Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Liver Transplant Recipients With Additional 12-month Follow-up and Long-term Extension

Study Overview
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Brief Summary
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The purpose of this study was to investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of two CFZ533 dose regimens in liver transplant recipients.

Detailed Description
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This study allowed assessment of the ability of CFZ533 to replace Calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while providing potentially better renal function with an expected similar safety and tolerability profile. Results of this study will inform the CFZ533 dose and regimen selection for investigation in later phases of clinical development.

Official Title
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A 12-month, Open-label, Multicenter, Randomized, Safety, Efficacy, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Two Regimens of Anti-CD40 Monoclonal Antibody, CFZ533 vs. Standard of Care Control, in Adult de Novo Liver Transplant Recipients With a 12-month Additional Follow-up and a Long-term Extension (CONTRAIL I)

Conditions
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Liver Transplant Rejection

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening period up to liver transplantation: -Written informed consent obtained before any assessment. Male or female subjects between 18 to 70 years of age. Recipients of a primary liver transplant from a deceased donor. Up to date vaccination as per local immunization schedules. Recipients tested negative for HIV. MELD score ≤30. At randomization: Recipients with no active HCV and HBV replication (no detectable RNA/DNA by PCR). Allograft is functioning at an acceptable level by the time of randomization as defined by AST, ALT, Alkaline Phosphatase levels ≤ 5 times ULN and Total bilirubin ≤ 2 times ULN. Renal function (eGFR, MDRD-4 formula) ≥ 30 mL/min/1.73 m2 based on most recent post-transplant value prior to randomization. Exclusion Criteria: Screening period up to liver transplantation: Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or of a split liver. A negative Epstein Barr virus (EBV) test. Recipients receiving an ABO incompatible allograft. History of malignancy of any organ system treated or untreated, within the past 5 years. Hepatocellular carcinoma that does not fulfill Milan criteria. Recipients transplanted for acute liver failure. Any use of antibody induction therapy, or use of any immunosuppressive medications Patients who have received a live vaccine within four weeks prior to transplantation. Recipients with donors HIV positive, HBsAg positive, HCV positive. Recipients with donors with hepatic steatosis > 30%. At randomization: Any post-transplant history of thrombosis, occlusion or stent placement in any hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period prior to randomization. Recipients with platelet count < 50,000/mm3, an absolute neutrophil count of < 1,000/mm³ or white blood cell count of < 2,000/mm³. Recipients with clinically significant systemic infection requiring use of intravenous (IV) antibiotics. Evidence of active tuberculosis (TB) infection. Any episode of acute rejection or suspected rejection prior to randomization. HCC participants whose explanted liver graft pathology report shows i) pTNM stage beyond T2N0M0, ii) presence of mixed carcinoma, iii) microvascular invasion despite pTNM stage. Participants with body weight &lt; 30 kg or &gt; 180 kg.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 CCFZ533A2202 is a randomized, 12-month, active-controlled, multicenter, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD of CFZ533, as compared to standard of care comprised of tacrolimus, MMF and corticosteroids, with a 12-month additional follow up.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Control/Standard of Care: TAC + MMF + Corticosteroids | Drug: Tacrolimus - MMF - corticosteroids<br>* Standard of care immunosupprevive regimen<br>|
| Experimental: Arm 2<br>CFZ533 600mg dose + MMF + Corticosteroids | Biological: CFZ533<br>* Comparison with standard of care immunosuppression<br>|
| Experimental: Arm 3<br>CFZ533 300mg dose + MMF + Corticosteroids | Biological: CFZ533<br>* Comparison with standard of care immunosuppression<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) over 12 months | Rate of composite efficacy failure | Baseline to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To mean eGFR up to Month 24 post-transplantation | Renal function at Month 24 measured by Estimated Glomerular Filtration Rate (eGFR) | Baseline to month 24 | 
| Proportion of patients with AEs and SAEs | Proportion of patients with AEs, SAEs, AEs related to study drug | Baseline to month 12 and month 24 | 
| Proportion of patients with premature discontinuation from study and premature discontinuation of study drug | Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment | Baseline to month 12 and month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, de novo recipients, deceased donor, CFZ533, CNI-free immunosuppression, Transplant rejection