NOMINATE/ Minimisation of Immunosuppression in Kidney Transplantation

NCT05073822 | Withdrawn Phase 1 DMC

• 1 other identifier: 140986
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief 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. 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.

Conditions

Renal Transplant Rejection; Renal Transplant Infection

Outcome Measures

Primary Outcomes (1)

• CMV viraemia

  Incidence of CMV viraemia as defined as any detectable virus by (PCR) above the threshold of 200 copies/ml in 1st year

  one year

Secondary Outcomes (1)

• Incidence of biopsy-proven acute rejection

  1 year

Study Arms (2)

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

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

Drug: Tacrolimus

Interventions

Tacrolimus DRUG

reduction of both standard Tacrolimus \& Mycophenolate mofetil does in one arm

Also known as: Tacrolimus, Mycophenolate mofetil

minimised immunosuppression (Min-IS) therapy; standard of care Immunosuppression (SOC-IS) therapy

Eligibility Criteria

• Age: 60 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• University College, London: lead

MeSH Terms

Interventions

Tacrolimus; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: September 16, 2021
• First Posted: October 12, 2021
• Study Start: February 20, 2023
• Primary Completion (Estimated): February 20, 2027
• Study Completion (Estimated): February 20, 2027
• Last Updated: May 11, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share