Transplant Trial Watch

Transplant Trial Watch

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

The Transplant Trial Watch (TTW) lists 10 recently published randomized controlled trials (RCTs) and Systematic Reviews in organ transplantation. The TTW includes a brief description of each study, 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). Studies 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.

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 February 2020 – Kidney Transplantation

Gomez-Ochoa, S. A. and A. Vega-Vera (2019). Systematic Review and Meta-Analysis of Asymptomatic Bacteriuria After Renal Transplantation: Incidence, Risk of Complications and Treatment Outcomes." Transplant Infectious Disease [record in progress].
Aim:
This study aimed to evaluate the benefit of treating asymptomatic bacteriuria (ASB) after kidney transplantation.
Interventions:
The Embase, EBSCOHost, PubMed, the Cochrane Central Register of Controlled Trials, SciELO, and LILACS were searched for randomized controlled trials (RCTs), cohort studies, and case-control studies that evaluated the effects of treating asymptomatic bacteriuria after renal transplantation regarding the risk of symptomatic urinary tract infection (UTI) and graft function.
Participants:
15 studies were included; eight exploored the primary outcome, comprising 1184 patients and 1667 episodes of bacteriuria. Five studies were used to assess secondary outcomes, yielding a total of 1485 patients. Finally, twelve studies evaluated the ASB incidence after KT, involving a total of 3727 patients.
Outcomes:
The primary outcome assessed was if treatment was associated with a lower risk of symptomatic UTI or an improved renal function at the end of the follow-up period. The secondary outcome was the risk of acute graft rejection (AGR).
CETs Conclusions:
This is a well-conducted systematic review following PRISMA guidelines with a pre-registered protocol on the PROSPERO system. Multiple databases were searched and data extracted in duplicate for the 15 included studies. Studies were assessed for bias, with most unfortunately being at high risk due their retrospective nature. Funnel plot was used to assess for publication bias and a sensitivity analysis to assess the impact of each individual study on the overall conclusion. The pooled incidence of asymptomatic bacteriuria was 22% in the first month after transplantation (three studies) and 32% in the first year after transplantation (10 studies). In meta-analysis there was no relationship between asymptomatic bacteriuria and allograft rejection. There was also no significant relationship between the development of symptomatic UTI whether asymptomatic bacteriuria was treated or not. Nor did the treatment for asymptomatic or bacteriuria have any relationship to later graft function. This systematic review shows that asymptomatic bacteriuria is common after transplantation, however treatment after the first month from date of transplant does not reduce the rate of UTI or improve renal function.
Trial Registration:
PROSPERO - CRD42018116561
Funding Source:
Not reported
Kapoor, A., et al. (2019). A prospective, randomized, pilot trial of a polyethylene glycol (PEG)-coated collagen patch for intraoperative hemostasis during deceased donor renal transplant." Canadian Urological Association Journal [record in progress].
Aim:
The objective of this study was to evaluate the safety and feasibility of using a polyethylene glycol (PEG)-coated collagen patch (Hemopatch®) in patients undergoing deceased donor renal transplant.
Interventions:
Patients were randomized to receive the PEG-coated patch (n=15) or standard hemostasis (n=15).
Participants:
A total of 30 deceased renal transplant donors were enrolled over a 15 month period (17 men and 13 women; mean age = 62.5).
Outcomes:
The primary outcome was the amount of intraoperative estimated blood loss in those patients receiving the patch compared to without. Secondary outcomes were the subjective achievement of hemostasis, perigraft collection, and drop in hemoglobin 48 hours postoperatively.
Follow Up:
30 days
CETs Conclusions:
This is a small randomised study of a technical intervention for intra-operative bleeding. The study was very small and therefore I don’t think capable of demonstrating superiority. Patients were randomised prior to transplant surgery, regardless of their requirement for haemostatic adjuncts, and are therefore a dilute population that does not concentrate on those that best benefit from additional haemostatic therapies. Patients in the standard treatment group who required additional haemostatic therapies were also excluded and perhaps should have been included as examples of failure of normal treatment (pressure, ties and clips). The assessment of haemostasis by the operating surgeon is very subjective and not an objective or blinded outcome. The study showed no significant difference in intra-operative blood loss, drop in haemoglobin or requirement for transfusion. No firm conclusions can be drawn from this pilot study and a large trial comparing this product to other haemostatic agents is what is required to follow on from this.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT0263367
Funding Source:
Not reported
McGuire, C., et al. (2019). "Patient Survival Following Renal Transplantation in Indigenous Populations: A Systematic Review." Clinical Transplantation [record in progress].
Aim:
This study aimed to evaluate patient survival and other post-transplant outcomes of kidney transplantation among indigenous patients compared with non-indigenous populations.
Interventions:
The MEDLINE, EMBASE, and Google Scholar database were searched for articles comparing survival of indigenous vs non-indigenous patients following renal transplantation.
Participants:
Twelve retrospective studies examining inidiginous patients, published between 2004 and 2018 were included.
Outcomes:
Primary outcomes being assessed in this systematic review include: patient survival, graft survival, and delayed graft function.
Follow Up:
5 years
CETs Conclusions:
This is a well-conducted systematic review that highlights the differences in transplant outcomes between indigenous and non-indigenous populations. It included 12 studies and a good number of patients overall. Multiple databases were searched, following PRISMA guidelines and data extracted in duplicate. Included studies were assessed for quality and overall were of high quality. Meta-analysis was not possible due to non-standard outcomes however. Post-transplant outcomes including patient survival, rejection and graft loss were significantly worse amongst indigenous populations, and likely multifactorial. This paper provides a starting point for addressing these issues and does offer some discussion of ways forward. The outcomes presented here likely represent the inequality in delivery of healthcare to indigenous populations in several countries. However, the impact of modifiable risk factors, pre-existing comorbidities and time on the waiting list are also likely to be very important.
Trial Registration:
Not reported
Funding Source:
Not reported
Waterman, A. D., et al. (2019). Direct Delivery of Kidney Transplant Education to Black and Low-Income Patients Receiving Dialysis: A Randomized Controlled Trial." American Journal of Kidney Diseases 74(5): 640-649.
Aim:
This study aimed to evaluate whether an 8-month Explore Transplant @ Home education program, with or without telephonic support from an educator, could help improve transplantation knowledge, informed decision-making, pro-transplantation attitudes and steps toward kidney transplantation compared to traditional dialysis center kidney transplantation for low-income black and white patients.
Interventions:
Patients were randomly assigned to one of 3 inerventions: patient-guided intervention and standard care, educator-guided intervention and standard care or standard of care only.
Participants:
561 black and white dialysis patients from Missouri.
Outcomes:
The primary otucome being assessed was patients’ knowledge of living donor kidney transplantation (LDKT) and deceased donor kidney transplantation (DDKT). Secondary outcomes included informed decision making, LDKT and DDKT attitudes and new steps towards transplantation.
Follow Up:
8 months
CETs Conclusions:
The RCT evaluated the efficacy of three educational interventions in black and white, low-income dialysis patients to increase knowledge of living and deceased donor kidney transplantation. Patients (n=561) were randomly allocated to standard of care, Explore Transplant @Home patient-guided education or Explore Transplant @Home educator-guided education. The sample size calculation showed that 150 patients per arm were needed to achieve 80% power. The modified intention to treat analysis included all patients who completed the study and included 456 patients and the per-protocol analysis included 369 patients. Groups were comparable at baseline. There were significant increases in transplantation knowledge in the educator- and patient-guided intervention arms compared with standard of care. Higher proportions of patients in the educator- and patient-guided intervention arms were able to make informed decisions. Patients in all groups took new steps towards transplantation compared to baseline. Exploratory analyses were conducted to identify differences in the effects within subgroups of patients.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Modified Intention To Treat (mITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT02268682
Funding Source:
Industry funded

Transplant Trial Watch February 2020 – Lung Transplantation

Paez-Vega, A. et al. (2019). Efficacy and safety of the combination of reduced duration prophylaxis followed by immuno-guided prophylaxis to prevent cytomegalovirus disease in lung transplant recipients (CYTOCOR STUDY): an open-label, randomised, non-inferiority clinical trial." BMJ Open 9(8): e030648.
Aim:
This study aims to evaluate the efficacy of reduced prophylaxis (3 months) followed by immuno-guided prophylaxis to prevent cytomegalovirus (CMV) disease in right lung transplant recipients in comparison with the usual strategy of universal prophylaxis (6 months) followed by pre-emptive therapy for 6 months. A second aim of this study is to assess whether, in the patients of experimental group who develop CMV disease, an IFNG cut-off point could predict protection against CMV more reliably.
Interventions:
Patients will be randomized to either the control group (universal prophylaxis and pre-emptive therapy) or the experimental group (reduced prophylaxis and immuno-guided prophylaxis).
Participants:
Patients that will be recruited into this trial must be lung transplant recipients with positive pre-transplant CMV serology, over 18 years of age, with an expected time of prophylaxis with valganciclovir of 6 months post-transplant and written informed consent.
Outcomes:
Primary outcome being assessed is Incidence of CMV disease at 18 months post-transplant and secondary outcome is incidence of CMV replication (excluding replication blips in periods of prophylaxis).
Follow Up:
12 months
CETs Conclusions:
This manuscript describes the protocol for the CYTOCOR study, which investigates the use of Quantiferon-CMV immune monitoring to reduce the duration of CMV prophylaxis required in lung transplant recipients. The study is relevant and interesting, and the protocol is well described. Inclusion and exclusion criteria and outcome definitions are well-described. The study may have relevance to other solid organ transplant types if successful. The sample size estimate is based upon a success rate of 85% in standard practice, but no data or reference is provided to support this assumption. There is also perhaps a missed opportunity, in that the data required for a health economic analysis (resource use and quality of live) is not being collected.
Trial Registration:
ClinicalTrials.gov - NCT03699254
Funding Source:
Industry funded

Transplant Trial Watch February 2020 – Heart Transplantation

Aleksova, N., et al. (2019). Risk prediction models for survival after heart transplantation: A systematic review." American Journal of Transplantation [record in progress].
Aim:
This study aimed to review prediction model characteristics and performance for all available scores that predict survival after heart transplantation (HT).
Interventions:
Ovid Medline and Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Clinical Trials were searched from inception to December 2018. Eligible articles included adult patients in prospective or retrospective studies using single center or multicenter data, which reported a score or formula to predict mortality following HT.
Participants:
21 studies were included in the systematic review that derived and/or validated 16 scores.
Outcomes:
Outcomes being assessed included reporting study quality, model performance, external validation and performance.
Follow Up:
1 year
CETs Conclusions:
This systematic review identified studies reporting risk prediction models for the prediction of survival following cardiac transplantation. The authors identify 16 models and look at study and reporting quality, validation and performance. Overall, quality of the studies was relatively poor and performance of the models was suboptimal, particularly for longer-term survival. The review is comprehensive and the methodology is generally very good. Exclusion of conference abstracts and proceedings may risk publication bias, which could not be formally assessed.
Trial Registration:
Not reported
Funding Source:
No funding

Transplant Trial Watch February 2020 – Various Transplantation

Bashir, B., et al. (2018). Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers." Clinical and translational science 11(6): 590-596.
Aim:
This study aimed to examine the drug interactions between cyclosporine and tacrolimus (inhibitors of CYP3A4, P-gp, and BCRP) with apixaban.
Interventions:
Patients were randomized to sequence A or B. Patients randomized to sequence A received apixaban alone in period I. The subjects then received cyclosporine 100 mg once daily for 3 days followed by another dose of apixaban in period II. In period III, subjects received 5 mg tacrolimus once daily followed by 10 mg apixaban. Whereas those randomized to sequence B received tacrolimus 5 mg once daily for 3 days followed by apixaban in period I. In treatment period II, subjects received 10 mg apixaban alone. The subjects then received cyclosporine 100 mg once daily for 3 days followed by apixaban.
Participants:
12 healthy male volunteers were included in this study (non-smoking, aged 18–55 years with a body mass index of 19–33 kg/m2).
Outcomes:
Outcomes assessed includeed plasma concentration‐time profiles and pharmacokinetic parameters of apixaban (APX) with and without cyclosporine (CsA).
Follow Up:
3 days
CETs Conclusions:
The study tested whether cyclosporine and tacrolimus would alter apixaban exposure. The phase I, open-label, cross-over randomised controlled trial randomly allocated 12 healthy, male volunteers to one of two treatment sequences. The sample size was calculated showing that 12 participants would provide 98% power based on previously reported drug to drug interactions. Administration of of apixaban with cyclosporine or tacrolimus resulted in small changes in apixaban PK parameters that are not clinically meaningful. The authors conclude that they would expect a similar exposure profile in solid organ transplant recipients and that no dose adjustments are needed for transplant patients on cyclosporine or tacrolimus.
Reporting Quality:
Jadad Score 
1
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT03083782
Funding Source:
Industry funded
Bernad, I., et al. (2019). Daylight photodynamic therapy for prevention of new actinic keratosis and keratinocyte carcinomas in organ transplants. A cryotherapy-controlled randomized clinical trial." Journal of the European Academy of Dermatology & Venereology [record in progress].
Aim:
To determine whether repeated treatments of field cancerization with daylight photodynamic therapy (DPDT) are effective in preventing new actinic keratosis (AK) and keratinocyte carcinomas (KC) in organ transplant recipients (OTR).
Interventions:
Each patient’s side of the face and/or scalp was randomly allocated to receive field- therapy with DPDT (to treat AK and field cancerization) or lesion-specific treatment with cryotherapy (to treat only AK in isolation, but not field cancerization). The control side was treated with lesion-directed cryotherapy at baseline, at 3, and at 9 months.
Participants:
Twenty three 1-year post-organ transplant recipients, with at least 5 AK on each side of the face and/or scalp, were analysed at 3 months; and 21, at 9, 15 and 21 months.
Outcomes:
The primary outcome of this study was to determine if there was a difference in the total number of skin lesions (new and persistent AK, and KC) at 21 months after initial treatment. Secondary outcomes included evaluating difference at 3, 9 and 15 months. Time to KC was also measured.
Follow Up:
15 and 21 months
CETs Conclusions:
The RCT compared daylight photodynamic therapy versus cryotherapy to prevent the occurrence of new actinic keratosis (AK) and keratinocyte carcinomas (KC). Adult heart, liver and kidney transplant recipients who were at least 1 year posttransplant and had at least five AKs on each side of the face or scalp were included. The sides of the face or scalp were allocated according to a computer-generated sequence by central randomisation to six sessions of field therapy with DPDT or three sessions of lesion-specific cryotherapy. A blinded outcome assessor evaluated the skin at 3, 9, 15 and 21 months. The sample size calculation showed that 22 patients were needed to ensure a power of 80%. Twenty-four Caucasian patients were included in the study and 3 patients withdrew from the study. At baseline the number of AKs was similar between groups. There were no differences in new AKs and KC at 21 months and not differences in persistent AK at 3, 9 or 15 months. DPDT was better tolerated, patients were more satisfied with DPDT at 21 months and preferred DPDT over cryotherapy. Quality of life scores were improved from baseline to the 21 month follow up but there were no differences between groups. There were no serious adverse events.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intention To Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
EudraCT Number: 2015-002663-42
Funding Source:
Industry funded
L'Huillier, A. G., et al. (2019). Cell-Mediated Immune Responses after Influenza Vaccination of Solid Organ Transplant Recipients: a Secondary Outcomes Analysis of a Randomized Controlled Trial." Journal of Infectious Diseases [record in progress].
Aim:
This study aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine in solid organ transplant recipients.
Interventions:
This is a substudy of the CMI study. Patients were randomized 1:1 to receive either HD vaccine containing 60 µg of antigen per strain or SD vaccine containing 15 µg of antigen per strain.
Participants:
60 patients from the CMI substudy (30 high dose vaccine vs 30 standard dose vaccine).
Outcomes:
The main outcome being assessed was the proportion of influenza-specific polyfunctional T cells elicited by vaccine antigens. Seroconversion was defined as a ≥4-fold increase in antibody titers compared with prevaccination as well as reaching a seroprotective titer.
Follow Up:
6 months
CETs Conclusions:
This manuscript reports a study on a subset of patients from a randomized trial of high versus low-dose influenza vaccine in solid organ transplant recipients. The authors demonstrate a significantly higher cellular immune response in the high dose group. The finding is interesting as it has been suggested that cell-mediated immunity is important in protection against influenza in immunosuppressed patients. There are some limitations – it is not clear whether the response in either group is clinically protective or sustained, and the patients included in this substudy represent a small self-selected cohort from the overall study.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Available Case Analysis (AC)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT03139565
Funding Source:
Industry funded
Vondrak, K. et al. (2019). Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus." Clinical Transplantation [record in progress].
Aim:
To compare efficacy and safety of immediate‐release tacrolimus (IR‐T) vs prolonged‐release tacrolimus (PR‐T) in de novo kidney, liver, and heart transplant recipients.
Interventions:
Patients were randomized to receive either prolonged‐release tacrolimus or immediate‐release tacrolimus within 4 days of surgery.
Participants:
44 solid organ transplant recipients.
Outcomes:
Safety, efficacy, and tacrolimus trough level data were obtained during follow‐up visits on Day 60, 90, 180, and 365. The efficacy endpoints after 365 days measured the number of clinical acute rejections, BCAR episodes (including severity), patient and graft survival, and efficacy failure (a composite endpoint of death, graft loss, BCAR, or unknown outcome).
Follow Up:
1 year
CETs Conclusions:
Given that there is little information published about prolonged release tacrolimus in paediatric transplant patients so this is an important Phase-2, open-label, study. It included recipients of heart, kidney and liver transplants randomised to immediate-release (twice daily) or prolonged-release (once-daliy) tacrolimus. The early (4-week) pharmacokinetic study has previously been published and this paper concentrates on the longer-term follow up at 1 year. Each centre was able to give the rest of their routine immune suppression regimen as required. Over one year of follow up the mean tacrolimus doses and trough levels were similar between the two arms of the study. In the prolonged-release arm there was 1 case of biopsy confirmed rejection (BCAR) in a liver recipient and 1 case of clinical rejection in a heart recipient. In the immediate-release arm there were 4 cases of BCAR in liver recipients, 1 case of clinical rejection in a heart recipient and 2 kidney recipients. There were no cases of graft loss or death during the study period. There was no significant difference in the composite end-point of “efficacy failure” although it appeared to favour the prolonged-release preparation. However, this was due to the inclusion of patients with unknown outcome that left the study early (removed consent, other adverse outcome, non-compliant with study visits). There was no significance in overall adverse events or drug-related adverse events. It should be noted that the study targeted older children and hence the median age is 10.6 years and 95% were Caucasian.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01614665
Funding Source:
Industry funded