This study has been transitioned to CTIS with ID 2024-516509-22-00 check the CTIS register for the current data. 1. To test the hypothesis that an age adapted immunosuppressive regimen targeted at reduced immunosuppression with low calcineurin…
ID
Source
Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primay outcome is succesfull transplantation. As outcome is expected to be
markedly different in stratum A and stratum B, different primary outcome
criteria will be used. We have defined successful transplantation as our
primary outcome variable combining patient and graft survival with a minimum
level of renal function. In our opinion this endpoint combines the most
relevant outcomes for the patient. Stratum A: Primary endpoint: successful
transplantation at 1 year after transplantation defined as: absence of graft or
patient loss in the presence of an eGFR above 30 ml/min/1.73m2. Stratum B:
Primary endpoint: successful transplantation at 1 year after transplantation
defined as absence of graft or patient loss in the presence of an eGFR above 45
ml/min/ 1.73m2. Both strata are pooled for analysis.
Secondary outcome
Secondary outcomes both strata: • Incidence of individual endpoints of death,
graft loss, rejection eGFR below 30 or 45 ml/min/ 1.73m2 rejection at Months 12
and 24. • Rejection treatment and type of rejection treatment • The evolution
of renal function (eGFR) over time by slope analysis. • The incidence of
adverse events, serious adverse events and adverse reactions • The incidence of
clinically relevant infections, new onset diabetes mellitus and malignancies •
Presence of frailty at 3, 12 and 24 months after transplantation and change in
frailty from baseline •Presence of markers for immunosenescence at 12 and 24
months and changes from baseline •hrQOL at 3, 12 and 24 months and changes from
baseline. •Development of donor specific antibodies.
Background summary
Elderly patients increasingly contribute to both the dialysis and transplant
population. In 2015 more than 30% of the transplant patients in the Netherlands
were above 65 years of age while more than 50% of the dialysis population is
older than 65 years. Kidney transplantation has some important age-dependent
characteristics. Older patients with increased frailty and co-morbidity clearly
have different risk profiles when compared with younger patients. While graft
loss in younger patients is largely due to loss of the kidney with the
recipient needing an alternative form of renal function replacement (e.g.
dialysis and/or re-transplantation), death censored graft loss is a relatively
rare phenomenon in older patients. Increased rates of malignancy and
infection-related mortality have been reported in older transplant recipients.
On the other hand, it has become clear that the aging immune system renders
elderly recipients less prone to rejection. Kidneys from elderly donors are
preferentially allocated to older recipients. A recent analysis of the results
of deceased donor kidney transplantation in the elderly showed that in these
patients graft loss is dominated by patient loss. Poor renal function in these
patients may be both related to chronic damage of the kidney prior to
transplantation (due to older donor age), and to an increased susceptibility to
the toxicity of the immune suppressant tacrolimus. Especially in elderly
recipients receiving marginal grafts it is essential to shift the focus from
prevention of rejection to a stronger focus on preservation of graft function
and preventing over-immunosuppression. In this study two immunosuppressive
regimes will be tested; the standard therapy consisting of prednisolone,
mycophenolate acid and tacrolimus once daily (Envarsus®), or the comparator in
which mycophenolate acid will be replaced by everolimus combined with strongly
reduced levels of tacrolimus once daily (Envarsus®). The hypothesis is that
reduced CNI exposure will lead to improved allograft function, a reduced
incidence of complications and improved quality of life. This study will
consist of two strata: Stratum A: Elderly recipients (>=65 years) of kidneys
from elderly deceased donors (>=65 years) within the Eurotransplant Senior
Program Stratum B: Elderly recipients (>=65 years) of kidneys from living donors
(all ages) or deceased donors (<65 years). The primary endpoint will be
successful transplantation defined as survival with a functioning allograft
with a minimum estimated GFR of 30 ml/min in stratum A and 45 ml/min in stratum
B, after 2 years. The study will be performed by almost all Dutch transplant
centers,1 Belgian centre and the Dutch Kidney Patient Organization (NVN) will
participate. This study will form a starting point for future collaboration
between the renal transplant groups of the university medical centers in The
Netherlands, who never before have participated together in a prospective
clinical trial. Furthermore, this study will provide important guidance for the
treatment of the elderly renal transplant population.
Study objective
This study has been transitioned to CTIS with ID 2024-516509-22-00 check the CTIS register for the current data.
1. To test the hypothesis that an age adapted immunosuppressive regimen
targeted at reduced immunosuppression with low calcineurin inhibitor exposure
will result in improved outcome in elderly recipients of A: kidneys from older
deceased donors (>64 years) and B: Kidneys from living donors (all ages) and
younger deceased donors (<65 years). 2. To evaluate the impact of
transplantation and adapted immunosuppression on frailty and quality of life in
older Dutch transplant recipients 3. To monitor the function of the aged immune
system after transplantation and the effect of everolimus based
immunosuppression on parameters of immunosenescence compared to standard
tacrolimus based immunosuppression. 4. To establish a national platform for
trials in kidney transplantation as a basis for future high impact clinical
trials. 5. To identify immunologic parameters that may serve as biomarkers of
immunosenescence for future clinical application.
Study design
Open label randomized national multicentre intervention trial comparing
standard immunosuppression with tacrolimus and mycophenolate mofetil with a low
exposure tacrolimus regimen in combination with everolimus. The trial will
consist of two strata: Stratum A: Elderly recipients (>=65 years) of kidneys
from elderly deceased donors (>=65 years) within the Eurotransplant Senior
Program Stratum B: Elderly recipients (>=65 years) of kidneys from living donors
(all ages) or deceased donors (<65 years).
Intervention
Study patients will be randomized to the following regime in both stratum A and
stratum B in a 1:1ratio. Arm 1: Basiliximab (B) induction (20 mg iv on days 0
and 4), prednisolone taper to 5 mg at 3 months after transplantation,
tacrolimus once daily (Envarsus®) with an initial target trough level of 8-12
tapered to 5-8ug/l at 6 months after transplantation, mycophenolate mofetil at
dose of 500 mg bd throughout the trial. Arm 2: Basiliximab (B) induction (20 mg
iv on days 0 and 4), prednisolone taper to 5 mg at 3 months after
transplantation, tacrolimus once daily (Envarsus®) with initial target trough
level of 5-7 tapered to 2-4 ug/l from 3 months, and 1.5-4 ug/l from 6 months
after transplantation, everolimus (EVL) will be initiated at a starting dose of
1.5 mg bid with target trough level of 3-6 ug/l throughout the trial.
Study burden and risks
Benefit: The combination of everolimus and tacrolimus in a lower dose can
provide better renal function and a lower mortality rate. Burden: Completing
forms can take some extra time Everolimus has, as all immunnosuppresive agents,
its own side effects Taking bloodsamples might be painfull and can cause
bruises (in the study 162.5 ml extra
Hanzeplein 1 Hanzeplein 1
9700 RB Groningen 9700 RB
NL
Hanzeplein 1 Hanzeplein 1
9700 RB Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
nclusion criteria 1. Written informed consent must be obtained before any
assessment is performed 2. Male or female subject >= 65 years old 3. Subject
randomized within 24 hours of completion of transplant surgery 4. Stratum A:
Recipient of a primary (or secondary, if first graft is not lost due to
immunological reasons) renal transplant from a deceased donor aged 65 years or
older 5. Stratum B: Recipient of a primary (or secondary, if first graft is not
lost due to immunological reasons) renal transplant from a deceased donor aged
below 65 years or a living donor of any age
Exclusion criteria
Exclusion criteria for both stratum A and B 1. Subject is a multi-organ
transplant recipient 2. Recipient of ABO incompatible allograft or CDC
cross-match positive transplant 3. Subject at high immunological risk for
rejection as determined by local practice for assessment of anti-donor
reactivity 4. Recipient of a kidney with a CIT > 24 hr 5. Recipients of a
kidney from an HLA identical related living donor 6. Known intolerability for
one or more of the study drugs 7. Subject who is HIV positive 8. HBsAg and/or a
HCV positive subject with evidence of elevated LFTs (ALT/AST levels >= 2.5 times
ULN). Viral serology results obtained within 6 months prior to randomization
are acceptable * 9. Recipient of a kidney from a donor who tests positive for
human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or
anti-hepatitis C virus (HCV) 10. Subject with a BMI greater than 35 11. Subject
with severe systemic infections, current or within the two weeks prior to
randomization 12. Subject requiring systemic anticoagulation that cannot be
temporarily interrupted and which would preclude renal biopsy 13. History of
malignancy of any organ system (other than localized basal cell carcinoma of
the skin), treated or untreated, within the past 5 years, regardless of whether
there is evidence of local recurrence or metastases 14. Subject with severe
restrictive or obstructive pulmonary disorders 15. Subject with severe
hypercholesterolemia or hypertriglyceridemia that cannot be controlled 16.
Subject with white blood cell (WBC) count <= 2,000 /mm3 or with platelet count <=
50,000 /mm3
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-516509-22-00 |
| EudraCT | EUCTR2018-003194-10-NL |
| ClinicalTrials.gov | NCT03797196 |
| CCMO | NL68661.042.18 |