Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Kidney Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of three CFZ533 dose regimens in kidney transplant recipients. This study will allow assessment of the ability of CFZ533 to replace Calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while providing better renal function with a better safety and tolerability profile. Results of this study will be used to inform the CFZ533 dose and regimen selection for investigation in later phases of clinical development.

Official Title
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A Partially-blinded, Active-controlled, Multicenter, Randomized Study Evaluating Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in de Novo and Maintenance Kidney Transplant Recipients (CIRRUS I)

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Biological: CFZ533 - MMF - CS
* Drug: Tacrolimus - MMF - +/- corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained before any assessment. Male or female patient ≥ 18 years old. Up to date vaccination as per local immunization schedules. Recipients of a kidney transplant Recipients of a primary kidney transplant from a heart-beating deceased, living unrelated or non-HLA identical living related donors. Exclusion Criteria: Multi-organ transplant recipients or prior kidney transplant. Recipients of an organ from a non-heart beating donor. Recipient of an organ from an HLA identical living related donor. ABO incompatible or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant Recipients of kidneys from donors who are older than 65 years. Recipients of kidneys from donors with terminal serum creatinine > 2 mg/dL. Patients at high immunological risk for rejection Patient who is anti-HIV positive, HBsAg-positive or anti-HCV positive (without proof of sustained viral response (SVR) after anti-HCV treatment). Recipient of a kidney from a donor who tests positive for HIV, HBsAg/HBc positive or HCV. A negative Epstein Barr virus (EBV) test. Evidence of advanced liver disease (Child-Pugh C), or any sign of liver decompensation. Patient with severe systemic infections, current or within the two weeks prior to randomization. History of malignancy of any organ system, treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, with the exception of localized excised non-melanomatous skin lesions.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Study CCFZ533A2201 is a randomized, 60-month, active-controlled, partially-blinded, multicenter, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD of CFZ533 in 2 different cohorts, as compared to standard of care comprised of tacrolimus, MMF and corticosteroids.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1/Cohort 1<br>CFZ533 dose A+ MMF + Corticosteroids | Biological: CFZ533 - MMF - CS<br>* Comparison with standard of care immunosuppression<br>|
| Experimental: Arm 2/Cohort 1<br>CFZ533 dose B + MMF + Corticosteroids | Biological: CFZ533 - MMF - CS<br>* Comparison with standard of care immunosuppression<br>|
| Active Comparator: Arm 3/Cohort 1<br>Control/Standard of Care: TAC + MMF + Corticosteroids | Drug: Tacrolimus - MMF - +/- corticosteroids<br>* Standard of care immunosupprevive regimen<br>|
| Experimental: Arm 1/Cohort 2<br>CFZ533 dose C + MMF ± Corticosteroids | Biological: CFZ533 - MMF - CS<br>* Comparison with standard of care immunosuppression<br>|
| Active Comparator: Arm 2/Cohort 2<br>Tac + MMF ± Corticosteroids | Drug: Tacrolimus - MMF - +/- corticosteroids<br>* Standard of care immunosupprevive regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with composite event (BPAR, Graft Loss or Death) | Cohorts 1 and 2-Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1 and 2-Mean eGFR over 12 months | Renal function at Month 12 | Baseline to month 12 | 
| Cohorts 1 and 2-Cohorts 1 and 2-safety of CFZ533 regimens compared to a tacrolimus based regimen | Proportion of patients with AEs, SAEs, infections, malignancies, thromboembolic events, major adverse cardiovascular events, new onset diabetes mellitus (NODM). | Baseline to month 12 | 
| Cohorts 1 and 2-Cohorts 1 and 2 - tolerability of CFZ533 regimens compared to a tacrolimus based regimen | Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment | Baseline to month 12 | 
| Cohorts 1 and 2-pharmacokinetics of CFZ533 during the 60 months treatment period and explore the dose-exposure relationship | Free CFZ533 plasma concentrations over time | Baseline to month 60 | 
| Cohorts 1 and 2-immunogenicity of CFZ533 during the 60 months treatment period | Semi-quantitative analysis of anti-CFZ533 antibodies in plasma | Baseline to month 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, CFZ533, CNI-free immunosuppression, transplant rejection, allograft rejection.