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 (CONTRAIL I)

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 Additionalr Follow-up and a Long-term Extension (CONTRAIL I)

This was a multicenter, open-label, active-controlled study to evaluate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of two CFZ533 maintenance doses in de novo liver transplant recipients.

Study Overview

• Status: Terminated
• Conditions: Liver Transplant Rejection
• Intervention / Treatment: Biological: CFZ533; Drug: Tacrolimus - MMF - corticosteroids

Detailed Description

The study was designed as a randomized, 36-month clinical trial comprised of:

• A screening period (up to 2 months) starting from informed consent, screening visit, and including successful liver transplantation (LTx).
• A run-in treatment period following successful transplantation that ended on the day of randomization or randomization failure, at Day 8 (with visit window of +/- 2 days) post-LTx.
• The primary treatment period (Treatment Period 1) starting at randomization Day 8 +/- 2 post-LTx up to Month 12 followed by a 12-month follow-up treatment period (Treatment Period 2) until Month 24.
• The long-term extension period (Treatment Period 3) starting post Month 24 until the end of the study (EOS).
• A minimum 12-week safety follow-up period for all patients after EOS.

The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1280AEB
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1181ACH
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1118AAT
      • Novartis Investigative Site
• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Czechia
  • Prague 4, Czechia, 146 24
    • Novartis Investigative Site
• France
  • Chambray les Tours, France, 37170
    • Novartis Investigative Site
  • Lille, France, 59037
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Villejuif, France, 94805
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
• Italy
  • PI
    • Pisa, PI, Italy, 56124
      • Novartis Investigative Site
• Netherlands
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 GD
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28009
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Aurora
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Michigan
    • Detroit, Michigan, United States, 48202 2689
      • Henry Ford Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Wash U School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univ Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina MUSC
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

Screening period up to liver transplantation:

• Written informed consent obtained before any assessment.
• Male or female patients 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.
• Transplantation to occur within defined screening period following informed consent signature.

At randomization (Day 8 +/- 2):

• Recipients with no active HCV and HBV replication.
• Allograft is functioning at an acceptable level by the time of randomization as defined by AST, ALT and 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.
• Recipients who have been initiated on an immunosuppressive regimen that contains TAC, mycophenolate mofetil (MMF) and corticosteroids (CS) as per protocol.

Key Exclusion Criteria:

Screening period up to liver transplantation:

• Use of other investigational drugs at screening within 30 days or 5 half-lives of screening.
• Recipients of multiple solid organ or islet cell transplants, or recipients that have previously received a tissue transplant, or a combined liver-kidney transplant.
• Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or of a split liver.
• Recipient who tested negative for Epstein Barr virus (EBV) within 28 days prior to baseline visit.
• Recipients receiving an ABO incompatible allograft.
• History of malignancy of any organ system (except hepatocellular carcinoma (HCC) or localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there was evidence of local recurrence or metastases.
• Hepatocellular carcinoma that did not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3 nodules all ≤ 3 cm, without evidence of metastatic disease or vascular invasion) at the time of transplantation.
• Recipients transplanted for acute liver failure (does not apply to acute on chronic liver failure).
• Any use of antibody induction therapy, or use of any immunosuppressive medications (or other medications prohibited by the protocol).
• Patients who have received a live vaccine within four weeks prior to transplantation.
• Recipients with HIV positive donor.
• Recipients with donors HBsAg positive.
• Recipients who were HCV antibody-positive without documented sustained viral response (SVR) at 12 weeks after finishing anti HCV treatment (e.g., direct-acting antivirals).
• Recipients with HCV RNA-positive donors.
• Recipients with donors with macrovesicular steatosis > 30%.
• Pregnant or nursing (lactating) women.

At randomization (Day 8 +/- 2):

• 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. Absence of any graft vascular thrombosis or occlusion (by diagnostic method used at the site to assess vascular patency) must be confirmed by imaging prior to randomization.
• Recipients with platelet count < 50,000/mm3.
• Recipients with 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.
• Recipients who are in a critical care setting at the time of randomization requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents.
• Recipients who were on renal replacement therapy at randomization.
• Any episode of acute rejection or suspected rejection prior to randomization.
• HCC patients whose explanted liver graft pathology report shows (i) pathologic Tumor-Node-Metastasis (pTNM) stage beyond T2N0M0, (ii) presence of mixed carcinoma, (iii) microvascular invasion despite pTNM stage.
• Patients with body weight < 30 kg or > 180 kg.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TAC Control; Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.	Drug: Tacrolimus - MMF - corticosteroids; Standard of care immunosuppresive regimen
Experimental: CFZ533 600 mg regimen; Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.	Biological: CFZ533; Comparison with standard of care immunosuppression
Experimental: CFZ533 300 mg regimen; Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.	Biological: CFZ533; Comparison with standard of care immunosuppression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months	The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation.	Baseline to Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12	Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if Black].	Baseline to Month 12
Number of Participants With Treatment Emergent Adverse Events	The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters.	Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment	The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22.	Baseline to Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2019
• Primary Completion (Actual): April 20, 2023
• Study Completion (Actual): April 20, 2023

Study Registration Dates

• First Submitted: December 18, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Liver transplantation; CFZ533; de novo recipients; deceased donor; CNI-free immunosuppression; Transplant rejection
• Additional Relevant MeSH Terms: Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: CCFZ533A2202 (Novartis); 2018-001836-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No