Renal Transplant RejectionPhase 1/2NCT05073822
NOMINATE/ Minimisation of Immunosuppression in Kidney Transplantation
A Phase 1/2 study testing Tacrolimus in people with Renal Transplant Rejection and Renal Transplant Infection, run by University College, London.
Trial summary
Kidney transplantation provides the optimal form of kidney replacement therapy for the majority of people with end-stage kidney disease, and has now become the commonest form of kidney replacement therapy. Read more about this study
- Who is it for?
- Ages 60 to 85 years
- Conditions the study is for
- Renal Transplant Rejection, Renal Transplant Infection
- What is being tested?
- Tacrolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 20 Feb 2023to 20 Feb 2027
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 85 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participant must be first time adult recipients of either a deceased or living donor kidney transplant.
- Participant must be a recipient of a single organ transplant only.
- Participant must be above the age of 60 years.
- Participant must have a negative screen for donor-specific antibody prior to transplantation (MFI<2000).
Who cannot join
- Recipients of a transplant who are highly sensitised (cRF >85%).
- Inability to participate in frequent monitoring of renal transplant function and clinical visits (every 4 weeks) during dd-cfDNA monitoring and IS minimisation.
- Participants with immune-mediated renal disease in which IS minimisation is inadvisable.
- EBV negative recipient (as IS minimisation is part of standard protocol)
- Inability to comply with study directed treatment
About this study
Official title: A Phase III, Randomised, Single-site Trial on the Minimisation of Immunosuppression In Elderly Renal Transplant Recipients.
Kidney transplantation provides the optimal form of kidney replacement therapy for the majority of people with end-stage kidney disease, and has now become the commonest form of kidney replacement therapy. However, donor and recipient demographics have changed considerably over the past few decades: increasingly older donor kidneys are transplanted into progressively older recipients with greater comorbidities. Increasing age remains a major risk factor for death after kidney transplantation, with the commonest causes of deaths for recipients aged 70 and over being cardiovascular, infection, and malignancies. Immunosuppressant drugs which are critical for the maintenance of the transplanted organ can contribute to increased morbidity and mortality, by direct effects or through lowered immunity predisposing to infection. Cytomegalovirus (CMV) is one of the most common opportunistic infections that affects renal transplant patient outcome and can be monitored prospectively. Hence, minimising immunosuppression, especially in older recipients, may result in better graft and patient outcomes as many side-effects are dose dependant. However, to date drug doses have never been adjusted based on age, despite significant changes that occur to immune responsiveness as patients grow older. In addition , researchers have not had a biomarker to help define appropriate immunosuppressive levels for each individual.
The investigators therefore aim to study the effect of reducing the target immunosuppression drug levels( of tacrolimus and mycophenolate) in kidney transplant recipients >60 years, using CMV viraemia as a main outcome measure, and investigating rates of rejection and development of de novo donor-specific anti-HLA antibodies. The investigators will assess the clinical utility of donor-derived cell free DNA (dd-cfDNA) as a means to guide immunosuppression minimisation. The investigators propose that the use of lower doses of immunosuppression will result in fewer infection-related complications, translating to improved patient outcomes. The research will be carried out in kidney transplant centres where prospective CMV monitoring is practiced.
Read the detailed description
Older kidney transplant recipients are at increased risk of infection and death from infectious causes compared to younger transplant recipients, and despite knowledge of age related immunological changes, the immunosuppressive protocol for older recipients was not yet adjusted. Our provisional data suggest that standard dose immunosuppression in the older patients results in more infections and fewer rejection episodes. Achieving a better balance by reducing risk of infection would be highly desirable. Defining age-specific target drug levels and doses should therefore be tested in a formal trial to establish its validity.
Transplant recipients are especially at risk from viral and opportunistic infections; CMV is a particular problem, as infections can be both donor-derived or due to re-activation of latent virus in the recipient. In the transplant population, CMV infection can cause significant morbidity, including bone marrow suppression, pneumonitis, colitis, retinitis and encephalitis, and as a consequence, increased mortality. However, as this will be measured prospectively, it can also be utilised as a marker of the degree of ( over) immunosuppression in our patients.
There are no current recommendations regarding optimal dose or target drug levels, and importantly, no age-specific standards. This trial could provide some specific recommendations.
There is an increasing body of evidence that demonstrates age-related changes to the immune system, termed immunosenescence, characterized by reduced responsiveness to both newly and previously encountered antigens. In transplantation, it is thought that such immunosenescence may influence both the immune response of the recipient and the immunogenicity of the donor organ. Understanding if this is in any way related to physical frailty may be helpful in informing patients of risk of transplantation.
Donor-derived cell-free DNA (dd-cfDNA) detected in the plasma of transplant recipients has been increasingly reported as a noninvasive biomarker of acute rejection(AR)-with transplant organ damage leading to release of more of the donor DNA into the bloodstream. A recent systematic review showed that all but one of 48 relevant studies reported significant elevations of dd-cfDNA at the time of biopsy-proven AR (BPAR), with successful treatment of AR resulting in restoration of dd-cfDNA levels back to baseline. Furthermore, a rise in dd-cfDNA can be detected before the clinical manifestations of rejection, with elevated levels seen up to a month or more before diagnosis of BPAR in some studies. Using the stability of the marker( a lack of rise) as a means of customising therapy has not been attempted, and our study could provide the rationale for this strategy.
- Being tested
- Tacrolimus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Tacrolimus, Mycophenolate mofetil
reduction of both standard Tacrolimus \& Mycophenolate mofetil does in one arm
| Study group | Role | What they receive |
|---|---|---|
| standard of care Immunosuppression (SOC-IS) therapy | Other | serum tacrolimus level : target tacrolimus levels 8-12ng/ml in the first 3 months target tacrolimus levels 6-8ng/ml in months 4-12 target tacrolimus level 4-8ng/ml after the 1st year
Mycophenolate mofetil dose :
2g/day for 1 month 1.5mg/day between months 2-12
1g/day after the 1st year Receives: Drug: Tacrolimus |
| minimised immunosuppression (Min-IS) therapy | Other | serum tacrolimus level : target tacrolimus levels 6-8ng/ml for first 3 months target tacrolimus levels 4-8ng/ml in months 4-12.
Mycophenolate mofetil dose:
1.5g/day in the first month
1g/day until 1 year post-transplantation Receives: Drug: Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
CMV viraemia
Incidence of CMV viraemia as defined as any detectable virus by (PCR) above the threshold of 200 copies/ml in 1st year
Measured: one year
Secondary outcomes (1)
Incidence of biopsy-proven acute rejection
1.Incidence of biopsy-proven acute rejection by 12 months after randomization
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Oct 2021
- Study start20 Feb 2023 (estimated)
- Primary completion20 Feb 2027 (estimated)
- Study completion20 Feb 2027 (estimated)
Why it stopped: Funding not secured
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal Transplant RejectionStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The investigators propose to conduct the study in two phases. Phase I will randomise renal transplant recipients over the age of 60yrs to either standard of care Immunosuppression (SOC-IS) or minimised immunosuppression (Min-IS) therapy, with monitoring of plasma dd-cfDNA levels over the first post-transplant year. There will be different target drug levels for tacrolimus: SOC-IS target levels of 8-12ng/ml in the first 3 months, 6-8ng/ml in months 4-12 and 4-8ng/ml after the 1st year; Min-IS levels 6-8ng/ml for first 3 months and 4-8ng/ml in months 4-12, For mycophenolate there will be two doses used: SOC-IS dose starting at 2g/day for 1 month, then 1.5mg/day between months 2-12, and then 1g/day after the 1st year; for Min-IS 1.5g/day in the first month and then 1g/day until 1 year post-transplantation. Outcomes will be assessed by the end of year 1
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05073822
- Sponsor's protocol ID
- 140986
- Status last verified
- May 2023
- First submitted
- 16 Sep 2021
- Last updated
- 11 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase III, Randomised, Single-site Trial on the Minimisation of Immunosuppression In Elderly Renal Transplant Recipients.
- ClinicalTrials.gov ID
- NCT05073822
- Acronym / sponsor ID
- 140986
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Funding not secured
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Study start
- 20 Feb 2023 (estimated)
- Primary completion
- 20 Feb 2027 (estimated)
- Study completion
- 20 Feb 2027 (estimated)
- First posted
- 12 Oct 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Kidney transplantation provides the optimal form of kidney replacement therapy for the majority of people with end-stage kidney disease, and has now become the commonest form of kidney replacement therapy. However, donor and recipient demographics have changed considerably over the past few decades: increasingly older donor kidneys are transplanted into progressively older recipients with greater comorbidities. Increasing age remains a major risk factor for death after kidney transplantation, with the commonest causes of deaths for recipients aged 70 and over being cardiovascular, infection, and malignancies. Immunosuppressant drugs which are critical for the maintenance of the transplanted organ can contribute to increased morbidity and mortality, by direct effects or through lowered immunity predisposing to infection. Cytomegalovirus (CMV) is one of the most common opportunistic infections that affects renal transplant patient outcome and can be monitored prospectively. Hence, minimising immunosuppression, especially in older recipients, may result in better graft and patient outcomes as many side-effects are dose dependant. However, to date drug doses have never been adjusted based on age, despite significant changes that occur to immune responsiveness as patients grow older. In addition , researchers have not had a biomarker to help define appropriate immunosuppressive levels for each individual.
The investigators therefore aim to study the effect of reducing the target immunosuppression drug levels( of tacrolimus and mycophenolate) in kidney transplant recipients >60 years, using CMV viraemia as a main outcome measure, and investigating rates of rejection and development of de novo donor-specific anti-HLA antibodies. The investigators will assess the clinical utility of donor-derived cell free DNA (dd-cfDNA) as a means to guide immunosuppression minimisation. The investigators propose that the use of lower doses of immunosuppression will result in fewer infection-related complications, translating to improved patient outcomes. The research will be carried out in kidney transplant centres where prospective CMV monitoring is practiced.
Detailed description
Older kidney transplant recipients are at increased risk of infection and death from infectious causes compared to younger transplant recipients, and despite knowledge of age related immunological changes, the immunosuppressive protocol for older recipients was not yet adjusted. Our provisional data suggest that standard dose immunosuppression in the older patients results in more infections and fewer rejection episodes. Achieving a better balance by reducing risk of infection would be highly desirable. Defining age-specific target drug levels and doses should therefore be tested in a formal trial to establish its validity.
Transplant recipients are especially at risk from viral and opportunistic infections; CMV is a particular problem, as infections can be both donor-derived or due to re-activation of latent virus in the recipient. In the transplant population, CMV infection can cause significant morbidity, including bone marrow suppression, pneumonitis, colitis, retinitis and encephalitis, and as a consequence, increased mortality. However, as this will be measured prospectively, it can also be utilised as a marker of the degree of ( over) immunosuppression in our patients.
There are no current recommendations regarding optimal dose or target drug levels, and importantly, no age-specific standards. This trial could provide some specific recommendations.
There is an increasing body of evidence that demonstrates age-related changes to the immune system, termed immunosenescence, characterized by reduced responsiveness to both newly and previously encountered antigens. In transplantation, it is thought that such immunosenescence may influence both the immune response of the recipient and the immunogenicity of the donor organ. Understanding if this is in any way related to physical frailty may be helpful in informing patients of risk of transplantation.
Donor-derived cell-free DNA (dd-cfDNA) detected in the plasma of transplant recipients has been increasingly reported as a noninvasive biomarker of acute rejection(AR)-with transplant organ damage leading to release of more of the donor DNA into the bloodstream. A recent systematic review showed that all but one of 48 relevant studies reported significant elevations of dd-cfDNA at the time of biopsy-proven AR (BPAR), with successful treatment of AR resulting in restoration of dd-cfDNA levels back to baseline. Furthermore, a rise in dd-cfDNA can be detected before the clinical manifestations of rejection, with elevated levels seen up to a month or more before diagnosis of BPAR in some studies. Using the stability of the marker( a lack of rise) as a means of customising therapy has not been attempted, and our study could provide the rationale for this strategy.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- The investigators propose to conduct the study in two phases. Phase I will randomise renal transplant recipients over the age of 60yrs to either standard of care Immunosuppression (SOC-IS) or minimised immunosuppression (Min-IS) therapy, with monitoring of plasma dd-cfDNA levels over the first post-transplant year. There will be different target drug levels for tacrolimus: SOC-IS target levels of 8-12ng/ml in the first 3 months, 6-8ng/ml in months 4-12 and 4-8ng/ml after the 1st year; Min-IS levels 6-8ng/ml for first 3 months and 4-8ng/ml in months 4-12, For mycophenolate there will be two doses used: SOC-IS dose starting at 2g/day for 1 month, then 1.5mg/day between months 2-12, and then 1g/day after the 1st year; for Min-IS 1.5g/day in the first month and then 1g/day until 1 year post-transplantation. Outcomes will be assessed by the end of year 1
| Arm | Type | Receives |
|---|---|---|
| standard of care Immunosuppression (SOC-IS) therapy | Other | Drug: Tacrolimusserum tacrolimus level : target tacrolimus levels 8-12ng/ml in the first 3 months target tacrolimus levels 6-8ng/ml in months 4-12 target tacrolimus level 4-8ng/ml after the 1st year Mycophenolate mofetil dose : 2g/day for 1 month 1.5mg/day between months 2-12 1g/day after the 1st year |
| minimised immunosuppression (Min-IS) therapy | Other | Drug: Tacrolimusserum tacrolimus level : target tacrolimus levels 6-8ng/ml for first 3 months target tacrolimus levels 4-8ng/ml in months 4-12. Mycophenolate mofetil dose: 1.5g/day in the first month 1g/day until 1 year post-transplantation |
Who may qualify
- Ages
- 60 to 85 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Participant must be first time adult recipients of either a deceased or living donor kidney transplant.
- Participant must be a recipient of a single organ transplant only.
- Participant must be above the age of 60 years.
- Participant must have a negative screen for donor-specific antibody prior to transplantation (MFI<2000).
Key exclusion criteria (5 listed)
- Recipients of a transplant who are highly sensitised (cRF >85%).
- Inability to participate in frequent monitoring of renal transplant function and clinical visits (every 4 weeks) during dd-cfDNA monitoring and IS minimisation.
- Participants with immune-mediated renal disease in which IS minimisation is inadvisable.
- EBV negative recipient (as IS minimisation is part of standard protocol)
- Inability to comply with study directed treatment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: Tacrolimus, Mycophenolate mofetilreduction of both standard Tacrolimus \& Mycophenolate mofetil does in one arm | Drug | minimised immunosuppression (Min-IS) therapy, standard of care Immunosuppression (SOC-IS) therapy |
Primary outcome
CMV viraemia
Time frame: one year
Incidence of CMV viraemia as defined as any detectable virus by (PCR) above the threshold of 200 copies/ml in 1st year
1 secondary outcome
Incidence of biopsy-proven acute rejection
Time frame: 1 year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Tacrolimus in people with Renal Transplant Rejection and Renal Transplant Infection, run by University College, London.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 11 May 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CMV viraemia (time frame: one year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2023.