TocIlizumab in Chronic Antibody-mediated Rejection in Kidney Transplant Recipients

Study Overview
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Brief Summary
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This multi-center study is an investigator-driven randomized controlled parallel group open-label clinical trial designed to evaluate the efficacy of addition of anti-IL-6 antibody tocilizumab (TCZ) to the standard of care (SOC) treatment as compared to the SOC alone in reducing the decline of graft function in kidney transplant recipients with chronic antibody-mediated rejection (cAMR). A total of 50 recipients will be allocated to receive either TCZ (n=25) added to the standard of care (SOC) or SOC alone (n=25) for a period of 24 months. Patients will be followed for an additional 12 months. Protocol kidney graft biopsies will be performed at 12 and 24 months. The primary outcome is the mean rate of change in graft function as assessed by estimated glomerular filtration rate (eGFR) slope from baseline to 24 months after start of treatment.

Official Title
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A Randomized Controlled Open-label Multi-center Study to Assess the Efficacy of TCZ in Treatment of Chronic Active Antibody-mediated Rejection in Kidney Transplant Recipients

Conditions
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Antibody-mediated Rejection

Intervention / Treatment
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* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has given their written informed consent to participate in the study Recipient of living donor or deceased donor kidney transplant Age ≥18 years At least 12 months post-transplantation at randomization Biopsy-proven diagnosis of cAMR according to the Banff 2017 criteria in index biopsy eGFR ≥20 ml/min/1.73 m2 Epstein-Barr Virus (EBV) IgG-positive For female participants of childbearing potential: use of adequate contraception and a negative pregnancy test Subject known to have COVID-19 previously must meet all of the following conditions: Asymptomatic for at least 1 month before the start of screening Re-established on background immunosuppressants for at least 1 month prior to the randomization Exclusion Criteria: Inability to tolerate any of the SOC treatment- tacrolimus, mycophenolate acid (MPA) or prednisolone Recipient of multi-organ transplants De novo or recurrent renal disease that is considered to be the predominant cause of the current graft dysfunction Active viral infections such as BK virus (BKV), cytomegalovirus (CMV), EBV, COVID-19, hepatitis C virus (HCV) or hepatitis B virus (HBV) infections based on polymerase chain reaction (PCR) testing Ongoing serious infections as per Investigator's opinion History of recurrent infections requiring hospitalization History of tuberculosis (TB) Active TB or latent TB (positive QuantiFERON-TB-Gold test, Chest X-ray) Abnormal liver function tests alanine transaminase (ALT), aspartate transaminase (AST), bilirubin > 1.5 x upper limit of normal) Other significant liver disease as per Investigator's opinion Neutropenia (<2 x109/L) or thrombocytopenia (<100 x109/L) Signs of post-transplant lymphoproliferative disorder Signs of malignancy. Exceptions are basal cell carcinoma/squamous cell carcinoma or non-malignant melanoma History of malignancy, unless subject has been considered to have fully recovered from malignancy since > 2 years, without any signs of relapse History of diverticulitis, inflammatory bowel disease or gastrointestinal perforation Active alcohol or illicit substance abuse Serious medical or psychiatric illness likely to interfere with participation in the study as per Investigator's opinion Mental inability that results in difficulties in understanding the meaning of study participation Woman of childbearing potential who is unwilling/unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug Woman with a positive pregnancy test or who is pregnant or breastfeeding Current or recent (within last 3 months) participation in another clinical drug trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Standard of care (SOC) + tocilizumab (TCZ)<br>SOC, as below + TCZ (162 mg every week, subcuataneous administration) | Drug: Tocilizumab<br>* Tocilizumab is a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor<br>* Other names: RoActemra;|
| No Intervention: Arm B: SOC<br>Tacrolimus (target concentration 6 ±1 µg/L) + MPA (1.5-2 g/day as tolerated) + prednisolone (not less than 5 mg/day), all oral administration | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in eGFR at 24 months | Comparison of eGFR decline (eGFR slope) from baseline at 24 months after start of treatment in the two arms. The eGFR will be assessed by measured creatinine values using MDRD formula in mL/min/1.73m^2. MDRD formula is based on age, sex, ethnicity, and serum creatinine (in mg/dl) and eGFR values are calculated as follows: GFR in mL/min per 1.73 m^2 = 175 x Serum Cr^1.154 x age^-0.203 x 1.212 (if patient is black) x 0.742 (if female). | Baseline and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite risk prediction score iBox | Efficacy of the treatment regimen by assessing the iBox score | baseline and upto 24 months | 
| Incidence of adverse and serious events related to TCZ treatment | Assessments of incidence of any side effects including infectious complications associated with TCZ therapy | up to 25 months | 
| Change in Donor-specific anti-HLA antibodies (DSA) | Change in DSA from baseline based on luminex assessments every 12 months | baseline and up to 36 months | 
| Histologic changes in protocol biopsy | Histologic changes at 12 and 24 months will be compared with those in the baseline biopsies. If the criteria for cAMR are no longer fulfilled in the follow-up biopsies, response to therapy is assumed. The response will be assessed as a yes/no categorical variable. In all biopsies, which still meet the required criteria for cAMR, means of individual Banff lesion scores will be compared between the baseline biopsy and the 12- and 24-months biopsies | baseline and up to 24 months | 
| Changes in proteinuria | Assessed by urine albumin creatinine ratio (UACR) at baseline and every 12 months | baseline and up to 36 months | 
| Renal function assessed by measured GFR (mGFR) | Changes from baseline in renal function as assessed by mGFR using iohexol clearance | baseline and up to 36 months | 
| Renal function assessed by eGFR | Changes from baseline in renal function at 12 and 36 months after start of treatment, as assessed by eGFR (CKD-EPI) | baseline and up to 36 months | 
| Patient survival | Incidence of patient survival at 12, 24 and 36 months after start of treatment | up to 36 months | 
| Death-censored graft survival | Incidence of death-censored graft survival at 12, 24 and 36 months after start of treatment | up to 36 months | 
| Possible change in experienced transplant-specific well-being and symptom burden | Assessed using a validated self-reported questionnaires at baseline and every 12 months | upto 36 months | 
| Possible change in experienced perceived threat of the risk of graft rejection | Assessed using a validated self-reported questionnaires at baseline and every 12 months | upto 36 months | 
| Possible change in adherence to immunosuppressive medications | Assessed using a validated self-reported questionnaires at baseline and every 12 months | upto 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adherence, Kidney transplant, Chronic rejection, Antibody-mediated rejection, Graft function, Donor specific antibodies (DSA), Transplant-specific well-being