TAR:GET-1

Transplant Antibody-Mediated Rejection: Guiding Effective Treatments

Research summary

Kidney transplantation is the treatment of choice for most patients with end-stage kidney disease (ESKD), resulting in improved health and patient survival, quality of life and health economic benefit in comparison to remaining on dialysis. The use of current immunosuppression regimens, along with careful immunological selection of transplant recipients, has improved short term renal allograft survival over recent decades. However, long term allograft survival has remained unchanged, with the average lifespan of a kidney transplant being up to 15 years. Chronic antibody-mediated rejection (chronic AMR) remains the leading cause of allograft failure and one of the commonest causes of ‘ESKD’ as patients with failed allografts have to return to dialysis and the transplant wait list. Of the 7% of patients who will experience acute AMR in the first-year post-transplant, half (3.5%) will develop histological evidence of chronic AMR within one year. Despite its impact on the development of chronic AMR and graft failure, the current evidence comes from one under-powered randomised controlled trial and several cohort studies to guide treatment of acute AMR. Existing treatments are expensive and their use by UK and international transplant centres is, at best, driven by anecdotal evidence, clinical experience and resources, and at worst, determined by chance. There is an urgent need to provide high-quality data on the safety and effectiveness of treatments currently used in the UK to treat acute AMR.

Contemporary treatment for acute AMR is heterogeneous and includes plasma exchange (PEX), intravenous immunoglobulin (IVIg), glucocorticoids, anti-thymocyte globulin (ATG), rituximab, bortezomib and eculizumab. These treatments are used in differing combinations depending upon local experience, physician preference and resources. Clinical practice guidelines published by the British Transplant Society (BTS) and Kidney Disease Improving Global Outcomes (KDIGO) initiative have concluded that firm recommendations of optimal treatments could not be provided given a lack of evidence. Treatment for patients presenting with AMR in the UK has been entirely dependent upon the hospital they present to and the clinician they see. This situation is particularly undesirable given the high human and economic cost of treatment failure, and the high side-effect burden and cost most of these treatments confer.

Given the complete lack of evidence to guide treatment of acute AMR and the absence of existing trials of the most promising interventions already in use in UK transplant centres, there is an urgent need to conduct a high quality randomised trial to evaluate efficacy and safety of candidate treatments in the context of the NHS. We propose a 2-arm open-label randomised controlled trial of SOC (consisting of PEX, glucocorticoids and IVIg) versus SOCR for the treatment of acute AMR across the UK transplant centres.

This is a phase 3, open-label, two-arm, randomised, controlled trial designed to evaluate the safety and efficacy of adding rituximab to standard of care (consisting of plasma exchange, intravenous immunoglobulins and corticosteroids) in treating acute antibody-mediated rejection (AMR) in kidney transplantation patients. This is a multi-centre trial and will take place at approximately 24 UK transplant centres. A total of approximately 170 participants with a new diagnosis of acute AMR following their renal transplant will be randomised in a 1:1 ratio to either SOC or SOCR. Paediatric patients 5 years old and older will be eligible to participate. Trial duration will consist of up to 2 weeks for screening, up to a total of 5 weeks of treatment (including rituximab treatment, up to 3 weeks for SOC treatment) and a minimum of 48 months follow-up period. Eligible patients will be permitted to enter the trial up to 2 weeks post-biopsy to allow for diagnosis of AMR confirmation and as long as PEX treatment has not been completed.

clinicaltrials.gov

Main inclusion criteria

  1. Willing and able to give written informed consent by patient aged 16 years and over; or by a parent or legal guardian for patients who are under 16 years old

  2. 5 years old or older

  3. A diagnosis of acute active AMR as defined by:

  4. The presence of ≥1 donor specific antibodies (DSA)

  5. An adequate renal transplant biopsy (≥7 glomeruli and ≥1 artery) with histological features consistent with active AMR with no evidence of chronicity as defined by the Banff histological classification of allograft pathology:

    1. If C4d positive (2 or 3):

      1. v score ≥1 and/or

      2. g score ≥1 and/or

      3. thrombotic microangiopathy and/or

      4. ptc score ≥1

      5. or if co-existent cellular rejection, a g score of ≥1 OR

    2. If C4d negative (0 or 1):

      1. microcirculation inflammatory score (g + ptc) ≥2

      2. or if co-existing cellular rejection, a g score ≥1 and (g + ptc) ≥2 AND

      3. Chronic glomerulopathy (cg) score 0 or 1a

      4. Tubulo-interstitial fibrosis <50% and glomerular obsolescence <50%

Main exclusion criteria

  1. Patients who have received an ABO incompatible transplant

  2. Patients who have received rituximab as part of induction or post-transplant for any other indications (eg. recurrent focal and segmental glomerular sclerosis)

  3. Patients who have received complete PEX treatment prior to the index biopsy on the suspicion of acute AMR in the absence of histology

  4. Have active infection including bacterial, viral (including CMV (cytomegalovirus) and EBV (Epstein-Barr virus)), fungal or tuberculosis, which in the investigator's opinion could affect the conduct of the trial

  5. Co-existing BK (BK virus) nephropathy

  6. Patients with hepatitis B (patients with prior exposure to hepatitis B may be enrolled at the discretion of the PI)

  7. Have active hepatitis C (patients may be included if a negative hepatitis C recombinant immunoblot assay is confirmed or have a negative hepatitis C virus RNA [qualitative] test)

  8. Have suspected human immunodeficiency virus (HIV)

  9. Active malignancy

  10. Patients with known allergy, intolerance or contraindication to treatments in the standard of care arm or rituximab as outlined in the Summaries of Product Characteristics (SmPCs)

  11. Clinically significant comorbidity

  12. Females must be either post-menopausal for at least 1 year, surgically sterile or, if of child-bearing potential, must not be pregnant or lactating. If sexually active, female participants must agree to use an acceptable method of birth control for 12 months post treatment with rituximab. Female participants must also agree not to breastfeed for 12 months post treatment with rituximab.

Chief investigator

Dr Michelle Willicombe

Contact details

Clinical Trials Coordinator: Dr Ashley Foster

Telephone: 01223 216809 | Email: [email protected]