TOCILIZUMAB for Chronic active antibody-mediated rejection (kidney transplant recipients)

Inclusion criteria

• {"criterion_text":"- The subject has given their written informed consent to participate in the trial.\n- Recipient of living donor or deceased donor kidney transplant\n- Age ≥18 years\n- At least 6 months post-transplantation at randomization\n- Biopsy-proven diagnosis of late active (≥ 6 months posttransplant) or chronic active AMR according to the Banff 2022 criteria in index biopsy [Repeat biopsy and DSA-testing if required for diagnosis should be performed 2 months ± 2 weeks if the patient has received any treatment for AMR after the initial diagnostic biopsy or at randomization if the last biopsy is older than 12 months (+ 2 weeks) at randomization (Visit 2)].\n- eGFR ≥20 ml/min/1.73 m2 (not older than 1 month at randomization).\n- EBV IgG-positive\n- For female participants of childbearing potential: use of adequate contraception and a negative pregnancy test\n- Subject known to have been previously had COVID-19 must meet the following conditions: •\tAsymptomatic for at least 1 month before screening visit •\tRe-established on background immunosuppressants for at least 1 month prior to randomization"}

Exclusion criteria

• {"criterion_text":"- Recipient of multi-organ transplants\n- De novo or recurrent renal disease, if it is considered to be the predominant cause of the current graft dysfunction\n- Active viral infections such as BK virus (BKV), cytomegalovirus (CMV), SARS COV-2 (COVID-19), EBV, hepatitis C virus (HCV) or hepatitis B virus (HBV) infections, based on polymerase chain reaction (PCR) testing\n- Ongoing serious infections as per Investigator’s opinion\n- History of recurrent serious infections requiring hospitalization\n- Signs of post-transplant lymphoproliferative disorder\n- Active tuberculosis (TB)\n- Untreated latent TB (positive QuantiFERON-TB-Gold test, Chest X-ray)\n- Abnormal liver function tests alanine transaminase (ALT), aspartate transaminase (AST), bilirubin > 1.5 x upper limit of normal)\n- Other significant liver disease as per Investigator’s opinion\n- Neutropenia (<2 x109/L) or thrombocytopenia (<100 x109/L)\n- Signs of malignancy. Exceptions are basal cell carcinoma/squamous cell carcinoma or non-malignant melanoma\n- History of malignancy, unless subject has been considered to have fully recovered from malignancy since > 2 years, without any signs of relapse\n- History of diverticulitis, inflammatory bowel disease (IBD) or gastrointestinal perforation\n- Ongoing alcohol or illicit substance abuse\n- Serious medical or psychiatric illness likely to interfere with participation in the study as per Investigator’s opinion\n- Mental inability or reluctance that result in difficulties in understanding the meaning of study participation\n- 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 trial drug\n- Woman with a positive pregnancy test or who is pregnant or breastfeeding\n- Current or recent (within last 3 months) participation in another clinical drug trial"}

Primary endpoints

• {"endpoint_text":"- The primary efficacy endpoint is mean rate of change in eGFR decline from baseline to 24 months after start of treatment and at 1 month, then every 3 months for 36 months, and evaluating the results as a continuous variable using Modification of Diet for Renal Disease (MDRD) 4-variable equation, as it has been shown to better predict kidney function in kidney transplant recipients especially at low level of kidney function. Testing will be performed directly by accredited chemistry laboratories","definition_or_measurement_approach":"Mean rate of change in eGFR decline from baseline to 24 months after start of treatment; eGFR calculated using MDRD 4-variable equation; testing performed by accredited chemistry laboratories; assessments at 1 month, then every 3 months up to 36 months."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in mean composite iBox risk score at 12 and 24 months after start of treatment","definition_or_measurement_approach":"Change from baseline in composite iBox risk prediction score at 12 and 24 months"}
• {"endpoint_text":"- Safety: incidence, nature and severity of adverse events (AE) and serious AE (SAE) during 24 months of treatment period","definition_or_measurement_approach":"Incidence, nature and severity of AEs and SAEs recorded during 24-month treatment period"}
• {"endpoint_text":"- Evolution of DSA, as assessed by appearance of new DSA, and change in strength of both immunodominant (iDSA) and cumulative DSA (cDSA), measured as MFI, from baseline at 12, 24 and 36 months after start of treatment","definition_or_measurement_approach":"Appearance of new DSA and change in MFI for iDSA and cDSA at 12, 24 and 36 months"}
• {"endpoint_text":"- Histologic changes from baseline in protocol biopsy at 12 and 24 months after start of treatment","definition_or_measurement_approach":"Comparison of graft histology from protocol biopsies at baseline vs 12 and 24 months"}
• {"endpoint_text":"- Changes from baseline in proteinuria at 12, 24 and 36 months after start of treatment, as assessed by urine albumin/creatinine ratio (UACR)","definition_or_measurement_approach":"UACR measurements at 12, 24 and 36 months"}
• {"endpoint_text":"- Changes from baseline in renal function at 12, 24 and 36 months after start of treatment, as assessed by mGFR using iohexol clearance","definition_or_measurement_approach":"Measured GFR by iohexol clearance at 12, 24 and 36 months"}
• {"endpoint_text":"- Changes from baseline in renal function at 12 and 36 months after start of treatment, as assessed by eGFR","definition_or_measurement_approach":"eGFR assessments at 12 and 36 months"}
• {"endpoint_text":"- Incidence of patient survival at 12, 24 and 36 months after start of treatment","definition_or_measurement_approach":"Patient survival incidence at specified timepoints"}
• {"endpoint_text":"- Incidence of graft survival (overall and death-censored) at 12, 24 and 36 months after start of treatment","definition_or_measurement_approach":"Graft survival (overall and death-censored) incidence at 12, 24 and 36 months"}
• {"endpoint_text":"- Incidence of acute rejection (overall and by biopsy‐proven/clinical diagnosis), its type and Banff-grade if biopsy-proven at 12, 24 and 36 months after start of treatment","definition_or_measurement_approach":"Incidence of acute rejection, classification by biopsy-proven/clinical diagnosis, type and Banff grade at 12, 24, 36 months"}
• {"endpoint_text":"- Incidence and Banff-grade of new chronic active T-cell mediated rejection at 12, 24 and 36 months after start of treatment","definition_or_measurement_approach":"Incidence and Banff grade of new chronic active T-cell mediated rejection at specified timepoints"}
• {"endpoint_text":"- Experienced transplant-specific well-being, symptom burden, perceived threat of the risk of graft rejection and adherence to immunosuppressive medications at baseline,12, 24 and 36 months after start of treatment, and possible changes from baseline at each time-point as well as in comparison with other transplant recipients not suffering","definition_or_measurement_approach":"Patient-reported outcomes and adherence assessments at baseline, 12, 24 and 36 months; comparisons with other transplant recipients not suffering from AMR"}
• {"endpoint_text":"- Sex-, occupation-, civil- and educational status-related differences in transplant-specific well-being, symptom burden, perceived threat of the risk of graft rejection and adherence to immunosuppressive medications at baseline, 12, 24 and 36 months as well as in comparison with other transplant recipients not suffering","definition_or_measurement_approach":"Subgroup analyses of PROs and adherence by sex, occupation, civil and educational status at specified timepoints"}

Sweden

Earliest CTIS Part Ii Submission Date

04-01-2024

Latest Decision Or Authorization Date

16-08-2025

Processing Time Days

590

Number Of Sites

3

Number Of Participants

35

Spain

Earliest CTIS Part Ii Submission Date

31-10-2024

Latest Decision Or Authorization Date

11-03-2025

Processing Time Days

131

Number Of Sites

4

Number Of Participants

15

Primary sponsor

Full Name

Vaestra Goetalandsregionen

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Sweden