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 January 2020 – Kidney Transplantation

Ahmed, Z., Uwechue, R. et al. (2019). "Prophylaxis of Wound Infections-antibiotics in Renal Donation (POWAR): A UK Multicentre Double blind Placebo Controlled Randomised Trial." Annals of Surgery [record in progress].
Aim:
This study aimed to assess if a single preoperative antibiotic dose can reduce post hand-assisted laparoscopic donor nephrectomy (HALDN) infections.
Interventions:
Patients were randomized to receive either intravenous co-amoxiclav 1.2g or the equivelant volume of normal saline (0.9% saline) at the time of induction of anesthesia.
Participants:
293 adult renal transplant donors undergoing HALDN. Patients who had a known allergy or previous adverse rection due to antibiotics were excluded.
Outcomes:
Primary outcomes being assessed comprised postoperative infections, including, surgical site infections (SSIs), urinary tract infections (UTIs) and lower respirtory tract infections (LRTIs). Secondary outcomes included postoperative hospital stay, 30-day readmission rates and reoperation rates.
Follow Up:
30 days
CETs Conclusions:
This multicentre UK study investigated the use of single-dose pre-operative antibiotics in hand-assisted donor nephrectomy. The study is randomised and blinded by use of a saline placebo. The investigators demonstrate a significant reduction in the risk of post-operative infection, including surgical site and lower respiratory tract infections. The study is well designed and reported, with clear outcome definitions. It is interesting that the baseline infection rate is considerably higher that that reported in the previous literature, which is likely due to under-reporting in retrospective studies rather than an excess of infection in the current study. Given the burden of infection in these patients, and the size of the reduction seen, it would appear that antibiotic prophylaxis is warranted. It is, however, not clear whether these findings extend to patients undergoing fully laparoscopic nephrectomy.
Reporting Quality:
Jadad Score 
5
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
Yes
Trial Registration:
EudraCT Number: 000942-36
Funding Source:
Non-Industry funded
Han, A., Min, S. I. et al. (2019). "Mobile medication manager application to improve adherence with immunosuppressive therapy in renal transplant recipients: A randomized controlled trial." PLoS ONE [Electronic Resource] 14(11): e0224595.
Aim:
This study aimed to evaluate if the use of the mobile medication application, Adhere4U, can improve adherence amongst renal transplant recipients, 1 year post-transplantation.
Interventions:
The intervention for this study was a medication manager that was developed for transplantation patients in Korea, known as Adhere4U. The app has several features, including: audible and/or visual reminders able to reflect medication tapers, nondaily administration, and start and stop dates; personal tracking data on missed and taken doses by providing a daily checklist of medication and when it was taken; medication adherence report; detailed information on all immunosuppressants; an educational video on the importance of IST; and patient’s laboratory test results. Patients were randomized to either receive conventional care (control group) or the intervention, which was the use of the Adhere4U app (mobile group).
Participants:
138 renal transplant recipients (incusion criteria included being 15–70 years, an android smartphone user and current use of twice-daily tacrolimus or cyclosporine as the principal immunosuppressant following renal allograft).
Outcomes:
The primary outcome was the nonadherence rate to index immunosuppressant (tacrolimus or cyclosporine), which was monitored using an electronic medication event monitoring system. The secondary outcome being measured was self-reported adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) and the visual analog scale (VAS) based on a 4-week recall on days 28, 90, and 180.
Follow Up:
180 days
CETs Conclusions:
This interesting study from Korea investigated the effect of a smartphone medication reminder app on adherence in stable renal transplant recipients. Use of the app did not improve adherence (either measured by electronic medication monitoring or self-reported) or clinical outcomes, and sustained use of the app was poor. The manuscript is well written and there is an excellent discussion as to the potential reasons for the negative findings. There are some limitations to the study: (1) patients were enrolled between 2013 and 2015 – it is unclear how this would translate to more recent smartphones and app capabilities, (2) all patients were eligible for enrolment, rather than focussing on those that were non-adherent at baseline and (3) the treating clinician was blinded to app use, removing the potential for feedback and education to non-adherent patients during the study. Attrition in app use during the study was high and associated with poorer medication adherence, suggesting that feedback of use and adherence to the treating clinician may have the potential improve engagement and adherence.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
IRB no. 1306-031-496 and Clinicaltrials.gov: NCT01905514
Funding Source:
Industry funded
Rummo, O., Carmellini, M. et al. (2019). "Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients." Transplant International [record in progress].
Aim:
This study aimed to evaluate long‐term graft survival in kidney transplant recipients, treated with once‐daily prolonged‐release tacrolimus‐based therapy. Secondary objectives included evaluation of the long‐term impact of prolonged‐release tacrolimus on patient survival, renal function, and acute rejections (ARs).
Interventions:
This was a long-term, non-interventional, follow-up of the ADHERE study to assess prolonged-release tacrolimus-based immunosuppression.
Participants:
Patients were eligible for this study if they had received a kidney transplant and had been assigned to prolonged‐release tacrolimus as participants of the ADHERE study. 587 patients from the ADHERE study were prospectvely followed up to assess long-term, immunosuppression.
Outcomes:
Outcomes being assessed included: 5-year acute rejection-free survival rate, biopsy-confirmed acute rejection-free survival rate, renal function and eGFR.
Follow Up:
5 years
CETs Conclusions:
The paper reports the long-term follow up of the ADHERE trial that compared prolonged-release tacrolimus with either MMF or sirolimus in de novo adult kidney transplant patients and the primary outcome of the analysis was long-term graft survival. The 1-year ADHERE trial randomised 730 patients and the 4-year non-interventional follow up was completed by 510 patients. At one-year posttransplant the overall graft survival rate was 93% and at 5 years posttransplant the overall graft survival rate was 84% and similar between the two study arms (89.3% for the MMF arm and 87.6% for the sirolimus arm). The patient survival rate was 97.8% at 1 year posttransplant and 90.8% at 5 years posttransplant (91.9% for the MMF arm and 93.3% for the sirolimus arm). Renal function was stable throughout the study period and there were no differences in the adverse events between study arms.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
Yes
Trial Registration:
ClinicalTrials.gov - NCT01363752
Funding Source:
Industry funded
Schroppel, B., Akain, E. et al. (2019). "Peri-transplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: results of two randomized controlled pilot trials." American Journal of Transplantation [record in progress].
Aim:
This report aimed to explore the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent delayed graft function (DGF) in recipients of deceased donor kidney transplants in two, randomized controlled trials: the pilot study and multicentre study.
Interventions:
Patients in the pilot study were randomized to receive either saline placebo or Ecu at a dose of 1200mg, prior to transplant surgery. Patients in the Multicenter study were randomized to either saline placebo or two doses of Ecu (an initial dose of 1200mg and second dose of 900mg after 12-24hrs of the initial dose). All patients were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and followed for 6 months.
Participants:
8 participants were recruited for the pilot study. The inclusion criteria for participation was ≥18 years of age, recipient of a primary kidney transplant from a deceased, “standard criteria donor” (SCD) with cold ischemia time (CIT) of >24 hours, or from an “extended criteria donor” (ECD) kidney. A total of 19 participants from the multicenter trial were included; these subjects were eligible on the basis of being ≥18 years of age, the recipient of a primary, HLA‐mismatched, kidney transplant from a deceased, SCD kidney with CIT of 18 to 40 hours, or from an ECD kidney.
Outcomes:
The primary outcome of the pilot study was the composite of DGF alongside slow graft function (SGF). DGF was defined by at least one dialysis treatment during the first 7 days after transplantation. Whereas, for the multicenter study, the primary endpoint was the need for at least one dialysis treatment during the first 7 days after transplantation, regardless of cause.
Follow Up:
6 months
CETs Conclusions:
This is a pooled analysis of two small (unpublished) double-blinded, randomised controlled trials evaluating the efficacy and safety of anti-C5 monoclonal antibody eculizumab (Ecu) to reduce the rate of delayed graft function (DGF) in adult recipients of standard criteria donor or extended criteria donor kidneys. A small single-centre pilot study included 8 participants and was followed by a multicentre study including 19 patients, which was terminated early as the results of the similar PROTECT study showed no efficacy for Ecu in reducing DGF. The research pharmacist prepared the Ecu infusion and used a web-based randomisation application to randomise patients to Ecu or saline. Infusion bags were covered by the pharmacist to ensure blinding of all study personnel and participants throughout the study. Power analysis showed that 48 patients were needed to providing 50% power to detect a reduction in DGF from 40% to 17.5% (the goal of the multicentre study was justify a subsequent larger study). Data were analysed according to the intention to treat principle which included all randomised patients who received the study drug. Data were analysed for each trial separately and a pooled analysis of both trials was performed despite some differences in the design of the two studies and definition of DGF. The small studies and the pooled analysis did not find significant differences between the Ecu and control arms in terms of DGF and adverse events, which is similar to the results of the PROTECT study.
Trial Registration:
ClinicalTrials.gov - NCT01403389 and NCT01919346.
Funding Source:
No funding
Sullivan, C. M., Barnswell, K. V. et al. (2018). "Impact of Navigators on First Visit to a Transplant Center, Waitlisting, and Kidney Transplantation: A Randomized, Controlled Trial." Clinical Journal of The American Society of Nephrology: CJASN 13(10): 1550-1555.
Aim:
This study aimed to determine the effect of navigators on helping patients overcome the barriers and steps required to obtain a kidney transplant.
Interventions:
Patients were randomized to control or intervention. Control patients received care from their nephrologists and hemodialysis facilities, but did not have Navigators interaction. Whereas, the intervention group had a navigator to assist.
Participants:
The study included 40 hemodialysis facilities and four transplant centers in Ohio, Kentucky, and Indiana from January 1, 2014 to December 31, 2016.
Outcomes:
Primary study outcomes were waiting list placement and receipt of a deceased or living donor transplant. Secondary outcome included the first visit to a transplant center.
Follow Up:
N/A
CETs Conclusions:
Ten haemodialysis facilities were randomly selected from those within 30 miles of each of 4 transplant centres. Five of these haemodialysis facilities were randomly assigned to the control group and five to the study group (cluster randomisation). Each transplant centre in the intervention group hired a kidney transplant recipient to act as a navigator for patients on haemodialysis. Navigators are individuals who educate patients and help them to navigate through the health care system. Navigators underwent a 3-day training session. The study overall included 1877 patients, which was considerably more than would have been required to power the trial to detect an increase in annual listing from 18% to 25% and an increase in transplant rate from 6% to 10%. Navigators identified 869 eligible patients, 324 of whom declined to participate. On average navigators met with each participating patient 9.7 times. At the end of the trial, there were no significant differences in the proportion of patients making a first visit to the transplant unit, going onto the waiting list, or receiving a transplant. There were no significant differences between the groups identified on multivariate analysis either. The significant number of patients that declined to participate with the study arm will likely have influenced the results. The incremental value of the navigators may also be small given the work already done by the participating haemodialysis centres.
Reporting Quality:
Jadad Score 
2
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrial.gov - NCT01981603
Funding Source:
Industry funded
van Buren, M. C., Schellekens, A. et al. (2019). "Long term graft survival and graft function following pregnancy in kidney transplant recipients: a systematic review and meta-analysis." Transplantation [record in progress].
Aim:
This systematic review and meta-analysis aimed to provide an update on graft survival in non-pregnant kidney transplant recipients, as well as long-term (up to 10 year) graft function, measured by serum creatinine (SCr), after pregnancy.
Interventions:
The Pubmed, Embase and Cochrane library database was searched to identify all studies on SCr and graft loss after pregnancy in kidney transplant recipients up until September 2018.
Participants:
A total of 38 studies on renal graft loss (n=2453) and 18 studies on renal graft function, as measured by serum creatinine following pregnanct were retrieved for inclusion.
Outcomes:
Outcomes being assessed included graft loss, survival and function.
Follow Up:
10 years
CETs Conclusions:
This systematic review and meta-analysis explored the literature on graft outcomes following pregnancy after kidney transplantation. The authors identified 43 studies reporting either graft loss, serum creatinine, or both following transplant. 10 studies also reported a nulliparous control cohort. Overall incidence of graft loss over time is reported, and does not appear to differ significantly to controls (although this comparison was not subjected to meta-analysis). Reported risk factors for graft loss following pregnancy included pre-pregnancy proteinuria, hypertension and poor baseline function. The review is comprehensive and the methodology sound. The data reported are useful when counselling patients and identifying risk factors. One potential limitation is that some patients in the smaller included studies may also be in the larger, registry-based studies leading to double-counting.
Trial Registration:
Not reported
Funding Source:
No funding
Woodle, E. S., Kaufman, D. et al. (2019). "Belatacept-Based Immunosuppression With Simultaneous Calcineurin Inhibitor Avoidance and Early Corticosteroid Withdrawal: A Prospective, Randomized Multicenter Trial." American Journal of Transplantation [record in progress].
Aim:
This trial compares two belatacept-based calcineurin inhibitor avoidance (CNIA)/ early corticosteroid withdrawal (ESW) regimens with a tacrolimus-based ESW regimen to determine the safety and efficacy of these regimens.
Interventions:
Kidney transplant recipients were randomized to receive alemtuzumab/belatacept (n=107), or rabbit antithymocyte globulin (rATG)/belatacept (n=104), or rATG/ tacrolimus (n=105).
Participants:
16 patients, ≥ 18 years of age, and recipients of a living or deceased donor kidney transplant were enrolled between September 2012 and December 2016.
Outcomes:
The primary outcomes measured included: the rate of the composite endpoint at 12 months of patient death, or allograft loss, or eGFR < 45ml/min/1.73m2. Secondary endpoints included: composite endpoint at 6 months, rates of each of the three individual components of the composite endpoint, biopsy confirmed acute rejection (BCAR) stratified by type (acute cellular rejection (ACR), antibody mediated rejection (AMR), or mixed acute rejection (MAR), death censored graft survival, proportion of patients with eGFR (MDRD) <30ml/min/1.73m2, and proportion of patients developing anti-HLA antibodies against the donor (donor specific antibodies (DSA)) after transplantation.
Follow Up:
12 months
CETs Conclusions:
This 3-arm study investigated the use of CNI avoidance using belatacept and lymphocyte depleting induction therapy with either rATG or Alemtuzumab. No difference was seen in the primary composite endpoint (death, graft loss or GFR <45 ml/min) or in renal function at 12 months, but acute cellular rejection rates were higher in the belatacept arms. These results are perhaps surprising in that the renal function benefit from belatacept seen in the BENEFIT studies was not replicated. However, a trend towards improved eGFR distribution appears to be emerging at 12 months (figures 2i and 2j), suggesting that longer-term follow-up data will be essential to determine any potential benefit from sustained CNI avoidance. One limitation of the study is that the original sample-size calculation was based on incidence of the primary endpoint of 50% in the control tacrolimus group; in fact it only occurred in 13.3% leaving the study underpowered to detect a difference in the primary endpoint. Inclusion criteria were quite limited, with exclusion of DCD and ECD donors and sensitised recipients.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01729494
Funding Source:
Not reported

Transplant Trial Watch January 2020 – Heart Transplantation

Ayesta, A., Urrútia, G. et al. (2019). "Sex-mismatch influence on survival after heart transplantation. A systematic review and meta-analysis of observational studies." Clinical Transplantation; 33(12): e13737.
Aim:
This systematic review and meta-analysis aims to synthesize the evidence on the effect of donor/recipient sex mismatch after heart transplantation (HT).
Interventions:
The PubMed and EMBASE database was searched until November 2017 for comparitive cohort and registry studies.
Participants:
Ten studies (n=76175 heart transplant patients) were included in the quantitative meta-analysis.
Outcomes:
Primary outcome being assessed was one-year mortality, following heart transplantation.
Follow Up:
1 year
CETs Conclusions:
This is a well written report of a well conducted systematic review. Pubmed and EMBASE were searched for papers and they were filtered in duplicate. Three reviewers extracted data but it is unclear if this was done in triplicate or in parallel. A large number of transplants were included (76,175) represented in 10 papers and the authors took steps to prevent duplication of results. Despite one study dominating the results due to its very large size (the ISHLT registry) all of the other studies favoured no mismatch in donor and recipient sex, even if not statistically significantly. Heterogeneity as assessed by I-squared statistic was 0%. Overall the meta-analysis showed a 30% increase in survival when donor and recipient sex were matched. When separating male and female recipients, male recipients did significantly worse if receiving a female donor heart, whilst for female recipients the donor sex was not statistically significant (p=0.06). It has been speculated that differences in predicted cardiac mass are to blame, although some analyses have not supported this. The reasons for the interaction between sex mismatch and early survival are not clear.
Trial Registration:
Not reported
Funding Source:
Industry funded

Transplant Trial Watch January 2020 – Lung Transplantation

Iacono, A., Wijesinha, M. et al. (2019). "A randomised single-centre trial of inhaled liposomal cyclosporine for bronchiolitis obliterans syndrome post-lung transplantation." Erj Open Research 5(4).
Aim:
This study aimed to investigate the effects of inhaled liposomal cyclosporine (L-CsA) to prevent bronchiolitis obliterans syndrome (BOS) following lung transplantation.
Interventions:
Patients with BOS were assigned to either receive L-CsA, twice daily at doses of 5mg or 10mg for 24 weeks with standard-of-care (SOC) oral immunosuppression, tacrolimus (0.06 mg·kg−1·day−1), mycophenolate mofetil (2000 mg·day−1) and prednisone (10–20 mg·day−1) (L-CsA group) or SOC (SOC-alone group).
Participants:
21 recipients of a single or bilateral pulmonary allograft, ≥18 years of age who were clinically diagnosed BOS grade 1 or 2 and receiving tacrolimus-based immunosuppression.
Outcomes:
There were two primary end-points being measured: 1) a composite of BOS progression-free survival, defined as time from randomisation to ≥20% decline in FEV1, re-transplantation or death (prolonged mechanical ventilation and irreversible respiratory failure equivalent to ≥20% decline of FEV1), and 2) BOS grade progression by grade changes from randomisation to study completion. A decline in FEV1 was validated for absence of concurrent illness.
Follow Up:
24 weeks
CETs Conclusions:
This is a well written report of a good quality phase II study. The study was terminated early due to lower than expected enrolment rates, including 21 patients rather than the target of 30. There was no significant difference in the primary outcome, however the absolute values indicate that in a larger study a significant effect might be seen. L-CsA seemed to stabilise FEV1 and FVC compared to standard treatment alone and improve levels of the cytokines IL-2, IL-10and IFN-gamma. There were no adverse events that required cessation of the study drug. This was an exploratory study and further trials are now needed, indeed the phase III multicentre trial using L-CsA for bronchiolitis obliterans has begun.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Strict Intention To Treat (sITT)
Allocation Concealment 
No
Trial Registration:
ClinicalTrials.gov - NCT01650545
Funding Source:
Not reported

Transplant Trial Watch January 2020 – Various Transplantation

Korus, M., Cruchley, E. et al. (2019). "Assessing the acceptability and efficacy of teens taking charge: Transplant-A pilot randomized control trial." Pediatric Transplantation [record in progress].
Aim:
This pilot trial aimed to determine the feasibility and estimated efficacy of a web-based, TTC program.
Interventions:
Patients were randomized to either an intervention group that accessed TTC or a control group that did not access the program.
Participants:
42 participants, including both renal and liver transplant candidates were enrolled over a 2 year period.
Outcomes:
Outcomes measured included feasibility, programme use, pre- and post-intervention health-related outcomes evaluating self-management, self-efficacy, mood, use of healthcare services, and knowledge. These outcomes were obtained via semi-structured interviews.
Follow Up:
1 year
CETs Conclusions:
This pilot randomised controlled trial aimed to determine the feasibility of the Teens Take Charge (TTC) programme that addresses self-management for adolescent liver and kidney transplant candidates and recipients. Preliminary estimates of efficacy were calculated and interviews with participants were held regarding their experiences and perspectives of the TTC programme at the 3-month follow up. Forty-four pre-transplant and transplanted patients aged 12-18 were randomised using a web-based randomisation programme to either the TTC programme or the control group that was not given access to the TTC programme. Three participants withdrew from the study. The preliminary results show that participants considered the website reliable and would recommend it to others, however on average participants spent very little time using the website. No differences were found for any of the self-report health-related outcomes. Further research should take into account the reported barriers such as not being able to access the site on a mobile device and participants reporting being too busy to access the site.
Reporting Quality:
Jadad Score 
3
Data Analysis 
Modified Intent to Treat (mITT)
Allocation Concealment 
No
Trial Registration:
Not reported
Funding Source:
Non-Industry funded