TAC Registry (Study Name: CHORUS)
Research type
Research Study
Full title
European Multicentre Kidney Transplant ADVAGRAF™ Conversion Registry. A non-interventional post-authorisation study (PAS)
IRAS ID
160291
Contact name
Cassie Winter
Contact email
Sponsor organisation
Astellas Pharma Europe Ltd
Duration of Study in the UK
7 years, 10 months, 28 days
Research summary
Summary of Research
To investigate the potential benefit of ADVAGRAF on long term outcomes in kidney transplant patients under conditions of routine clinical practice. The primary objective is to is to evaluate changes over time in renal function from Baseline (time of conversion) up until five years post conversion in kidney transplant patients converted from tacrolimus BD formulations to a once daily formulation as ADVAGRAF. Within Europe, the anticipated total enrolment to this registry will be approximately 6000 patients.
Summary of Results
Global Multicentre Kidney Transplant Advagraf Conversion Registry. A non-interventional post-authorisation study (PAS) “CHORUS”
Sponsor for this study is Astellas Pharma Europe BV, Sylviusweg 62, 2333 BE Leiden, Netherlands.
Summary
This non-interventional study was conducted to investigate the long-term outcomes in kidney transplant patients on Advagraf under conditions of routine clinical practice.
This was a multicenter long-term (up to 5 years post-conversion), non-interventional registry in kidney transplant patients who had been converted from tacrolimus BD to Advagraf. Patients who were on tacrolimus BD and identified for conversion to Advagraf were eligible for enrollment in this registry.
4389 patients were enrolled in the study (Enrolled patients set (EPS): N = 4389, Full Analysis Set (FAS): N = 4028) from 127 centers in 25 countries in Europe, Asia and Canada.
Patients who were on tacrolimus BD and identified for conversion to Advagraf were eligible for enrollment in the registry. Patients were entered into the registry prospectively following the initiation of the registry.
Data were collected from all sources where data were captured and recorded in routine clinical practice including paper as well as electronic hospital medical records (inclusive of any reports or laboratory investigations completed as part of routine clinical practice) and Adverse Drug Reaction worksheets.Results
Overall, in the FAS, change from baseline in renal function, as measured by estimated Glomerular filtration rate (eGFR), using the Modification Diet in Renal Disease (MDRD-4) formula, was consistent with previous tacrolimus studies and remained stable 5 years post-conversion and throughout the study.
In the early converter (EC) cohort, change from baseline in renal function, as measured by eGFR (MDRD-4), showed an initial clinically relevant improvement and remained stable over time.
In the FAS, mean eGFR values, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) formula, were slightly higher than eGFR values calculated according to the MDRD-4 formula, but in general, showed similar trends over time.
The most commonly used concomitant immunosuppressant (IS) medications (other than tacrolimus) included selective ISs (most common: mycophenolate mofetil and mycophenolate sodium) and glucocorticoids.
Overall, 3.0% of patients had at least 1 clinical acute rejection (AR) episode prior to conversion compared to 3.3% of patients after conversion. The Kaplan-Meier estimate for clinically acute rejection (AR)-free survival was > 90% throughout the study.
Prior to conversion, BPARs were recorded for 2.1% of patients in the FAS, compared to 1.9% of patients after conversion. The majority biopsy proven acute rejection (BPARs) included T-cell mediated BPAR (1.8% of patients prior to conversion and 1.4% of patients after conversion). The Kaplan-Meier estimate for BPAR-free survival was > 90% throughout the study.
Overall, 258 patients in the FAS died during the study period. The Kaplan-Meier estimate for patient survival was high (> 97%) at 60 months (5 years) post transplantation and remained high (> 95%) at 84 months (7 years) post transplantation. Overall, ≥ 95% patient survival rate was observed in all subgroup variables for 60 months (5 years) post transplantation and > 90% for 84 months (7 years) post transplantation.
Overall, 458 patients in the FAS experienced a graft loss after their latest transplantation during the study period. The Kaplan-Meier estimate for graft survival rate was high (≥ 95%) at 60 months (5 years) post transplantation and remained high (> 92%) at 84 months (7 years) post transplantation. Overall, > 85% graft survival was observed in all subgroup variables for 60 months (5 years) post transplantation and > 80% for 84 months (7 years) post transplantation.
Overall, a higher percentage of patients had occurrence of donor specific antibody (DSA) after conversion to Advagraf compared to prior to or at conversion to Advagraf (28.2% vs. 18.3% of patients).
Overall, 30.5% of patients discontinued from treatment with Advagraf. The primary reasons (> 3% of patients) for Advagraf discontinuation were due to adverse event (AE), ‘other’ reasons, lost to follow-up and death.
Overall, in the EPS, AEs were reported in 72.4% of patients (at least 1 AE was considered Advagraf-related in 19.3% of patients). SAEs were reported in 50.6% in patients (at least 1 serious adverse event (SAE) was considered Advagraf-related in 10.4% of patients). AEs leading to permanent discontinuation of Advagraf were reported in 11.8% of patients (at least 1 AE leading to permanent discontinuation of Advagraf was considered Advagraf-related in 5.5% of patients). Overall, 7.0% of patients had an AE leading to death (at least 1 AE leading to death was considered Advagraf-related in 0.4% of patients).
Overall, the most common AEs included diarrhea, urinary tract infection, acute kidney injury, edema peripheral and anemia. The most common Advagraf-related AEs included tremor, diarrhea and urinary tract infection.
The most common severe AEs included acute kidney injury, death, coronavirus disease 2019 (COVID-19) and sepsis. The most common severe Advagraf-related AEs were acute kidney injury and renal graft infection.
The most common AEs leading to permanent discontinuation of Advagraf included tremor and death. The most common reported Advagraf-related AEs leading to permanent discontinuation of Advagraf included tremor and diarrhea.
The most common AEs of special interest included hypertension, basal cell carcinoma, squamous cell carcinoma, cytomegalovirus infection, diabetes mellitus, BK virus infection and atrial fibrillation.
Occurrence of expected medical conditions and infections were low throughout the study, observed in ≤ 4.0% of patients.
There were no noteworthy trends noted in clinical laboratory results and vital signs during this study.Asian countries cohort:
In the FAS (Asian countries cohort, N = 887), change from baseline in renal function, as measured by eGFR (MDRD-4), remained stable 5 years post-conversion and throughout the study. Mean eGFR values were slightly higher throughout the study compared to the overall patient cohort.
Mean eGFR values, calculated according to the CKD-Epi formula, were slightly higher than the eGFR values calculated according to the MDRD-4 formula, but in general, showed similar trends over time.
The Kaplan-Meier estimate for clinically AR-free survival was > 93% throughout the study.The Kaplan-Meier estimate for BPAR-free survival was > 94% throughout the study.
Overall, 29 patients in the FAS died during the study period. The Kaplan-Meier estimate for patient survival was high (> 98%) at 60 months (5 years) post transplantation and remained high (> 97%) at 84 months (7 years) post transplantation.
Overall, 55 patients in the FAS experienced a graft loss after their latest transplantation. The Kaplan-Meier estimate for graft survival rate was high (> 97%) at 60 months (5 years) post transplantation and remained high (≥ 96%) at 84 months (7 years) post transplantation.
Overall, a higher percentage of patients had occurrence of DSA after conversion to Advagraf compared to prior to or at conversion to Advagraf (26.9% vs. 22.2% of patients).
In the EPS (Asian countries cohort, N = 910), AEs were reported in 58.1% of patients (at least 1 AE was considered Advagraf-related in 9.1% of patients). SAEs were reported in 37.0% of patients (at least 1 SAE was considered Advagraf-related in 6.4% of patients). AEs leading to permanent discontinuation of Advagraf were reported in 5.2% of patients (at least 1 AE leading to permanent discontinuation of Advagraf was considered Advagraf-related in 2.4% of patients). Overall, 3.5% of patients had an AE leading to death.
The most common AEs included nasopharyngitis and urinary tract infection. The most common Advagraf-related AEs included gastroenteritis, herpes zoster, urinary tract infection, diarrhea and upper respiratory tract infection.Exposure and Tacrolimus Trough Levels:
In the FAS, from conversion (baseline) to 12 months after conversion, the median daily dose of Advagraf remained stable at 4.00 mg, thereafter, decreased to 3.50 mg at 18 months after conversion and remained stable to End of Treatment (EOT).
Overall, the median tacrolimus trough level was 6.70 ng/mL (mean 7.22 ng/mL) at conversion and 5.70 ng/mL (mean 5.86 ng/mL) at End of Study (EOS). At all timepoints (12 months after conversion to EOS) > 60% of patients had tacrolimus trough levels between 5 and 10 ng/mL.
In the Asian countries cohort (FAS), the median daily dose remained stable (from conversion to EOT) at 3.00 mg. The median tacrolimus trough level was 5.70 ng/mL (mean 6.14 ng/mL) at conversion and 4.90 ng/mL (mean 5.11 ng/mL) at EOS.
COVID-19 impact:
Overall, 133 visits for 2.9% of patients and 436 non-visit-based assessments in 4.2% of patients were affected by the COVID-19 pandemic. During this study, 196 AEs with diagnosis of COVID-19 infection or suspected COVID-19 were reported in 4.1% of patients and in 0.3% of patients the AEs were considered Advagraf-related. Overall, 0.5% of patients had AEs with diagnosis of COVID-19 infection or suspected COVID-19 leading to death.
Discussion and Conclusion
Favorable outcomes were observed in the analysis of the large kidney transplantation recipient population included in the study after 5 years post-conversion to Advagraf under conditions of routine clinical practice.REC name
London - City & East Research Ethics Committee
REC reference
15/LO/0189
Date of REC Opinion
10 Feb 2015
REC opinion
Further Information Favourable Opinion