Albuminuria and Allograft Failure, Cardiovascular Disease Events, and All-Cause Death in Stable Kidney Transplant Recipients: A Cohort Analysis of the FAVORIT Trial. Am J Kidney Dis. 2018; [record in progress].
Aim:
To determine the relationship of albuminuria with cardiovascular and kidney outcomes in kidney transplant recipients.
Interventions:
Participants in the FAVORIT Trial were randomly assigned to receive either a standard multivitamin with high doses of folic acid, vitamin B6, and vitamin B12 or a multivitamin containing low doses of vitamin B6 and vitamin B12 without folic acid. The two study treatment groups were combined for this post hoc cohort analysis.
Participants:
3511 stable kidney transplant recipients with elevated homocysteine levels were included. 599 participants were excluded due to missing outcome data.
Outcomes:
The primary outcomes were time to allograft failure and time to a cardiovascular disease (CVD) event. Secondary outcomes included all-cause mortality and a composite of allograft failure and all-cause mortality.
Follow Up:
Up to 5.5 years.
CETs Conclusions:
This is an interesting post-hoc analysis of the FAVORIT study that combines both study arms to analyse the relationship between albuminuria (urine albumin:creatinine ratio, ACR) and cardiovascular disease and overall graft survival. The ACR was taken at the time of enrolment in the study. A multivariate analysis was undertaken, incorporating multiple relevant factors from a large population of patients (N=3,511). Albumin:creatinine ratio (ACR) 30-299mg/g and ≥300mg/g were associated with a significantly increased hazard ratio for graft failure (HR=3.3 and HR=9.9) compared to ACR<10mg/g. Higher ACR was also significantly associated with cardiovascular events and all-cause mortality. The association between ACR and outcomes in kidney transplant recipients is similar to that in the general population.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Quality Notes 
Previously assessed as Bostom AG, Carpenter MA, Kusek JW, et al. Circulation;123:1763-70, 2011.
Trial Registration:
ClinicalTrials.gov - NCT00064753
Funding Source:
Non-Industry funded

Transplant Trial Watch January 2019 – Lung Transplantation

Dhar R, Stahlschmidt E, et al. A Randomized Controlled Trial of Naloxone for Optimization of Hypoxemia in Lung Donors after Brain Death. Transplantation. 2018; [record in progress].
Aim:
To evaluate whether naloxone is able to improve oxygenation in brain dead (BD) lung donors with hypoxemia.
Interventions:
Eligible donors were randomized to naloxone (8 mg IV) or saline placebo as soon as possible after the initial arterial blood gas (ABG). ABGs were collected as per standard Organ Procurement Organizations practices (approx. every 6-8 hours) with a final ABG collected prior to organ procurement.
Participants:
199 lung-eligible BD donors were randomized (naloxone, n=98; placebo, n=101). Eligible patients were age 13-70 years without established lung disease who had hypoxemia, defined as PaO2:FiO2 ratio (PFR) <300 on arterial blood gas (ABG) performed after BD declaration.
Outcomes:
The primary outcome was change in PFR from baseline to final ABG. The secondary efficacy outcome was proportion of donors enrolled who had lungs transplanted. Primary analyses were performed using intention-to-treat principles. Outcomes were also evaluated in a per protocol analysis.
Follow Up:
Median total time from BD to procurement was 41 hours (IQR 32-47).
CETs Conclusions:
This muticentre, placebo-controlled study investigated the use of IV naloxone in brain-dead organ donors as a strategy to reduce neurogenic pulmonary oedema. The study demonstrated no difference in the primary outcome of improvement in PaO2:FiO2 ratio, and no difference in transplant rates from the donors recruited. The study is well designed, and it appears that there is no benefit to this intervention in this subset of donors with all-cause hypoxemia. Interestingly, reversal of hypoxemia through other donor management protocols was significantly associated with increased chance of transplant, highlighting the importance of interventions to improve this in donors. It should also be noted that no transplant outcomes were assessed: it is important that in any donor intervention the transplant rates and outcomes of all transplanted organs from the donors are documented, as what is good for one organ may be detrimental to the outcomes of another.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT02581111
Funding Source:
No funding
Westall GP, Cristiano Y, et al. A Randomized Study of Quantiferon-CMV-Directed Versus Fixed Duration Valganciclovir Prophylaxis to Reduce Late CMV Following Lung Transplantation. Transplantation. 2018; [record in progress].
Aim:
To assess whether QuantiFERON-CMV (QFN-CMV) assay-directed antiviral prophylaxis is more effective than standard of care (SOC) prophylaxis at reducing the incidence of late CMV infection/reactivation within the lung allograft.
Interventions:
SOC was continuing CMV prophylaxis for 5 months following lung transplantation (LTx). At 5 months following LTx, patients were randomized (1:2) to either cessation of antiviral prophylaxis (SOC) or variable length QuantiFERON-CMV (QFN-CMV) assay-directed antiviral prophylaxis.
Participants:
Adult lung transplant recipients at risk of CMV infection (n = 118; QFN-CMV-directed prophylaxis n = 83, SOC, n = 36).
Outcomes:
The primary outcome measure was the difference in the incidence of CMV infection (>600 copies/ml) in the lung allograft within 18 months of transplant in patients at-risk of CMV reactivation. CMV infection was defined as detection of nucleic acid in the bronchoalveolar lavage. Secondary outcomes included CMV viremia in the blood, acute cellular rejection, chronic allograft dysfunction and death within 18 months of therapy.
Follow Up:
Up to 18 months post transplantation
CETs Conclusions:
This single-centre study investigates the role of targeted CMV prophylaxis using the Quantiferon (QFN) CMV assay to predict those at risk following lung transplantation. Patients were randomized to standard 5-month valganciclovir prophylaxis, or variable-duration prophylaxis determined by response to the QFN assay. The study found that incidence of CMV infection (on BAL) was significantly reduced with QFN-directed prophylaxis, with no difference in CMV viraemia or other endpoints. This is an interesting study and the results suggest that adaptation of the duration of prophylaxis by monitoring CMV immunity is a reasonable strategy. Future studies should determine whether this approach is cost-effective, and whether these findings translate to other transplant types.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Per Protocol
Allocation Concealment 
Yes
Trial Registration:
Australian Clinical Research Network - ACTRN - 12612000551897.
Funding Source:
Non-Industry funded

Transplant Trial Watch January 2019 – Heart Transplantation

Arora S, Andreassen AK, et al. Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients. Circ Heart Fail. 2018; 11(9):e004050
Aim:
To evaluated whether initiation of everolimus and early cyclosporine elimination can reduce cardiac allograft vasculopathy (CAV) development in heart transplantation recipients.
Interventions:
Patients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Intravascular ultrasound recordings were obtained at baseline, 12 and 36 months.
Participants:
115 de novo heart transplantation recipients were randomized. Seventy-six patients had matched intravascular ultrasound examinations at baseline, 12 and 36 months.
Outcomes:
Effect of everolimus initiation and CNI elimination on CAV at 12 and 36 months assessed by assessing percent atheroma volume (PAV) and total atheroma volume (TAV) (as alternative end points to maximal intimal thickness) as well as angiographic data. Inflammatory markers were measured in parallel. Plaque morphology was qualitatively assessed by virtual histology analysis at 12 and 36 months post randomization.
Follow Up:
36 months.
CETs Conclusions:
This was an open-label, multicentre RCT in cardiac transplantation. Unfortunately, only 66% of those randomised went on to have matched intravascular ultrasound at both 12 and 36 months, the most common reason for dropout was logistical/technical issues. Patients in the everolimus arm had a greater risk of progression in cardiac allograft vasculopathy (CAV, as defined on intravascular ultrasound), and in multivariate analysis everolimus was an independent predictor of CAV progression, along with recipient sex and donor age. Worryingly there was a significantly higher risk of rejection graded ≥2R in the everolimus group (41% versus 13%), but there were no cases of humoral rejection or rejection with haemodynamic compromise and there were slightly more deaths in the ciclosporin arm (7 versus 3). Angiographic assessment of CAV progression did not show a significant difference between the two study arms, possibly due to the short follow-up period.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Available case analysis
Allocation Concealment 
Yes
Quality Notes 
Previously assessed as Andreassen AK, Andersson B, et al. Am J Transplant; 14:1828-38, 2014.
Trial Registration:
ClinicalTrials.gov - NCT01266148
Funding Source:
Industry funded

Transplant Trial Watch January 2019 – Liver Transplantation

Troisi RI, Vanlander A et al. Somatostatin as Inflow Modulator in Liver-transplant Recipients With Severe Portal Hypertension: A Randomized Trial. Ann Surg. 2018; [record in progress].
Aim:
To investigate the safety and efficacy of somatostatin (SST) as liver inflow modulator in patients with end-stage liver disease (ESLD) and clinically significant portal hypertension (CSPH) undergoing liver transplantation (LT).
Interventions:
Patients were randomized (2:1) to receive SST or placebo. Hepatic and systemic hemodynamics were measured, along with liver function tests and clinical outcomes. Ischemia-reperfusion injury (IRI) was analyzed through histological and protein expression analysis. Blood samples were taken daily for the first 7 postoperative days (PODs) and at POD 14. Further samples were obtained as required according to the patient’s clinical condition.
Participants:
33 adult liver transplant recipients with ESLD and CSPH.
Outcomes:
The primary endpoint was the hemodynamic response (defined as a 20% reduction of hepatic venous portal gradient (HVPG) in response to the SST bolus). Secondary endpoints included hemodynamic response, liver function tests and clinical outcomes in the short and long-term period.
Follow Up:
Median follow-up of 55.9 months (IQR 50.4–78).
CETs Conclusions:
This small placebo-controlled study investigated the role of somatostatin in reducing the portal venous pressure during liver transplantation in patients with portal hypertension. Use of somatostatin resulted in a significant reduction in the hepatic venous portal gradient compared to placebo. No difference was seen in the severity of the ischaemia-reperfusion injury or in clinical outcomes. This study is interesting, but ultimately underpowered to detect any differences in meaningful clinical outcomes. It does, however, provide strong justification for a larger study of the use of somatostatin in this group, and also possibly in patients with portal hypertension undergoing liver resection. How it compares to standard surgical management of portal hypertension (e.g. shunting or splenic vein ligation) is also unclear and would need further study.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Modified intention to treat
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01290172
Funding Source:
Industry funded, Non-Industry funded

Transplant Trial Watch January 2019 – Various Organ Transplantation

Knight SR, Thorne A, Faro MLL. Donor-specific Cell-Free DNA as a Biomarker in Solid Organ Transplantation. A Systematic Review. Transplantation. 2018; [record in progress].
Aim:
To examine the techniques and evidence for the relationship between donor-derived cell-free DNA (dd-cfDNA) levels and clinical outcomes in solid organ transplant recipients.
Interventions:
A systematic literature search was performed in OVID MEDLINE, EMBASE, the Transplant Library and the Cochrane Library. Reference lists of included studies and relevant reviews were screened. Unpublished and ongoing studies were also identified. Titles, abstracts and full text were assessed by two reviewers to confirm inclusion; differences were resolved by review and discussion. Risk of bias was assessed. All studies that reported dd-cfDNA levels in the urine or plasma of adult or pediatric solid organ transplant recipients and related these levels to 1 or more transplant-related outcomes were eligible for inclusion. No restrictions were placed on study design, publication language or date.
Participants:
95 manuscripts/abstracts from 47 studies met the inclusion criteria; 24 studies were reported in abstract form only. One study was a report of a single case, the rest were retrospective (n=17) and prospective (n=29) cohort studies. Transplant types were kidney (n=18), liver (n=7), heart (n=11), kidney-pancreas (n=1), lung (n=5) and multiple types (n=5). Searches identified 6 ongoing studies.
Outcomes:
Study-level data was extracted. Data relating dd-cfDNA to clinical outcomes were identified as acute rejection, other transplant related outcomes and response to treatment. Studies that compared the diagnostic accuracy of dd-cfDNA to other markers were also identified. The findings are reported as a narrative review as meta-analysis was not possible due to study heterogeneity and poor quality.
Follow Up:
To search date (June 12th 2018).
CETs Conclusions:
The systematic review aims to study techniques and evidence for the relationship between donor-derived cell-free DNA levels (dd-cfDNA) and clinical outcomes in adult and paediatric solid organ transplant recipients. The review was prospectively registered with PROSPERO. A comprehensive bibliographic search was conducted and in addition trial registries were searched to identify unpublished or ongoing studies. Study eligibility, data extraction and assessment of the risk of bias (QUADAS-2 tool) was performed by two independent reviewers. Forty-seven studies were included of which 24 were congress abstracts. Because of the heterogeneity among studies and low study quality, findings were reported in a narrative review. The authors concluded that there is evidence for the validity of using dd-cfDNA as a biomarker in solid organ transplantation. Studies show a strong relationship between dd-cfDNA and acute rejection and other causes of acute allograft injury.
Reporting Quality:
Quality Notes 
Systematic review ‒ QA assessment not appropriate
Trial Registration:
PROSPERO - CRD42017082273.
Funding Source:
No funding